Induction NN B-NP of IN B-PP NF-KB NN B-NP during IN B-PP monocyte NN B-NP differentiation NN I-NP by IN B-PP HIV NN B-NP type NN I-NP 1 CD I-NP infection NN I-NP . . O The DT B-NP production NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O progeny NN B-NP was VBD B-VP followed VBN I-VP in IN B-PP the DT B-NP U937 NN I-NP promonocytic JJ I-NP cell NN I-NP line NN I-NP after IN B-PP stimulation NN B-NP either CC B-PP with IN I-PP retinoic JJ B-NP acid NN I-NP or CC O PMA NN B-NP COMMA COMMA O and CC O in IN B-PP purified VBN B-NP human JJ I-NP monocytes NNS B-NP and CC O macrophages NNS B-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP and CC O Southwestern NN B-NP blotting NN I-NP experiments NNS I-NP were VBD B-VP used VBN I-VP to TO B-VP detect VB I-VP the DT B-NP binding NN I-NP of IN B-PP cellular JJ B-NP transactivation NN I-NP factor NN I-NP NF-KB NN I-NP to TO B-PP the DT B-NP double JJ I-NP repeat-KB JJ I-NP enhancer NN I-NP sequence NN I-NP located JJ B-ADJP in IN B-PP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O PMA NN B-NP treatment NN I-NP COMMA COMMA O and CC B-CONJP not RB I-CONJP retinoic JJ B-NP acid NN I-NP treatment NN I-NP of IN B-PP the DT B-NP U937 NN I-NP cells NNS I-NP acts VBZ B-VP in IN B-PP inducing VBG B-VP NF-KB NN B-NP expression NN I-NP in IN B-PP the DT B-NP nuclei NNS I-NP . . O In IN B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP monocytes NNS B-NP or CC O macrophages NNS B-NP COMMA COMMA O induction NN B-NP of IN B-PP NF-KB NN B-NP occurred VBD B-VP only RB B-SBAR if IN I-SBAR the DT B-NP cells NNS I-NP were VBD B-VP previously RB I-VP infected VBN I-VP with IN B-PP HIV-1 NN B-NP . . O When WRB B-ADVP U937 NN B-NP cells NNS I-NP were VBD B-VP infected VBN I-VP with IN B-PP HIV-1 NN B-NP COMMA COMMA O no DT B-NP induction NN I-NP of IN B-PP NF-KB NN B-NP factor NN I-NP was VBD B-VP detected VBN I-VP COMMA COMMA O whereas IN O high JJ B-NP level NN I-NP of IN B-PP progeny NN B-NP virions NNS I-NP was VBD B-VP produced VBN I-VP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR this DT B-NP factor NN I-NP was VBD B-VP not RB I-VP required VBN I-VP for IN B-PP viral JJ B-NP replication NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR in IN B-PP monocytic JJ B-NP cell NN I-NP lineage NN I-NP COMMA COMMA O HIV-1 NN B-NP could MD B-VP mimic VB I-VP some DT O differentiation\/activation JJ B-NP stimuli NNS B-NP allowing VBG B-VP nuclear JJ B-NP NF-KB NN I-NP expression NN I-NP . . O Positive JJ B-NP and CC I-NP negative JJ I-NP regulation NN I-NP of IN B-PP immunoglobulin NN B-NP gene NN I-NP expression NN I-NP by IN B-PP a DT B-NP novel JJ I-NP B-cell-specific JJ I-NP enhancer NN I-NP element NN I-NP . . O A DT B-NP new JJ I-NP B-cell-specific JJ I-NP enhancer NN I-NP element NN I-NP has VBZ B-VP been VBN I-VP identified VBN I-VP 3' JJ B-NP of IN B-PP E4 NN B-NP and CC O the DT B-NP octamerlike JJ I-NP motifs NNS I-NP in IN B-PP the DT B-NP human JJ I-NP immunoglobulin NN I-NP heavy-chain NN I-NP gene NN I-NP enhancer NN I-NP . . O Tandem JJ B-NP copies NNS I-NP of IN B-PP this DT B-NP 67-bp JJ I-NP MnlI-AluI NN I-NP fragment NN I-NP COMMA COMMA O when WRB B-ADVP fused VBN B-VP to TO B-PP the DT B-NP chloramphenicol JJ I-NP acetyltransferase NN I-NP gene NN I-NP driven VBN B-VP by IN B-PP the DT B-NP conalbumin JJ I-NP promoter NN I-NP COMMA COMMA O stimulated VBD B-VP transcription NN B-NP in IN B-PP B NN B-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP or CC O HeLa NN B-NP cells NNS I-NP . . O Footprinting NN B-NP analysis NN I-NP revealed VBD B-VP that IN B-SBAR the DT B-NP identical JJ I-NP sequence NN I-NP CCGAAACTGAAAAGG NN I-NP COMMA COMMA O designated VBN B-VP E6 NN B-NP COMMA COMMA O was VBD B-VP protected VBN I-VP by IN B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP B NN B-NP cells NNS I-NP COMMA COMMA O T NN B-NP cells NNS I-NP COMMA COMMA O or CC O HeLa NN B-NP cells NNS I-NP . . O Gel NN B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP using VBG B-VP a DT B-NP synthetic JJ I-NP E6 NN I-NP motif NN I-NP detected VBD B-VP a DT B-NP B-cell-specific JJ I-NP complex NN I-NP in IN B-PP addition NN I-PP to TO I-PP a DT B-NP ubiquitous JJ I-NP band NN I-NP found VBN B-VP also RB B-PP in IN I-PP T NN B-NP cells NNS I-NP and CC O HeLa NN B-NP cells NNS I-NP . . O In IN B-PP agreement NN I-PP with IN I-PP the DT B-NP results NNS I-NP of IN B-PP gel NN B-NP retardation NN I-NP assays NNS I-NP COMMA COMMA O tandem JJ B-NP copies NNS I-NP of IN B-PP the DT B-NP E6 NN I-NP motif NN I-NP stimulated VBD B-VP transcription NN B-NP in IN B-PP ARH77 NN B-NP and CC O Raji NN B-NP cells NNS B-NP but CC B-PP not RB B-PP in IN I-PP Jurkat NN B-NP or CC O HeLa NN B-NP cells NNS B-NP . . O Furthermore RB B-ADVP COMMA COMMA O a DT B-NP mutant JJ I-NP E6 NN I-NP motif NN I-NP lost VBD B-VP both CC O in FW B-NP vitro FW I-NP binding NN I-NP activity NN I-NP and CC B-PP in FW B-NP vivo FW I-NP enhancer NN I-NP activity NN I-NP . . O In IN B-PP striking JJ B-NP contrast NN I-NP to TO B-PP the DT B-NP mouse NN I-NP Ig NN I-NP heavy-chain JJ I-NP enhancer NN I-NP COMMA COMMA O in IN B-PP which WDT B-NP the DT B-NP octamer NN I-NP motif NN I-NP acts VBZ B-VP as IN B-PP a DT B-NP B-cell-specific JJ I-NP enhancer NN I-NP element NN I-NP COMMA COMMA O the DT B-NP human JJ I-NP enhancer NN I-NP contains VBZ B-VP an DT B-NP octamerlike JJ I-NP sequence NN I-NP with IN B-PP one CD B-NP base NN I-NP substitution NN I-NP which WDT B-NP bound VBD B-VP octamer-binding JJ B-NP proteins NNS I-NP with IN B-PP only RB B-NP very RB I-NP low JJ I-NP affinity NN I-NP and CC O showed VBD B-VP no DT B-NP enhancer NN I-NP activity NN I-NP of IN B-PP its PRP$ B-NP own JJ I-NP . . O Interestingly RB B-ADVP COMMA COMMA O the DT B-NP MnlI-AluI NN I-NP fragment NN I-NP could MD B-VP suppress VB I-VP the DT B-NP basal-level JJ I-NP activity NN I-NP of IN B-PP the DT B-NP conalbumin JJ I-NP promoter NN I-NP in IN B-PP both CC O Jurkat NN B-NP and CC O HeLa NN B-NP cells NNS B-NP . . O Moreover RB B-ADVP COMMA COMMA O simian JJ B-NP virus NN I-NP 40 CD I-NP enhancer NN I-NP activity NN I-NP was VBD B-VP blocked VBN I-VP by IN B-PP the DT B-NP MnlI-AluI NN I-NP fragment NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP B NN B-NP cells NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP novel JJ I-NP enhancer NN I-NP element NN I-NP identified VBN B-VP in IN B-PP this DT B-NP study NN I-NP is VBZ B-VP probably RB B-ADVP a DT B-NP target NN I-NP site NN I-NP for IN B-PP both CC B-NP positive JJ I-NP and CC I-NP negative JJ I-NP factors NNS I-NP . . O The DT B-NP NF NN I-NP kappa NN I-NP B NN I-NP independent JJ I-NP cis-acting JJ I-NP sequences NNS I-NP in IN B-PP HIV-1 NN B-NP LTR NN I-NP responsive NN B-ADJP to TO B-PP T-cell NN B-NP activation NN I-NP . . O The DT B-NP rate NN I-NP of IN B-PP transcription NN B-NP initiation NN I-NP directed VBN B-VP by IN B-PP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O of IN B-PP HIV-1 NN B-NP increases VBZ B-VP in IN B-PP response NN I-PP to TO I-PP mitogenic JJ B-NP stimuli NNS I-NP of IN B-PP T NN B-NP cells NNS I-NP . . O Here RB B-ADVP we PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP response NN I-NP of IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP may MD B-VP be VB I-VP governed VBN I-VP by IN B-PP two CD B-NP independent JJ I-NP sequences NNS I-NP located JJ B-ADJP 5' JJ B-NP to TO B-PP the DT B-NP site NN I-NP of IN B-PP transcription NN B-NP initiation NN I-NP sequences NNS I-NP that WDT B-NP bind VBP B-VP either CC O NFAT-1 NN B-NP or CC O NF NN B-NP kappa NN I-NP B NN I-NP . . O The DT B-NP rate NN I-NP of IN B-PP LTR-directed JJ B-NP gene NN I-NP expression NN I-NP increased VBD B-VP in IN B-PP response NN I-PP to TO I-PP treatment NN B-NP with IN B-PP either CC O a DT B-NP phorbol NN I-NP ester NN I-NP or CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP if IN B-SBAR either CC O the DT O NFAT-1 NN B-NP or CC O NF NN B-NP kappa NN I-NP B NN I-NP binding NN B-NP sites NNS I-NP were VBD B-VP deleted VBN I-VP COMMA COMMA O but CC O failed VBD B-VP to TO I-VP respond VB I-VP to TO B-PP these DT B-NP mitogenic JJ I-NP stimuli NNS I-NP if IN B-SBAR both DT B-NP sequences NNS I-NP were VBD B-VP absent JJ B-ADJP . . O The DT B-NP HIV-1 NN I-NP mutant JJ I-NP virus NN I-NP containing VBG B-VP both CC O NF NN B-NP kappa NN I-NP B NN I-NP and CC O NFAT-1 NN B-NP deletion NN B-NP was VBD B-VP able JJ B-ADJP to TO B-VP replicate VB I-VP although IN B-SBAR at IN B-PP a DT B-NP much JJ I-NP decreased VBN I-NP growth NN I-NP rate NN I-NP COMMA COMMA O while IN B-SBAR the DT B-NP deletion NN I-NP of IN B-PP NFAT-1 NN B-NP alone RB B-ADVP increased VBD B-VP the DT B-NP viral JJ I-NP growth NN I-NP rate NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O Neither CC O deletion NN B-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP nor CC O deletion NN B-NP of IN B-PP NFAT-1 NN B-NP decreased VBD B-VP activation NN B-NP of IN B-PP viral JJ B-NP replication NN I-NP by IN B-PP phorbol NN B-NP ester NN I-NP . . O Specific JJ B-NP depletion NN I-NP of IN B-PP the DT B-NP B-cell NN I-NP population NN I-NP induced VBN B-VP by IN B-PP aberrant JJ B-NP expression NN I-NP of IN B-PP human JJ B-NP interferon NN I-NP regulatory JJ I-NP factor NN I-NP 1 CD I-NP gene NN I-NP in IN B-PP transgenic JJ B-NP mice NNS I-NP . . O Interferons NNS B-NP ( ( O IFNs NNS B-NP ) ) O are VBP B-VP well RB I-VP known VBN I-VP both CC O as IN B-PP antiviral JJ B-NP proteins NNS I-NP and CC B-PP as IN B-PP potent JJ B-NP regulators NNS I-NP of IN B-PP cell NN B-NP growth NN B-NP and CC O differentiation NN B-NP . . O In IN B-PP fact NN B-NP COMMA COMMA O IFNs NNS B-NP inhibit VBP B-VP growth NN B-NP of IN B-PP various JJ B-NP normal JJ I-NP and CC I-NP transformed VBN I-NP cell NN I-NP types NNS I-NP . . O Previously RB B-ADVP COMMA COMMA O a DT B-NP nuclear JJ I-NP factor NN I-NP COMMA COMMA O IRF-1 NN B-NP ( ( O interferon NN B-NP regulatory JJ I-NP factor NN I-NP 1 CD I-NP ) ) O COMMA COMMA O which WDT B-NP binds VBZ B-VP to TO B-PP type NN B-NP I CD I-NP IFN NN I-NP and CC O some DT B-NP IFN-inducible JJ I-NP gene NN I-NP promoters NNS I-NP COMMA COMMA O was VBD B-VP identified VBN I-VP and CC O cloned VBN B-VP . . O Since IN B-SBAR the DT B-NP IRF-1 NN I-NP gene NN I-NP is VBZ B-VP both CC O virus NN B-NP and CC O IFN NN B-NP inducible JJ B-ADJP COMMA COMMA O an DT B-NP intriguing JJ I-NP issue NN I-NP is VBZ B-VP raised VBN I-VP as IN B-PP to TO I-PP whether IN B-SBAR the DT B-NP IRF-1 NN I-NP gene NN I-NP is VBZ B-VP functioning VBG I-VP in IN B-PP IFN-mediated JJ B-NP regulation NN I-NP of IN B-PP cell NN B-NP growth NN B-NP and CC O differentiation NN B-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP generated VBD B-VP transgenic JJ B-NP mice NNS I-NP carrying VBG B-VP the DT B-NP human JJ I-NP IRF-1 NN I-NP gene NN I-NP linked VBN B-VP to TO B-PP the DT B-NP human JJ I-NP immunoglobulin NN I-NP heavy-chain JJ I-NP enhancer NN I-NP . . O In IN B-PP the DT B-NP transgenic JJ I-NP mice NNS I-NP COMMA COMMA O all PDT B-NP the DT I-NP lymphoid JJ I-NP tissues NNS I-NP examined VBN B-VP showed VBD B-VP a DT B-NP dramatic JJ I-NP reduction NN I-NP in IN B-PP the DT B-NP number NN I-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP ( ( O B NN B-NP cells NNS I-NP ) ) O . . O Preparation NN B-NP and CC O analysis NN B-NP of IN B-PP bone NN B-NP marrow NN I-NP cells NNS I-NP from IN B-PP the DT B-NP chimeric JJ I-NP mice NNS I-NP indicated VBD B-VP that IN B-SBAR the DT B-NP bone NN I-NP marrow NN I-NP is VBZ B-VP the DT B-NP effective JJ I-NP site NN I-NP for IN B-PP specific JJ B-NP depletion NN I-NP of IN B-PP the DT B-NP B-cell NN I-NP population NN I-NP . . O In IN B-PP fact NN B-NP COMMA COMMA O transgenic JJ B-NP bone NN I-NP marrow NN I-NP cells NNS I-NP cocultured VBN B-VP with IN B-PP a DT B-NP bone NN I-NP marrow-derived JJ I-NP stromal JJ I-NP cell NN I-NP line NN I-NP revealed VBD B-VP an DT B-NP altered JJ I-NP B-cell NN I-NP maturation NN I-NP pattern NN I-NP . . O Identification NN B-NP and CC O cloning NN B-NP of IN B-PP TCF-1 NN B-NP COMMA COMMA O a DT B-NP T NN I-NP lymphocyte-specific JJ I-NP transcription NN I-NP factor NN I-NP containing VBG B-VP a DT B-NP sequence-specific JJ I-NP HMG NN I-NP box NN I-NP . . O CD3-epsilon NN B-NP expression NN I-NP is VBZ B-VP controlled VBN I-VP by IN B-PP a DT B-NP downstream JJ I-NP T NN I-NP lymphocyte-specific JJ I-NP enhancer NN I-NP element NN I-NP . . O We PRP B-NP report VBP B-VP the DT B-NP identification NN I-NP of IN B-PP a DT B-NP T NN I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O TCF-1 NN B-NP COMMA COMMA O binding VBG B-VP to TO B-PP this DT B-NP element NN I-NP . . O The DT B-NP multimerized JJ I-NP recognition NN I-NP motif NN I-NP of IN B-PP TCF-1 NN B-NP constituted VBD B-VP a DT B-NP T NN I-NP cell-specific JJ I-NP enhancer NN I-NP . . O Subsequent JJ B-NP cloning NN I-NP of IN B-PP TCF-1 NN B-NP identified VBD B-VP three CD B-NP splice NN I-NP alternatives NNS I-NP . . O TCF-1 NN B-NP contained VBD B-VP a DT B-NP single JJ I-NP DNA-binding JJ I-NP HMG NN I-NP box NN I-NP most RBS B-ADJP closely RB I-ADJP related JJ I-ADJP to TO B-PP similar JJ B-NP boxes NNS I-NP in IN B-PP the DT B-NP putative JJ I-NP mammalian JJ I-NP sex-determining JJ I-NP gene NN I-NP SRY NN I-NP and CC B-PP in IN B-PP the DT B-NP Schizosaccharomyces FW I-NP pombe FW I-NP Mc NN I-NP mating NN I-NP type NN I-NP gene NN I-NP . . O TCF-1 NN B-ADVP mRNA NN I-ADVP was VBD B-VP expressed VBN I-VP uniquely RB B-ADVP in IN B-PP T NN B-NP lymphocytes NNS I-NP . . O Upon IN B-PP cotransfection NN B-NP into IN B-PP non-T JJ B-NP cells NNS I-NP COMMA COMMA O TCF-1 NN B-NP could MD B-VP transactivate VB I-VP through IN B-PP its PRP$ B-NP cognate JJ I-NP motif NN I-NP . . O These DT B-NP results NNS I-NP identify VBP B-VP TCF-1 NN B-NP as IN B-PP a DT B-NP T NN I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O which WDT B-NP might MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP the DT B-NP establishment NN I-NP of IN B-PP the DT B-NP mature JJ I-NP T NN I-NP cell NN I-NP phenotype NN I-NP . . O Nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP activates VBZ B-VP proenkephalin NN B-NP transcription NN I-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP . . O Upon IN B-PP activation NN B-NP COMMA COMMA O T NN B-NP lymphocytes NNS I-NP accumulate VBP B-VP high JJ B-NP levels NNS I-NP of IN B-PP the DT B-NP neuropeptide NN I-NP enkephalin NN I-NP which WDT B-NP correlate VBP B-VP with IN B-PP high JJ B-NP levels NNS I-NP of IN B-PP proenkephalin NN B-NP mRNA NN I-NP in IN B-PP the DT B-NP cells NNS I-NP . . O Here RB B-ADVP we PRP B-NP investigated VBD B-VP the DT B-NP transcriptional JJ I-NP basis NN I-NP for IN B-PP these DT B-NP changes NNS I-NP . . O The DT B-NP proenkephalin NN I-NP promoter NN I-NP contains VBZ B-VP a DT B-NP sequence NN I-NP GGGGACGTCCCC NN I-NP COMMA COMMA O named VBN B-VP B2 NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP similar JJ B-ADJP to TO B-PP the DT B-NP kappa NN I-NP B NN I-NP sequence NN I-NP GGGGACTTTCC NN I-NP COMMA COMMA O the DT B-NP binding VBG I-NP site NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP nuclear JJ B-NP factor NN I-NP ( ( O NF NN B-NP ) ) O -kappa NN B-NP B NN I-NP . . O Activation NN B-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP induces VBZ B-VP an DT B-NP NF-kappa NN I-NP B-like JJ I-NP binding NN I-NP activity NN I-NP to TO B-PP the DT B-NP B2 NN I-NP site NN I-NP COMMA COMMA O concomitant JJ B-ADJP with IN B-PP activation NN B-NP of IN B-PP the DT B-NP proenkephalin NN I-NP promoter NN I-NP . . O Mutations NNS B-NP at IN B-PP the DT B-NP B2 NN I-NP site NN I-NP abolish VBP B-VP this DT B-NP transcriptional JJ I-NP activation NN I-NP . . O The DT B-NP purified VBN I-NP homodimer NN I-NP ( ( O two CD B-NP p50s NNS I-NP ) ) O of IN B-PP the DT B-NP DNA-binding JJ I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP binds VBZ B-VP the DT B-NP B2 NN I-NP site NN I-NP of IN B-PP proenkephalin NN B-NP relatively RB B-ADVP better JJR I-ADVP than IN B-SBAR does VBZ O the DT O heterotetramer NN B-NP ( ( O two CD B-NP p65s NNS I-NP plus CC O two CD B-NP p50s NNS I-NP ) ) O form NN B-NP of IN B-PP the DT B-NP factor NN I-NP . . O Thus RB B-ADVP COMMA COMMA O it PRP B-NP appears VBZ B-VP that IN B-SBAR the DT B-NP T-cell-specific JJ I-NP activation NN I-NP of IN B-PP the DT B-NP proenkephalin NN I-NP promoter NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP NF-kappa NN B-NP B NN I-NP . . O However RB B-ADVP COMMA COMMA O as IN B-SBAR NF-kappa NN B-NP B NN I-NP is VBZ B-VP ubiquitous JJ B-ADJP and CC O the DT B-NP transcriptional JJ I-NP activation NN I-NP through IN B-PP the DT B-NP B2 NN I-NP site NN I-NP is VBZ B-VP T NN B-NP cell NN I-NP specific JJ B-ADJP COMMA COMMA O yet RB B-NP another DT I-NP T-cell-specific JJ I-NP factor NN I-NP which WDT B-NP synergizes VBZ B-VP with IN B-PP NF-kappa NN B-NP B NN I-NP should MD B-VP be VB I-VP considered VBN I-VP . . O Expression NN B-NP of IN B-PP c-jun NN B-NP COMMA COMMA O jun NN B-NP B NN I-NP and CC O jun NN B-NP D NN I-NP proto-oncogenes NNS B-NP in IN B-PP human JJ B-NP peripheral-blood JJ I-NP granulocytes NNS I-NP . . O We PRP B-NP have VBP B-VP found VBN I-VP that IN B-SBAR purified VBN B-NP human JJ I-NP peripheral-blood JJ I-NP granulocytes NNS I-NP express VBP B-VP constitutively RB B-NP significant JJ I-NP levels NNS I-NP of IN B-PP proto-oncogenes NNS B-NP c-jun NN B-NP COMMA COMMA O jun NN B-NP B NN I-NP and CC O jun NN B-NP D NN I-NP mRNA NN B-NP . . O Upon IN B-PP functional JJ B-NP activation NN I-NP of IN B-PP granulocytes NNS B-NP by IN B-PP 4 CD B-NP beta-phorbol NN I-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O COMMA COMMA O the DT B-NP levels NNS I-NP of IN B-PP c-jun NN B-NP COMMA COMMA O jun NN B-NP B NN I-NP and CC O jun NN B-NP D NN I-NP transcripts NNS B-NP were VBD B-VP increased VBN I-VP . . O The DT B-NP three CD I-NP jun NN I-NP genes NNS I-NP showed VBD B-VP a DT B-NP similar JJ I-NP time NN I-NP course NN I-NP in IN B-PP their PRP$ B-NP induction NN I-NP by IN B-PP PMA NN B-NP COMMA COMMA O maximal JJ B-NP mRNA NN I-NP levels NNS I-NP being VBG B-VP reached VBN I-VP after IN B-PP 60 CD B-NP min NN I-NP of IN B-PP induction NN B-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR expression NN B-NP of IN B-PP c-jun NN B-NP COMMA COMMA O jun NN B-NP B NN I-NP and CC O jun NN B-NP D NN I-NP genes NNS B-NP might MD B-VP be VB I-VP involved VBN I-VP in IN B-PP terminal JJ B-NP granulocyte NN I-NP differentiation NN I-NP or CC B-PP in IN B-PP regulating VBG B-VP granulocyte NN B-NP functionality NN I-NP . . O Platelet-activating JJ B-NP factor NN I-NP induces VBZ B-VP phospholipid JJ B-NP turnover NN I-NP COMMA COMMA O calcium NN B-NP flux NN I-NP COMMA COMMA O arachidonic JJ B-NP acid NN I-NP liberation NN I-NP COMMA COMMA O eicosanoid NN B-NP generation NN I-NP COMMA COMMA O and CC O oncogene JJ B-NP expression NN I-NP in IN B-PP a DT B-NP human JJ I-NP B NN I-NP cell NN I-NP line NN I-NP . . O Platelet-activating JJ B-NP factor NN I-NP is VBZ B-VP a DT B-NP potent JJ I-NP mediator NN I-NP of IN B-PP the DT B-NP inflammatory JJ I-NP response NN I-NP . . O Studies NNS B-NP of IN B-PP the DT B-NP actions NNS I-NP of IN B-PP platelet-activating JJ B-NP factor NN I-NP have VBP B-VP centered VBN I-VP mainly RB B-PP around IN I-PP neutrophils NNS B-NP COMMA COMMA O monocytes NNS B-NP COMMA COMMA O and CC O platelets NNS B-NP . . O In IN B-PP this DT B-NP report NN I-NP we PRP B-NP begin VBP B-VP to TO I-VP uncover VB I-VP the DT B-NP influence NN I-NP of IN B-PP platelet-activating NN B-NP factor NN I-NP on IN B-PP B NN B-NP lymphocytes NNS I-NP . . O Employing VBG B-VP the DT B-NP EBV-transformed JJ I-NP human JJ I-NP B NN I-NP cell NN I-NP line NN I-NP SKW6.4 NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR platelet-activating JJ B-NP factor NN I-NP significantly RB B-ADVP alters VBZ B-VP membrane NN B-NP phospholipid JJ I-NP metabolism NN I-NP indicated VBN B-VP by IN B-PP the DT B-NP incorporation NN I-NP of IN B-PP 32P NN B-NP into IN B-PP phosphatidylcholine NN B-NP COMMA COMMA O phosphatidylinositol NN B-NP COMMA COMMA O and CC O phosphatidic JJ B-NP acid NN I-NP but CC B-PP not RB B-ADVP significantly RB I-ADVP into IN B-PP phosphatidylethanolamine NN B-NP at IN B-PP concentrations NNS B-NP ranging VBG B-VP from IN B-PP 10(-9) CD B-NP to TO B-PP 10(-6) CD B-NP M NN B-NP . . O The DT B-NP inactive JJ I-NP precursor NN I-NP COMMA COMMA O lyso-platelet-activating JJ B-NP factor NN I-NP COMMA COMMA O at IN B-PP a DT B-NP concentration NN I-NP as RB B-ADJP high JJ I-ADJP as IN B-PP 10(-7) CD B-NP M NN I-NP had VBD B-VP no DT B-NP effect NN I-NP on IN B-PP any DT B-NP of IN B-PP the DT B-NP membrane NN I-NP phospholipids NNS I-NP . . O We PRP B-NP also RB B-ADVP show VBP B-VP that IN B-SBAR platelet-activating JJ B-NP factor NN I-NP from IN B-PP 10(-12) CD B-NP to TO I-NP 10(-6) CD I-NP M NN I-NP induced VBD B-VP rapid JJ B-NP and CC I-NP significant JJ I-NP elevation NN I-NP in IN B-PP intracellular JJ B-NP calcium NN I-NP levels NNS I-NP COMMA COMMA O whereas IN O lyso-platelet-activating JJ B-NP factor NN I-NP was VBD B-VP again RB B-ADVP ineffective JJ B-ADJP . . O We PRP B-NP further RB B-ADVP demonstrate VBP B-VP the DT B-NP impact NN I-NP of IN B-PP platelet-activating JJ B-NP factor NN I-NP binding VBG B-VP to TO B-PP B NN B-NP cells NNS I-NP by IN B-PP measuring VBG B-VP platelet-activating JJ B-NP factor NN I-NP induced JJ B-NP arachidonic JJ I-NP acid NN I-NP release NN I-NP and CC O 5-hydroxyeicosatetraenoic JJ B-NP acid NN I-NP production NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O platelet-activating JJ B-NP factor NN I-NP was VBD B-VP capable JJ B-ADJP of IN B-PP inducing VBG B-VP transcription NN B-NP of IN B-PP the DT B-NP nuclear JJ I-NP proto-oncogenes NNS I-NP c-fos NN B-NP and CC O c-jun NN B-NP . . O Finally RB B-ADVP we PRP B-NP explored VBD B-VP the DT B-NP possible JJ I-NP role NN I-NP of IN B-PP 5-hydroxyeicosatetraenoic JJ B-NP acid NN I-NP as IN B-PP a DT B-NP regulator NN I-NP of IN B-PP arachidonic JJ B-NP acid NN I-NP liberation NN I-NP demonstrating VBG B-VP that IN B-SBAR endogenous JJ B-NP 5-lipoxygenase NN I-NP activity NN I-NP modulates VBZ B-VP platelet-activating JJ B-NP factor NN I-NP induced JJ B-NP arachidonic JJ I-NP acid NN I-NP release NN I-NP perhaps RB B-ADVP acting VBG B-VP at IN B-PP the DT B-NP level NN I-NP of IN B-PP phospholipase NN B-NP A2 NN I-NP . . O In IN B-PP summary NN B-NP COMMA COMMA O platelet-activating JJ B-NP factor NN I-NP is VBZ B-VP shown VBN I-VP here RB I-VP to TO I-VP have VB I-VP a DT B-NP direct JJ I-NP and CC I-NP profound JJ I-NP effect NN I-NP on IN B-PP a DT B-NP pure JJ I-NP B NN I-NP cell NN I-NP line NN I-NP . . O A DT B-NP novel JJ I-NP HIV-1 NN I-NP isolate JJ I-NP containing VBG B-VP alterations NNS B-NP affecting VBG B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP element NN I-NP . . O Three CD B-NP molecular JJ I-NP clones NNS I-NP of IN B-PP HIV-1 NN B-NP COMMA COMMA O derived VBN B-VP from IN B-PP a DT B-NP single JJ I-NP isolate NN I-NP ( ( O AL1 NN B-NP ) ) O COMMA COMMA O exhibited VBD B-VP distinct JJ B-NP replicative JJ I-NP and CC I-NP cytopathic JJ I-NP properties NNS I-NP during IN B-PP propagation NN B-NP in IN B-PP a DT B-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP . . O The DT B-NP phenotypic JJ I-NP differences NNS I-NP observed VBN B-VP were VBD B-VP attributable JJ B-ADJP COMMA COMMA O in IN B-PP large JJ B-NP part NN I-NP COMMA COMMA O to TO B-PP changes NNS B-NP affecting VBG B-VP the DT B-NP viral JJ I-NP LTR NN I-NP . . O Nucleotide NN B-NP sequence NN I-NP and CC O PCR NN B-NP analyses NNS I-NP demonstrated VBD B-VP the DT B-NP presence NN I-NP of IN B-PP novel JJ B-NP duplications NNS B-NP or CC O deletions NNS B-NP involving VBG B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP motif NN I-NP . . O These DT B-NP changes NNS I-NP in IN B-PP the DT B-NP enhancer NN I-NP element NN I-NP were VBD B-VP identified VBN I-VP in IN B-PP the DT B-NP original JJ I-NP AL1 NN I-NP virus NN I-NP stock NN I-NP . . O Subcloning NN B-NP of IN B-PP the DT B-NP variant JJ I-NP NF-kappa NN I-NP B NN I-NP segments NNS I-NP into IN B-PP LTR-driven JJ B-NP CAT NN I-NP expression NN I-NP vectors NNS I-NP confirmed VBD B-VP a DT B-NP correlation NN I-NP between IN B-PP promoter JJ B-NP activity NN I-NP and CC O replicative\/cytopathic JJ B-NP capacity NN I-NP . . O 1COMMA25-Dihydroxyvitamin NN B-NP D3 NN I-NP receptor NN I-NP RNA NN I-NP : : O expression NN B-NP in IN B-PP hematopoietic JJ B-NP cells NNS I-NP . . O 1COMMA25-Dihydroxyvitamin NN B-NP D3 NN I-NP { ( O 1COMMA25(OH)2D3 NN B-NP } ) O induces VBZ B-VP differentiation NN B-NP and CC O inhibits VBZ B-VP proliferation NN B-NP of IN B-PP myeloid JJ B-NP leukemic JJ I-NP cells NNS I-NP from IN B-PP various JJ B-NP lines NNS B-NP and CC O patients NNS B-NP ; : O these DT B-NP effects NNS I-NP are VBP B-VP probably RB I-VP mediated VBN I-VP through IN B-PP the DT B-NP 1COMMA25(OH)2D3 NN I-NP receptor NN I-NP . . O Little JJ B-NP is VBZ B-VP known VBN I-VP of IN B-PP expression NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP in IN B-PP hematopoietic JJ B-NP cells NNS I-NP . . O We PRP B-NP examined VBD B-VP the DT B-NP expression NN B-NP and CC O modulation NN B-NP of IN B-PP expression NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP in IN B-PP various JJ B-NP proliferating VBG I-NP and CC I-NP nonproliferating JJ I-NP hematopoietic JJ I-NP cells NNS I-NP . . O Constitutive JJ B-NP expression NN I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP various JJ B-NP kinds NNS I-NP of IN B-PP hematopoietic JJ B-NP cells NNS I-NP COMMA COMMA O including VBG B-PP macrophages NNS B-NP and CC O activated VBN B-NP T NN I-NP lymphocytes NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP cell NN B-NP lines NNS I-NP KG-1 NN B-NP ( ( O myeloblasts NNS B-NP ) ) O COMMA COMMA O HL-60 NN B-NP ( ( O promyelocytes NNS B-NP ) ) O COMMA COMMA O ML-3 NN B-NP ( ( O myelomonoblasts NNS B-NP ) ) O COMMA COMMA O U937 NN B-NP COMMA COMMA O THP-1 NN B-NP ( ( O monoblasts NNS B-NP ) ) O COMMA COMMA O K562 NN B-NP ( ( O erythroblasts NNS B-NP ) ) O COMMA COMMA O and CC O S-LB1 NN B-NP ( ( O HTLV-1-transfected JJ B-NP T NN I-NP lymphocytes NNS I-NP ) ) O . . O Receptor NN B-NP transcripts NNS I-NP were VBD B-VP 4.6 CD B-NP kilobases NNS B-NP ( ( O kb NN B-NP ) ) O COMMA COMMA O and CC O no DT B-NP variant JJ I-NP sizes NNS I-NP were VBD B-VP observed VBN I-VP . . O All DT B-NP cell NN I-NP lines NNS I-NP examined VBN B-VP in IN B-PP this DT B-NP group NN I-NP also RB B-ADVP expressed VBD B-VP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP . . O Most JJS B-NP B NN I-NP lymphocyte NN I-NP lines NNS I-NP expressed VBD B-VP negligible JJ B-NP levels NNS I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP and CC I-NP protein NN I-NP ; : O however RB O ; : O analysis NN B-NP of IN B-PP a DT B-NP lymphoid\/myeloid JJ I-NP somatic JJ I-NP hybrid NN I-NP suggested VBD B-VP that IN B-SBAR suppression NN B-NP of IN B-PP expression NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP in IN B-PP B NN B-NP lymphocytes NNS I-NP may MD B-VP be VB I-VP a DT B-NP dominant JJ I-NP characteristic NN I-NP . . O HL-60 NN B-NP cells NNS I-NP were VBD B-VP cultured VBN I-VP with IN B-PP 10(-7) CD B-NP mol\/L NN I-NP 1COMMA25(OH)2D3 NN B-NP for IN B-PP 24 CD B-NP to TO I-NP 72 CD I-NP hours NNS I-NP COMMA COMMA O and CC O levels NNS B-NP of IN B-PP expression NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP and CC O its PRP$ B-NP RNA NN I-NP were VBD B-VP examined VBN I-VP . . O Levels NNS B-NP of IN B-PP RNA NN B-NP coding NN B-VP for IN B-PP the DT B-NP receptor NN I-NP were VBD B-VP not RB I-VP modulated VBN I-VP by IN B-PP exposure NN B-NP to TO B-PP high JJ B-NP levels NNS I-NP of IN B-PP ligand NN B-NP . . O Levels NNS B-NP of IN B-PP occupied VBN B-NP 1COMMA25(OH)2D3 NN I-NP receptor NN I-NP protein NN I-NP increased VBD B-VP in IN B-PP these DT B-NP HL-60 NN I-NP cells NNS I-NP ; : O but CC O the DT B-NP total JJ I-NP number NN I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP decreased VBD B-VP about RB B-NP 50 CD I-NP % NN I-NP at IN B-PP 24 CD B-NP hours NNS I-NP and CC O returned VBD B-VP toward IN B-PP normal JJ B-NP at IN B-PP 72 CD B-NP hours NNS I-NP . . O Steady-state JJ B-NP levels NNS I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP were VBD B-VP not RB I-VP affected VBN I-VP by IN B-PP terminal JJ B-NP differentiation NN I-NP of IN B-PP HL-60 NN B-NP toward IN B-PP either CC O granulocytes NNS B-NP or CC O macrophages NNS B-NP . . O Nondividing JJ B-NP macrophages NNS I-NP from IN B-PP normal JJ B-NP individuals NNS I-NP also RB B-ADVP expressed VBD B-VP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O nondividing JJ B-NP peripheral JJ I-NP blood NN I-NP lymphocytes NNS I-NP from IN B-PP normal JJ B-NP individuals NNS I-NP did VBD B-VP not RB I-VP express VB I-VP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP ; : O with IN B-PP stimulation NN B-NP of IN B-PP proliferation NN B-NP of IN B-PP these DT B-NP cells NNS I-NP COMMA COMMA O accumulation NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP increased VBD B-VP markedly RB B-ADVP . . O Half-life NN B-NP ( ( O t1\/2 NN B-NP ) ) O of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP was VBD B-VP short JJ B-ADJP ( ( O 1 CD B-NP hour NN I-NP ) ) O as IN B-SBAR determined VBN B-VP by IN B-PP measuring VBG B-VP decay NN B-NP of IN B-PP the DT B-NP message NN I-NP after IN B-PP addition NN B-NP of IN B-PP actinomycin NN B-NP D NN I-NP . . O Consistent JJ B-ADJP with IN B-PP this DT B-NP short JJ I-NP t1\/2 NN I-NP COMMA COMMA O accumulation NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptor NN I-NP RNA NN I-NP increased VBD B-VP in IN B-PP cells NNS B-NP as IN B-SBAR their PRP$ B-NP protein NN I-NP synthesis NN I-NP was VBD B-VP inhibited VBN I-VP . . O Further JJ B-NP studies NNS I-NP are VBP B-VP required VBN I-VP to TO B-VP understand VB I-VP the DT B-NP physiologic JJ I-NP role NN I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP in IN B-PP myeloid JJ B-NP cells NNS I-NP and CC O proliferating VBG B-NP T NN I-NP lymphocytes NNS I-NP . . O Kappa NN B-NP B NN I-NP binding NN I-NP proteins NNS I-NP are VBP B-VP constitutively RB I-VP expressed VBN I-VP in IN B-PP an DT B-NP IL-2 NN I-NP autocrine NN I-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP . . O The DT B-NP IL-2 NN I-NP and CC O the DT B-NP IL-2-R NN I-NP alpha NN I-NP genes NNS B-NP are VBP B-VP both DT O expressed VBN B-VP transiently RB B-ADVP in IN B-PP normal JJ B-NP T NN I-NP lymphocytes NNS I-NP after IN B-PP Ag NN B-NP or CC O mitogen NN B-NP activation NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O IARC NN B-NP 301 CD I-NP COMMA COMMA O expresses VBZ B-VP these DT B-NP two CD I-NP genes NNS I-NP constitutively RB B-ADVP and CC O we PRP B-NP have VBP B-VP previously RB I-VP demonstrated VBN I-VP that IN B-SBAR its PRP$ B-NP growth NN I-NP depends VBZ B-VP on IN B-PP the DT B-NP autocrine JJ I-NP production NN I-NP of IN B-PP this DT B-NP T NN I-NP cell NN I-NP growth NN I-NP factor NN I-NP and CC O high JJ B-NP affinity NN I-NP IL-2R NN I-NP . . O To TO B-VP dissect VB I-VP the DT B-NP molecular JJ I-NP basis NN I-NP for IN B-PP the DT B-NP unusual JJ I-NP persistent JJ I-NP expression NN I-NP of IN B-PP the DT O IL-2 NN B-NP and CC O IL-2-R NN B-NP alpha NN I-NP genes NNS B-NP in IN B-PP these DT B-NP IARC NN I-NP 301 CD I-NP T NN I-NP cells NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP analyzed VBN I-VP the DT B-NP interactions NNS I-NP of IN B-PP constitutively RB B-NP expressed VBN I-NP nuclear JJ I-NP proteins NNS I-NP with IN B-PP the DT B-NP 5' JJ I-NP flanking JJ I-NP regions NNS I-NP of IN B-PP the DT O IL-2 NN B-NP and CC O IL-2-R NN B-NP alpha NN I-NP genes NNS B-NP using VBG B-VP both DT B-NP DNase NN B-NP I CD I-NP footprinting NN I-NP and CC O gel NN B-NP retardation NN I-NP techniques NNS B-NP . . O We PRP B-NP have VBP B-VP found VBN I-VP that IN B-SBAR a DT B-NP region NN I-NP in IN B-PP both DT B-NP genes NNS I-NP ( ( O -276 CD B-NP to TO O -250 CD B-NP for IN B-PP IL-2-R NN B-NP alpha NN I-NP and CC O -203 CD B-NP to TO O -183 CD B-NP for IN B-PP IL-2 NN B-NP ) ) O COMMA COMMA O which WDT B-NP corresponds VBZ B-VP to TO B-PP a DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP element NN I-NP COMMA COMMA O is VBZ B-VP specifically RB I-VP protected VBN I-VP by IN B-PP nuclear JJ B-NP proteins NNS I-NP from IN B-PP IARC NN B-NP 301 CD I-NP . . O In IN B-PP agreement NN I-PP with IN I-PP this DT B-NP finding NN I-NP COMMA COMMA O both CC O the DT O IL-2 NN B-NP and CC O IL-2-R NN B-NP alpha NN I-NP promoters NNS B-NP are VBP B-VP active JJ B-ADJP in IN B-PP transient JJ B-NP transfection NN I-NP assays NNS I-NP in IN B-PP IARC NN B-NP 301 CD I-NP cells NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O mutation NN B-NP of IN B-PP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP results VBZ B-VP in IN B-PP markedly RB B-NP attenuated VBN I-NP activities NNS I-NP of IN B-PP both DT B-NP promoters NNS I-NP . . O Two CD B-NP proteins NNS I-NP binding VBG B-VP the DT B-NP kappa NN I-NP B NN I-NP sequence NN I-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP and CC O KBF1 NN B-NP COMMA COMMA O are VBP B-VP constitutively RB I-VP expressed VBN I-VP in IN B-PP IARC NN B-NP 301 CD I-NP nuclei NNS I-NP and CC O induced VBN B-VP by IN B-PP PMA NN B-NP and CC O PHA NN B-NP in IN B-PP Jurkat NN B-NP . . O They PRP B-NP bind VBP B-VP to TO B-PP the DT B-NP kappa NN I-NP B NN I-NP motifs NNS I-NP with IN B-PP different JJ B-NP relative JJ I-NP affinities NNS I-NP that WDT B-NP may MD B-VP reflect VB I-VP their PRP$ B-NP different JJ I-NP contribution NN I-NP in IN B-PP the DT B-NP expression NN I-NP of IN B-PP various JJ B-NP promoters NNS I-NP . . O The DT B-NP functional JJ I-NP domains NNS I-NP of IN B-PP the DT B-NP murine JJ I-NP Thy-1 NN I-NP gene NN I-NP promoter NN I-NP . . O The DT B-NP Thy-1 NN I-NP gene NN I-NP promoter NN I-NP resembles VBZ B-VP a DT B-NP " `` I-NP housekeeping JJ I-NP " '' I-NP promoter NN I-NP in IN B-PP that IN B-SBAR it PRP B-NP is VBZ B-VP located JJ B-ADJP within IN B-PP a DT B-NP methylation-free JJ I-NP island NN I-NP COMMA COMMA O lacks VBZ B-VP a DT B-NP canonical JJ I-NP TATA NN I-NP box NN I-NP COMMA COMMA O and CC O displays VBZ B-VP heterogeneity NN B-NP in IN B-PP the DT B-NP 5'-end JJ I-NP termini NNS I-NP of IN B-PP the DT B-NP mRNA NN I-NP . . O Using VBG B-VP transgenic JJ B-NP mice NNS I-NP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR this DT B-NP promoter NN I-NP does VBZ B-VP not RB I-VP confer VB I-VP any DT B-NP tissue NN I-NP specificity NN I-NP and CC O is VBZ B-VP active JJ B-ADJP only RB B-PP in IN I-PP a DT B-NP position-dependent JJ I-NP manner NN I-NP . . O It PRP B-NP can MD B-VP only RB I-VP be VB I-VP activated VBN I-VP in IN B-PP a DT B-NP tissue-specific JJ I-NP manner NN I-NP by IN B-PP elements NNS B-NP that WDT B-NP lie VBP B-VP downstream RB B-ADJP of IN B-PP the DT B-NP initiation NN I-NP site NN I-NP . . O We PRP B-NP have VBP B-VP analyzed VBN I-VP the DT B-NP functional JJ I-NP domains NNS I-NP of IN B-PP the DT B-NP minimal JJ I-NP Thy-1 NN I-NP promoter NN I-NP and CC O show VB B-VP that IN B-SBAR the DT B-NP dominant JJ I-NP promoter NN I-NP elements NNS I-NP consist VBP B-VP of IN B-PP multiple JJ B-NP binding VBG I-NP sites NNS I-NP for IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP Sp1 NN I-NP COMMA COMMA O an DT B-NP inverted JJ I-NP CCAAT NN I-NP box NN I-NP COMMA COMMA O and CC O sequences VBZ B-NP proximal JJ B-ADJP to TO B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP . . O DNase NN B-NP I CD I-NP and CC I-NP gel NN I-NP mobility NN I-NP shift NN I-NP assays NNS I-NP show VBP B-VP the DT B-NP binding NN I-NP of IN B-PP a DT B-NP number NN I-NP of IN B-PP nuclear JJ B-NP factors NNS I-NP to TO B-PP these DT B-NP elements NNS I-NP COMMA COMMA O including VBG B-PP Sp1 NN B-NP and CC O CP1 NN B-NP . . O Our PRP$ B-NP results NNS I-NP show VBP B-VP that IN B-SBAR the DT B-NP structure NN I-NP of IN B-PP this DT B-NP promoter NN I-NP only RB B-ADVP permits VBZ B-VP productive JJ B-NP interactions NNS I-NP of IN B-PP the DT B-NP two CD I-NP transcription NN I-NP factors NNS I-NP Sp1 NN B-NP and CC O CP1 NN B-NP with IN B-PP the DT B-NP basal JJ I-NP transcription NN I-NP machinery NN I-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP enhancer NN B-NP sequences NNS I-NP . . O Comparison NN B-NP of IN B-PP constitutive JJ B-NP and CC I-NP inducible JJ I-NP transcriptional JJ I-NP enhancement NN I-NP mediated VBN B-VP by IN B-PP kappa NN B-NP B-related JJ I-NP sequences NNS I-NP : : O modulation NN B-NP of IN B-PP activity NN B-NP in IN B-PP B NN B-NP cells NNS I-NP by IN B-PP human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP tax NN I-NP gene NN I-NP . . O The DT B-NP kappa NN I-NP B NN I-NP sequence NN I-NP ( ( O GGGACTTTCC NN B-NP ) ) O binds VBZ B-VP a DT B-NP factor NN I-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP COMMA COMMA O that WDT B-NP is VBZ B-VP constitutively RB I-VP found VBN I-VP in IN B-PP its PRP$ B-NP functional JJ I-NP COMMA COMMA I-NP DNA NN I-NP binding NN I-NP form NN I-NP only RB B-PP in IN I-PP B NN B-NP lymphocytes NNS I-NP . . O A DT B-NP factor NN I-NP with IN B-PP apparently RB B-NP indistinguishable JJ I-NP sequence NN I-NP specificity NN I-NP can MD B-VP be VB I-VP induced VBN I-VP in IN B-PP many JJ B-NP other JJ I-NP cell NN I-NP types NNS I-NP COMMA COMMA O where WRB B-ADVP it PRP B-NP is VBZ B-VP used VBN I-VP to TO B-VP regulate VB I-VP inducible JJ B-NP gene NN I-NP expression NN I-NP . . O For IN B-PP example NN B-NP COMMA COMMA O kappa NN B-NP B-related JJ I-NP sequences NNS I-NP have VBP B-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP important JJ B-ADJP for IN B-PP the DT B-NP transcription NN I-NP of IN B-PP a DT B-NP few JJ I-NP inducible JJ I-NP genes NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP the DT B-NP interleukin NN I-NP 2 CD I-NP receptor NN I-NP alpha-chain NN I-NP gene NN I-NP and CC O the DT B-NP beta-interferon NN I-NP gene NN I-NP . . O However RB B-ADVP COMMA COMMA O these DT B-NP genes NNS I-NP are VBP B-VP not RB O constitutively RB B-ADJP active JJ I-ADJP in IN B-PP B NN B-NP lymphocytes NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR other JJ B-NP regulatory JJ I-NP mechanisms NNS I-NP must MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP determining VBG B-VP the DT B-NP patterns NNS I-NP of IN B-PP expression NN B-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP constitutive JJ I-NP and CC I-NP inducible JJ I-NP transcriptional JJ I-NP activity NN I-NP mediated VBN B-VP by IN B-PP five CD B-NP kappa NN I-NP B-related JJ I-NP sequence NN I-NP elements NNS I-NP in IN B-PP two CD B-NP different JJ I-NP cell NN I-NP types NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR in IN B-PP S194 NN B-NP plasma NN I-NP cells NNS I-NP the DT B-NP activity NN I-NP of IN B-PP each DT B-NP element NN I-NP correlates VBZ B-VP well RB B-ADVP with IN B-PP the DT B-NP relative JJ I-NP affinity NN I-NP of IN B-PP B-cell-derived JJ B-NP NF-kappa NN I-NP B NN I-NP for IN B-PP that DT B-NP element NN I-NP . . O This DT B-NP leads VBZ B-VP to TO B-PP significantly RB B-NP lower RBR I-NP transcription NN I-NP enhancement NN I-NP by IN B-PP sites NNS B-NP derived VBN B-VP from IN B-PP the DT O interleukin NN B-NP 2 CD I-NP receptor NN I-NP or CC O T-cell NN B-NP receptor NN I-NP genes NNS B-NP in IN B-PP S194 NN B-NP cells NNS B-NP . . O However RB B-ADVP COMMA COMMA O in IN B-PP either CC O EL-4 NN B-NP ( ( I-NP T NN I-NP ) ) I-NP cells NNS I-NP or CC O S194 NN B-NP cells NNS I-NP COMMA COMMA O both DT B-NP lower-affinity JJ I-NP sites NNS I-NP can MD B-VP be VB I-VP significantly RB I-VP induced VBN I-VP by IN B-PP the DT B-NP tax NN I-NP gene NN I-NP product NN I-NP of IN B-PP human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP COMMA COMMA O showing VBG B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP activity NN I-NP can MD B-VP be VB I-VP modulated VBN I-VP even RB B-PP in IN I-PP a DT B-NP B-cell NN I-NP line NN I-NP that WDT B-NP constitutively RB B-ADVP expresses VBZ B-VP this DT B-NP factor NN I-NP . . O Isolation NN B-NP of IN B-PP a DT B-NP rel-related JJ I-NP human JJ I-NP cDNA NN I-NP that WDT B-NP potentially RB B-ADVP encodes VBZ B-VP the DT B-NP 65-kD JJ I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP Science NNP B-NP 1991 CD I-NP Oct NNP I-NP 4 CD I-NP ; : I-NP 254 CD I-NP ( ( I-NP 5028 CD I-NP ) ) I-NP : : I-NP 11 CD I-NP } ) O A DT B-NP DNA NN I-NP probe NN I-NP that WDT B-NP spanned VBD B-VP a DT B-NP domain NN I-NP conserved VBN B-VP among IN B-PP the DT B-NP proto-oncogene NN I-NP c-rel NN I-NP COMMA COMMA O the DT B-NP Drosophila NN I-NP morphogen NN I-NP dorsal NN I-NP COMMA COMMA O and CC O the DT B-NP p50 NN I-NP DNA NN I-NP binding NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP was VBD B-VP generated VBN I-VP from IN B-PP Jurkat NN B-NP T NN I-NP cell NN I-NP complementary JJ I-NP DNA NN I-NP with IN B-PP the DT B-NP polymerase NN I-NP chain NN I-NP reaction NN I-NP ( ( O PCR NN B-NP ) ) O and CC O degenerate JJ B-NP oligonucleotides NNS I-NP . . O This DT B-NP probe NN I-NP was VBD B-VP used VBN I-VP to TO B-VP identify VB I-VP a DT B-NP rel-related JJ I-NP complementary JJ I-NP DNA NN I-NP that WDT B-NP hybridized VBD B-VP to TO B-PP a DT B-NP 2.6-kilobase JJ I-NP messenger NN I-NP RNA NN I-NP present JJ B-ADJP in IN B-PP human JJ O T NN B-NP and CC O B NN B-NP lymphocytes NNS B-NP . . O In FW B-NP vitro FW I-NP transcription NN B-NP and CC O translation NN B-NP of IN B-PP the DT B-NP complementary JJ I-NP DNA NN I-NP resulted VBD B-VP in IN B-PP the DT B-NP synthesis NN I-NP of IN B-PP a DT B-NP protein NN I-NP with IN B-PP an DT B-NP apparent JJ I-NP molecular JJ I-NP size NN I-NP of IN B-PP 65 CD B-NP kilodaltons NNS B-NP ( ( O kD NN B-NP ) ) O . . O The DT B-NP translated VBN I-NP protein NN I-NP showed VBD B-VP weak JJ B-NP DNA NN I-NP binding NN I-NP with IN B-PP a DT B-NP specificity NN I-NP for IN B-PP the DT B-NP kappa NN I-NP B NN I-NP binding VBG I-NP motif NN I-NP . . O This DT B-NP protein-DNA JJ I-NP complex JJ I-NP comigrated VBN B-VP with IN B-PP the DT B-NP complex NN I-NP obtained VBN B-VP with IN B-PP the DT B-NP purified VBN I-NP human JJ I-NP p65 NN I-NP NF-kappa NN I-NP B NN I-NP subunit NN I-NP and CC O binding NN B-NP was VBD B-VP inhibited VBN I-VP by IN B-PP I NN B-NP kappa NN I-NP B-alpha NN I-NP and CC O -beta NN B-NP proteins NNS B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O the DT B-NP 65-kD JJ I-NP protein NN I-NP associated VBN B-VP with IN B-PP the DT B-NP p50 NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O the DT B-NP kappa NN I-NP B NN I-NP probe NN I-NP to TO B-VP form VB I-VP a DT B-NP complex NN I-NP with IN B-PP the DT B-NP same JJ I-NP electrophoretic JJ I-NP mobility NN I-NP as IN B-PP the DT B-NP NF-kappa NN I-NP B-DNA JJ I-NP complex NN I-NP . . O Therefore RB B-ADVP the DT B-NP rel-related JJ I-NP 65-kD JJ I-NP protein NN I-NP may MD B-VP represent VB I-VP the DT B-NP p65 NN I-NP subunit NN I-NP of IN B-PP the DT B-NP active JJ I-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP complex NN I-NP . . O Lymphocyte NN B-NP glucocorticoid NN I-NP receptor NN I-NP number NN I-NP in IN B-PP posttraumatic JJ B-NP stress NN I-NP disorder NN I-NP . . O OBJECTIVE NN B-NP : : O The DT B-NP authors NNS I-NP ' POS B-NP objective NN I-NP was VBD B-VP to TO B-VP investigate VB I-VP the DT B-NP possibility NN I-NP that IN B-SBAR glucocorticoid NN B-NP receptor NN I-NP changes NNS I-NP may MD B-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP dysregulation NN I-NP of IN B-PP the DT O hypothalamic-pituitary-adrenal JJ O ( ( O HPA JJ B-ADJP ) ) O axis NN B-NP in IN B-PP posttraumatic JJ B-NP stress NN I-NP disorder NN I-NP ( ( O PTSD NN B-NP ) ) O . . O METHOD NN B-NP : : O They PRP B-NP measured VBD B-VP the DT B-NP number NN I-NP of IN B-PP lymphocyte NN B-NP cytosolic JJ I-NP glucocorticoid NN I-NP receptors NNS I-NP and CC O plasma NN B-NP cortisol NN I-NP concentrations NNS I-NP in IN O 15 CD B-NP consecutively RB I-NP admitted VBN I-NP male JJ I-NP combat NN I-NP Vietnam NN I-NP veterans NNS I-NP with IN B-PP PTSD NN B-NP and CC B-PP in IN B-PP a DT B-NP normal JJ I-NP comparison NN I-NP group NN I-NP of IN B-PP 11 CD B-NP subjects NNS I-NP . . O RESULTS NNS B-NP : : O Both CC O the DT B-NP patients NNS I-NP and CC O the DT B-NP normal JJ I-NP comparison NN I-NP subjects NNS I-NP showed VBD B-VP a DT B-NP morning-to-afternoon JJ I-NP decline NN I-NP in IN B-PP glucocorticoid NN B-NP receptor NN I-NP concentrations NNS I-NP COMMA COMMA O paralleling VBG B-VP the DT B-NP normal JJ I-NP diurnal JJ I-NP decline NN I-NP in IN B-PP cortisol NN B-NP levels NNS I-NP . . O The DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP was VBD B-VP 63 CD B-NP % NN I-NP greater JJR B-ADJP in IN B-PP the DT B-NP morning NN I-NP and CC O 26 CD B-NP % NN I-NP greater JJR B-ADJP in IN B-PP the DT B-NP afternoon NN I-NP in IN B-PP the DT B-NP patients NNS I-NP with IN B-PP PTSD NN B-NP than IN B-PP in IN B-PP the DT B-NP normal JJ I-NP subjects NNS I-NP . . O No DT B-NP group NN I-NP differences NNS I-NP in IN B-PP cortisol NN B-NP levels NNS I-NP were VBD B-VP observed VBN I-VP COMMA COMMA O nor CC O were VBD O glucocorticoid NN B-NP receptor NN I-NP number NN I-NP and CC O cortisol NN B-NP levels NNS I-NP correlated VBD B-ADJP . . O The DT B-NP number NN I-NP of IN B-PP morning NN B-NP glucocorticoid NN I-NP receptors NNS I-NP was VBD B-VP positively RB B-ADJP correlated VBN I-ADJP with IN B-PP symptoms NNS B-NP of IN B-PP PTSD NN B-NP and CC O anxiety NN B-NP . . O CONCLUSIONS NNS B-NP : : O These DT B-NP results NNS I-NP provide VBP B-VP further JJ B-NP evidence NN I-NP for IN B-PP a DT B-NP dysregulation NN I-NP of IN B-PP the DT B-NP HPA JJ I-NP axis NN I-NP in IN B-PP PTSD NN B-NP . . O The DT B-NP finding NN I-NP that IN B-SBAR patients NNS B-NP with IN B-PP PTSD NN B-NP had VBD B-VP a DT B-NP substantially RB I-NP greater JJR I-NP number NN I-NP of IN B-PP lymphocyte NN B-NP glucocorticoid NN I-NP receptors NNS I-NP than IN B-PP normal JJ B-NP comparison NN I-NP subjects NNS I-NP is VBZ B-VP consistent JJ B-ADJP with IN B-PP the DT B-NP authors NNS I-NP ' POS B-NP previous JJ I-NP observations NNS I-NP of IN B-PP low JJ B-NP 24-hour JJ I-NP urinary JJ I-NP cortisol NN I-NP excretion NN I-NP in IN B-PP subjects NNS B-NP with IN B-PP PTSD NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP receptor NN I-NP changes NNS I-NP observed VBN B-VP are VBP B-VP opposite JJ B-ADJP of IN B-PP those DT B-NP reported VBN B-VP in IN B-PP major JJ B-NP depressive JJ I-NP disorder NN I-NP . . O The DT B-NP present JJ I-NP data NNS I-NP COMMA COMMA O along IN B-PP with IN I-PP other JJ B-NP findings NNS I-NP of IN B-PP HPA JJ B-NP abnormalities NNS I-NP in IN B-PP PTSD NN B-NP COMMA COMMA O support VBP B-VP the DT B-NP possibility NN I-NP of IN B-PP a DT B-NP greater JJR I-NP negative JJ I-NP feedback NN I-NP sensitivity NN I-NP at IN B-PP one CD B-NP or CC I-NP more JJR I-NP levels NNS I-NP of IN B-PP the DT B-NP HPA JJ I-NP axis NN I-NP . . O A DT B-NP thymus-specific JJ I-NP member NN I-NP of IN B-PP the DT B-NP HMG NN I-NP protein NN I-NP family NN I-NP regulates VBZ B-VP the DT B-NP human JJ I-NP T NN I-NP cell NN I-NP receptor NN I-NP C NN I-NP alpha NN I-NP enhancer NN I-NP . . O The DT B-NP human JJ I-NP T NN I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP TCF-1 NN B-NP alpha NN I-NP plays VBZ B-VP a DT B-NP key JJ I-NP role NN I-NP in IN B-PP the DT B-NP tissue-specific JJ I-NP activation NN I-NP of IN B-PP the DT B-NP T NN I-NP cell NN I-NP receptor NN I-NP ( ( I-NP TCR NN I-NP ) ) I-NP C NN I-NP alpha NN I-NP enhancer NN I-NP and CC O binds VBZ B-VP to TO B-PP pyrimidine-rich JJ B-NP elements NNS I-NP ( ( O 5'-PyCTTTG-3' NN B-NP ) ) O present JJ B-ADJP in IN B-PP a DT B-NP variety NN I-NP of IN B-PP other JJ B-NP T NN I-NP cell-specific JJ I-NP control NN I-NP regions NNS I-NP . . O Using VBG B-VP amino NN B-NP acid NN I-NP sequence NN I-NP information NN I-NP derived VBN B-VP from IN B-PP the DT B-NP DNA NN I-NP affinity-purified JJ I-NP protein NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP now RB I-VP isolated VBN I-VP cDNA NN B-NP clones NNS I-NP encoding VBG B-VP TCF-1 NN B-NP alpha NN I-NP . . O The DT B-NP TCF-1 NN I-NP alpha NN I-NP cDNA NN I-NP contains VBZ B-VP a DT B-NP single JJ I-NP 68-amino-acid JJ I-NP domain NN I-NP that WDT B-NP is VBZ B-VP homologous JJ B-ADJP to TO B-PP a DT B-NP region NN I-NP conserved VBN B-VP among IN B-PP high-mobility JJ B-NP group NN I-NP ( ( O HMG NN B-NP ) ) O and CC O nonhistone JJ B-NP chromosomal JJ I-NP proteins NNS I-NP . . O Expression NN B-NP of IN B-PP full-length JJ B-NP and CC I-NP mutant JJ I-NP cDNA NN I-NP clones NNS I-NP in IN B-PP bacteria NNS B-NP reveal VBP B-VP that IN B-SBAR the DT B-NP single JJ I-NP HMG NN I-NP motif NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP predicted VBN I-VP to TO I-VP contain VB I-VP two CD B-NP extended VBN I-NP alpha-helical JJ I-NP segments NNS I-NP COMMA COMMA O is VBZ B-VP sufficient JJ B-ADJP to TO B-VP direct VB I-VP the DT B-NP sequence-specific JJ I-NP binding NN I-NP of IN B-PP TCF-1 NN B-NP alpha NN I-NP to TO B-PP DNA NN B-NP . . O Northern NN B-NP blot NN I-NP experiments NNS I-NP demonstrate VBP B-VP further RBR B-ADVP that IN B-SBAR TCF-1 NN B-NP alpha NN I-NP mRNA NN I-NP is VBZ B-VP highly RB B-ADJP tissue NN I-ADJP specific JJ I-ADJP COMMA COMMA O found VBN B-VP primarily RB B-ADVP in IN B-PP the DT B-NP thymus NN B-NP or CC O T NN B-NP cell NN I-NP lines NNS I-NP . . O The DT B-NP immature JJ I-NP CEM NN I-NP T NN I-NP cell NN I-NP line NN I-NP expresses VBZ B-VP relatively RB B-NP low JJ I-NP levels NNS I-NP of IN B-PP TCF-1 NN B-NP alpha NN I-NP mRNA NN I-NP COMMA COMMA O which WDT B-NP are VBP B-VP increased VBN I-VP upon IN B-PP activation NN B-NP of IN B-PP these DT B-NP cells NNS I-NP by IN B-PP phorbol NN B-NP esters NNS I-NP . . O Interestingly RB B-ADVP COMMA COMMA O the DT B-NP cloned VBN I-NP TCF-1 NN I-NP alpha NN I-NP protein NN I-NP is VBZ B-VP a DT B-NP potent JJ I-NP transcriptional JJ I-NP activator NN I-NP of IN B-PP the DT B-NP human JJ I-NP TCR NN I-NP alpha NN I-NP enhancer NN I-NP in IN B-PP nonlymphoid JJ B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O whereas IN O the DT B-NP activity NN I-NP of IN B-PP the DT B-NP endogenous JJ I-NP protein NN I-NP in IN B-PP T NN B-NP cell NN I-NP lines NNS I-NP is VBZ B-VP strongly RB B-ADJP dependent JJ I-ADJP on IN B-PP an DT B-NP additional JJ I-NP T NN I-NP cell-specific JJ I-NP protein NN I-NP that WDT B-NP interacts VBZ B-VP with IN B-PP the DT B-NP core NN I-NP enhancer NN I-NP . . O TCF-1 NN B-NP alpha NN I-NP is VBZ B-VP currently RB B-ADJP unique JJ I-ADJP among IN B-PP the DT B-NP newly RB I-NP emerging VBG I-NP family NN I-NP of IN B-PP DNA-binding JJ B-NP regulatory JJ I-NP proteins NNS I-NP that WDT B-NP share VBP B-VP the DT B-NP HMG NN I-NP motif NN I-NP in IN B-PP that IN B-NP it PRP B-NP is VBZ B-VP a DT B-NP highly RB I-NP tissue-specific JJ I-NP RNA NN I-NP polymerase NN I-NP II CD I-NP transcription NN I-NP factor NN I-NP . . O Immune JJ B-NP response NN I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP to TO B-PP HBx-antigen NN B-NP of IN B-PP hepatitis NN B-NP B NN I-NP virus NN I-NP . . O The DT B-NP hepatitis NN I-NP B NN I-NP virus NN I-NP genome NN I-NP encodes VBZ B-VP a DT B-NP transcriptional JJ I-NP transactivator NN I-NP protein NN I-NP designated VBN B-VP HBxAg NN B-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP whether IN B-SBAR this DT B-NP antigen NN I-NP is VBZ B-VP a DT B-NP target NN I-NP structure NN I-NP for IN B-PP human JJ B-NP T-lymphocytes NNS I-NP . . O Using VBG B-VP recombinant JJ B-NP HBxAg NN I-NP protein NN I-NP COMMA COMMA O we PRP B-NP found VBD B-VP HBxAg-specific JJ B-NP stimulation NN I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP acute JJ B-NP hepatitis NN I-NP B NN I-NP virus NN I-NP infection NN I-NP ( ( O 6 CD B-NP of IN B-PP 6 CD B-NP ) ) O and CC O chronic JJ B-NP hepatitis NN I-NP B NN I-NP virus NN I-NP infection NN I-NP ( ( O 6 CD B-NP of IN B-PP 17 CD B-NP ) ) O but CC B-PP not RB B-PP in IN I-PP healthy JJ B-NP individuals NNS I-NP . . O With IN B-PP HBxAg-specific JJ B-NP synthetic JJ I-NP polypeptides NNS I-NP COMMA COMMA O several JJ B-NP T-cell NN I-NP epitopes NNS I-NP were VBD B-VP identified VBN I-VP . . O Most JJS B-NP were VBD B-VP located JJ I-VP in IN B-PP the DT B-NP carboxyterminal JJ I-NP half NN I-NP of IN B-PP the DT B-NP HBxAg NN I-NP protein NN I-NP . . O Five CD B-NP T-cell NN I-NP clones NNS I-NP specific JJ B-ADJP for IN B-PP a DT B-NP T-cell NN I-NP epitope NN I-NP located JJ B-ADJP at IN B-PP the DT B-NP carboxyterminal JJ I-NP region NN I-NP of IN B-PP HBxAg NN B-NP were VBD B-VP established VBN I-VP and CC O found VBN B-VP to TO I-VP belong VB I-VP to TO B-PP the DT B-NP CD2\/CD4-positive JJ I-NP COMMA COMMA I-NP CD8-negative JJ I-NP subtype NN I-NP . . O These DT B-NP data NNS I-NP establish VBP B-VP for IN B-PP the DT B-NP first JJ I-NP time NN I-NP HBxAg NN B-NP as IN B-PP an DT B-NP antigen NN I-NP in IN B-PP the DT B-NP cellular JJ I-NP immune JJ I-NP response NN I-NP . . O A DT B-NP study NN I-NP on IN B-PP the DT B-NP circadian JJ I-NP rhythm NN I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP . . O Circadian JJ B-NP rhythm NN I-NP in IN B-PP glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O was VBD B-VP studied VBN I-VP in IN B-PP the DT O rat NN B-NP liver NN I-NP and CC O human JJ B-ADJP peripheral JJ I-ADJP leukocytes NNS B-NP . . O For IN B-PP rats NNS B-NP exposed VBN B-VP to TO B-PP a DT B-NP natural JJ I-NP environmental JJ I-NP photic JJ I-NP cycle NN I-NP or CC O a DT B-NP 12L NN I-NP : : I-NP 12D NN I-NP artificial JJ I-NP light NN I-NP regime NN I-NP COMMA COMMA O peak JJ B-NP values NNS I-NP of IN B-PP hepatic JJ B-NP GR NN I-NP were VBD B-VP detected VBN I-VP between IN B-PP 23:00 CD B-NP and CC I-NP 02:00 CD I-NP h NN I-NP . . O Except IN B-PP for IN I-PP a DT B-NP 4-hour JJ I-NP advancement NN I-NP of IN B-PP the DT B-NP peak NN I-NP COMMA COMMA O a DT B-NP similar JJ I-NP circadian JJ I-NP rhythm NN I-NP of IN B-PP hepatic JJ B-NP GR NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP rats NNS B-NP reared VBN B-VP under IN B-PP a DT B-NP reversed VBN I-NP lighting NN I-NP regimen NNS I-NP ( ( O 12D NN B-NP : : I-NP 12L NN I-NP ; : O lights NNS B-NP on IN B-ADVP between IN B-PP 18:30 CD B-NP and CC I-NP 06:30 CD I-NP h NN I-NP ) ) O . . O In IN B-PP human JJ B-NP leukocytes NNS I-NP COMMA COMMA O the DT B-NP peak JJ I-NP value NN I-NP of IN B-PP GR NN B-NP was VBD B-VP found VBN I-VP to TO I-VP parallel VB I-VP that DT B-NP of IN B-PP plasma NN B-NP cortisol NN I-NP with IN B-PP high JJ B-NP and CC I-NP low JJ I-NP values NNS I-NP detected VBN B-VP at IN B-PP 04:00-08:00 CD B-NP h NN I-NP and CC O 23:00-24:00 CD B-NP h NN I-NP COMMA COMMA O respectively RB B-ADVP . . O In IN B-PP patients NNS B-NP suffering VBG B-VP from IN B-PP Cushing NN B-NP 's POS B-NP syndrome NN I-NP COMMA COMMA O the DT B-NP circadian JJ I-NP rhythm NN I-NP of IN B-PP plasma NN B-NP cortisol NN I-NP either CC O disappeared VBD B-VP or CC O was VBD B-VP inverted VBN I-VP while IN B-SBAR that DT B-NP of IN B-PP GR NN B-NP did VBD B-VP not RB I-VP significantly RB I-VP deviate VB I-VP from IN B-PP the DT B-NP normal JJ I-NP subjects NNS I-NP . . O For IN B-PP apoplexic JJ B-NP patients NNS I-NP with IN B-PP lesions NNS B-NP localized JJ B-VP to TO B-PP the DT B-NP base NN I-NP of IN B-PP the DT B-NP brain NN I-NP as IN B-SBAR indicated VBN B-VP by IN B-PP computerized VBN B-NP tomography NN I-NP COMMA COMMA O the DT B-NP diurnal JJ I-NP variation NN I-NP of IN B-PP GR NN B-NP was VBD B-VP abolished VBN I-VP . . O Conversely RB B-ADVP COMMA COMMA O diurnal JJ B-NP rhythmicity NN I-NP persisted VBD B-VP in IN B-PP apoplexy NN B-NP patients NNS I-NP whose WP$ B-NP lesions NNS I-NP were VBD B-VP in IN B-PP the DT B-NP cerebral JJ I-NP cortex NN I-NP . . O Thus RB B-ADVP COMMA COMMA O we PRP B-NP postulated VBD B-VP that IN B-SBAR the DT B-NP circadian JJ I-NP modification NN I-NP of IN B-PP GR NN B-NP was VBD B-VP independent JJ B-ADJP of IN B-PP the DT B-NP diurnal JJ I-NP fluctuations NNS I-NP in IN B-PP plasma NN B-NP cortisol NN I-NP level NN I-NP or CC O the DT B-NP circadian JJ I-NP variations NNS I-NP in IN B-PP environmental JJ B-NP lighting NN I-NP and CC O that IN B-SBAR the DT B-NP rhythmicity NN I-NP might MD B-VP be VB I-VP regulated VBN I-VP by IN B-PP the DT B-NP ' `` I-NP circadian JJ I-NP pacemaker NN I-NP ' '' O located JJ B-ADJP in IN B-PP the DT B-NP human JJ I-NP basal JJ I-NP brain NN I-NP . . O These DT B-NP diurnal JJ I-NP variations NNS I-NP in IN B-PP GR NN B-NP might MD B-VP serve VB I-VP to TO I-VP coordinate VB I-VP the DT B-NP reactivity NN I-NP of IN B-PP the DT B-NP target NN I-NP cells NNS I-NP to TO B-PP cortisol NN B-NP because IN B-SBAR the DT B-NP diurnal JJ I-NP rhythms NNS I-NP of IN B-PP a DT B-NP GR-mediated JJ I-NP response NN I-NP COMMA COMMA O the DT B-NP fractional JJ I-NP inhibition NN I-NP of IN B-PP chemotactic JJ B-NP migration NN I-NP rate NN I-NP of IN B-PP polymorphonuclear JJ B-NP leukocytes NNS I-NP by IN B-PP cortisol NN B-NP COMMA COMMA O were VBD B-VP found VBN I-VP to TO I-VP be VB I-VP synchronous JJ B-ADJP with IN B-PP those DT B-NP of IN B-PP GR NN B-NP . . O Multiple JJ B-NP Oct2 NN I-NP isoforms NNS I-NP are VBP B-VP generated VBN I-VP by IN B-PP alternative JJ B-NP splicing NN I-NP . . O The DT B-NP interaction NN I-NP of IN B-PP the DT B-NP Oct2 NN I-NP transcription NN I-NP factor NN I-NP with IN B-PP the DT B-NP cognate JJ I-NP octamer NN I-NP motif NN I-NP ATGCAAAT NN I-NP is VBZ B-VP a DT B-NP critical JJ I-NP determinant NN I-NP of IN B-PP the DT B-NP lymphoid-specific JJ I-NP expression NN I-NP of IN B-PP immunoglobulin NN B-NP genes NNS I-NP . . O Ectopic JJ B-NP expression NN I-NP of IN B-PP cloned VBN B-NP Oct2 NN I-NP cDNA NN I-NP was VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP sufficient JJ B-ADJP to TO B-VP reconstitute VB I-VP at IN B-NP least JJS I-NP some DT I-NP aspects NNS I-NP of IN B-PP this DT B-NP regulation NN I-NP in IN B-PP non-lymphoid JJ B-NP cells NNS I-NP . . O We PRP B-NP describe VBP B-VP the DT B-NP isolation NN B-NP and CC O characterization NN B-NP of IN B-PP multiple JJ B-NP cDNAs NNS I-NP encoding VBG B-VP mouse NN B-NP Oct2 NN I-NP from IN B-PP a DT B-NP mature JJ I-NP B-cell NN I-NP line NN I-NP and CC O we PRP B-NP show VBP B-VP that IN B-SBAR a DT B-NP variety NN I-NP of IN B-PP isoforms NNS B-NP of IN B-PP this DT B-NP transcription NN I-NP factor NN I-NP is VBZ B-VP generated VBN I-VP from IN B-PP a DT B-NP single JJ I-NP gene NN I-NP by IN B-PP an DT B-NP alternative JJ I-NP splicing NN I-NP mechanism NN I-NP . . O All PDT B-NP the DT I-NP isoforms NNS I-NP retain VBP B-VP the DT B-NP previously RB I-NP characterized VBN I-NP POU-domain NN I-NP and CC O are VBP B-VP therefore RB B-ADVP able JJ B-ADJP to TO B-VP bind VB I-VP to TO B-PP the DT B-NP octamer NN I-NP motif NN I-NP . . O Different JJ B-NP amounts NNS I-NP of IN B-PP the DT B-NP various JJ I-NP isoforms NNS I-NP are VBP B-VP present JJ B-ADJP within IN B-PP the DT B-NP same JJ I-NP B-cell NN I-NP regardless RB B-ADVP of IN B-PP the DT B-NP developmental JJ I-NP stage NN I-NP of IN B-PP B-cell NN B-NP differentiation NN I-NP and CC O at IN B-ADVP least JJS I-ADVP some DT B-NP of IN B-PP the DT B-NP isoforms NNS I-NP are VBP B-VP conserved VBN I-VP between IN B-PP mouse NN B-NP and CC O humans NNS B-NP . . O In IN B-PP cotransfection NN B-NP experiments NNS I-NP we PRP B-NP show VBP B-VP that IN B-SBAR all PDT B-NP the DT I-NP isoforms NNS I-NP are VBP B-VP able JJ B-ADJP to TO B-VP activate VB I-VP an DT B-NP octamer NN I-NP containing VBG B-VP promoter NN B-NP element NN I-NP in IN B-PP fibroblasts NNS B-NP revealing VBG B-VP an DT B-NP unexpected JJ I-NP functional JJ I-NP redundancy NN I-NP . . O Finally RB B-ADVP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR one CD B-NP of IN B-PP the DT B-NP isoforms NNS I-NP encodes VBZ B-VP the DT B-NP previously RB I-NP described VBN I-NP lymphoid-specific JJ I-NP Oct2B NN I-NP protein NN I-NP which WDT B-NP has VBZ B-VP been VBN I-VP suggested VBN I-VP to TO I-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP function NN I-NP of IN B-PP the DT B-NP octamer NN I-NP motif NN I-NP in IN B-PP the DT I-PP context NN I-PP of IN I-PP the DT O immunoglobulin NN B-NP heavy-chain NN I-NP ( ( O IgH NN B-NP ) ) O enhancer NN B-NP . . O Murine JJ B-NP and CC I-NP human JJ I-NP T-lymphocyte NN I-NP GATA-3 NN I-NP factors NNS I-NP mediate VBP B-VP transcription NN B-NP through IN B-PP a DT B-NP cis-regulatory JJ I-NP element NN I-NP within IN B-PP the DT B-NP human JJ I-NP T-cell NN I-NP receptor NN I-NP delta NN I-NP gene NN I-NP enhancer NN I-NP . . O A DT B-NP family NN I-NP of IN B-PP transcriptional JJ B-NP activators NNS I-NP has VBZ B-VP recently RB I-VP been VBN I-VP identified VBN I-VP in IN B-PP chickens NNS B-NP ; : O these DT B-NP transcriptional JJ I-NP activators NNS I-NP recognize VBP B-VP a DT B-NP common JJ I-NP consensus NN I-NP motif NN I-NP ( ( O WGATAR NN B-NP ) ) O through IN B-PP a DT B-NP conserved VBN I-NP C4 NN I-NP zinc NN I-NP finger NN I-NP DNA-binding JJ I-NP domain NN I-NP . . O One CD B-NP of IN B-PP the DT B-NP members NNS I-NP of IN B-PP this DT B-NP multigene JJ I-NP family NN I-NP COMMA COMMA O cGATA-3 NN B-NP COMMA COMMA O is VBZ B-VP most RBS I-VP abundantly RB I-VP expressed VBN I-VP in IN B-PP the DT B-NP T-lymphocyte NN I-NP cell NN I-NP lineage NN I-NP . . O Analysis NN B-NP of IN B-PP human JJ B-NP and CC I-NP murine JJ I-NP GATA-3 NN I-NP factors NNS I-NP shows VBZ B-VP a DT B-NP striking JJ I-NP degree NN I-NP of IN B-PP amino NN B-NP acid NN I-NP sequence NN I-NP identity NN I-NP and CC O similar JJ B-NP patterns NNS I-NP of IN B-PP tissue NN B-NP specificity NN I-NP of IN B-PP expression NN B-NP in IN B-PP these DT B-NP three CD I-NP organisms NNS I-NP . . O The DT B-NP murine JJ I-NP and CC I-NP human JJ I-NP factors NNS I-NP are VBP B-VP abundantly RB I-VP expressed VBN I-VP in IN B-PP a DT B-NP variety NN I-NP of IN B-PP human JJ B-NP and CC I-NP murine JJ I-NP T-cell NN I-NP lines NNS I-NP and CC O can MD B-VP activate VB I-VP transcription NN B-NP through IN B-PP a DT B-NP tissue-specific JJ I-NP GATA-binding JJ I-NP site NN I-NP identified VBN B-VP within IN B-PP the DT B-NP human JJ I-NP T-cell NN I-NP receptor NN I-NP delta NN I-NP gene NN I-NP enhancer NN I-NP . . O We PRP B-NP infer VBP B-VP that IN B-SBAR the DT O murine JJ B-NP and CC O human JJ B-ADJP GATA-3 NN B-NP proteins NNS I-NP play VBP B-VP a DT B-NP central JJ I-NP and CC I-NP highly RB I-NP conserved VBN I-NP role NN I-NP in IN B-PP vertebrate NN B-NP T-cell-specific JJ I-NP transcriptional JJ I-NP regulation NN I-NP . . O Processing NN B-NP of IN B-PP the DT B-NP precursor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP by IN B-PP the DT B-NP HIV-1 NN I-NP protease NN I-NP during IN B-PP acute JJ B-NP infection NN I-NP . . O Transcription NN B-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type-1 NN I-NP ( ( O HIV-1 NN B-NP ) ) O genome NN B-NP is VBZ B-VP regulated VBN I-VP in IN B-PP part NN B-NP by IN B-PP cellular JJ B-NP factors NNS I-NP and CC O is VBZ B-VP stimulated VBN I-VP by IN B-PP activation NN B-NP of IN B-PP latently RB B-NP infected JJ I-NP T NN I-NP cells NNS I-NP . . O T-cell NN B-NP activation NN I-NP also RB B-ADVP correlates VBZ B-VP with IN B-PP the DT B-NP induction NN I-NP of IN B-PP the DT B-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP which WDT B-NP binds VBZ B-VP to TO B-PP two CD B-NP adjacent JJ I-NP sites NNS I-NP in IN B-PP the DT B-NP HIV-1 NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O This DT B-NP factor NN I-NP consists VBZ B-VP of IN B-PP two CD B-NP DNA-binding JJ I-NP subunits NNS I-NP of IN B-PP relative JJ B-NP molecular JJ I-NP mass NN I-NP 50COMMA000 CD B-NP ( ( O 50K CD B-NP ) ) O associated VBN B-VP with IN B-PP two CD B-NP 65K CD I-NP subunits NNS I-NP . . O It PRP B-NP is VBZ B-VP located JJ B-ADJP in IN B-PP the DT B-NP nucleus NN I-NP in IN B-PP mature JJ B-NP B NN I-NP cells NNS I-NP COMMA COMMA O but CC O is VBZ B-VP present JJ B-ADJP in IN B-PP other JJ B-NP cell NN I-NP types NNS I-NP as IN B-PP an DT B-NP inactive JJ I-NP cytoplasmic JJ I-NP complex NN I-NP . . O External JJ B-NP stimuli NNS I-NP COMMA COMMA O including VBG B-PP those DT B-NP that WDT B-NP activate VBP B-VP T NN B-NP cells NNS I-NP COMMA COMMA O result VBP B-VP in IN B-PP nuclear JJ B-NP translocation NN I-NP of IN B-PP active JJ B-NP NF-kappa NN I-NP B NN I-NP . . O The DT B-NP cloning NN I-NP of IN B-PP the DT B-NP complementary JJ I-NP DNA NN I-NP for IN B-PP the DT B-NP 50K CD I-NP subunit NN I-NP helped VBD B-VP to TO I-VP identify VB I-VP an DT B-NP exclusively RB I-NP cytoplasmic JJ I-NP 105K CD I-NP precursor NN I-NP ( ( O p105 NN B-NP ) ) O ( ( O V.B. NNP B-NP COMMA COMMA O P.K. NNP B-NP and CC O A.I. NNP B-NP COMMA COMMA O manuscript NN B-NP submitted VBN B-VP ) ) O . . O The DT B-NP expression NN I-NP of IN B-PP active JJ B-NP NF-kappa NN I-NP B NN I-NP might MD B-VP therefore RB I-VP also RB I-VP be VB I-VP regulated VBN I-VP by IN B-PP the DT B-NP extent NN I-NP of IN B-PP processing NN B-NP of IN B-PP p105 NN B-NP . . O Because IN B-SBAR HIV-1 NN B-NP requires VBZ B-VP active JJ B-NP NF-kappa NN I-NP B NN I-NP for IN B-PP efficient JJ B-NP transcription NN I-NP COMMA COMMA O we PRP B-NP tested VBD B-VP the DT B-NP effect NN I-NP of IN B-PP HIV-1 NN B-NP infection NN I-NP on IN B-PP the DT B-NP processing NN I-NP of IN B-PP the DT B-NP human JJ I-NP 105K CD I-NP precursor NN I-NP . . O We PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP HIV-1 NN I-NP protease NN I-NP can MD B-VP process VB I-VP p105 NN B-NP and CC O increases VBZ B-VP levels NNS B-NP of IN B-PP active JJ B-NP nuclear JJ I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP . . O Vitamin NN B-NP D NN I-NP receptor NN I-NP expression NN I-NP in IN B-PP human JJ B-NP lymphocytes NNS I-NP . . O Signal NN B-NP requirements NNS I-NP and CC O characterization NN B-NP by IN B-PP western NN B-NP blots NNS I-NP and CC O DNA NN B-NP sequencing NN I-NP . . O The DT B-NP signals NNS I-NP controlling VBG B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP receptor NN I-NP protein NN I-NP for IN B-PP 1 CD B-NP alphaCOMMA25-dihydroxyvitamin NN I-NP D3 NN I-NP in IN B-PP normal JJ B-NP human JJ I-NP lymphocytes NNS I-NP and CC O the DT B-NP relationship NN I-NP of IN B-PP this DT B-NP protein NN I-NP to TO B-PP the DT B-NP classical JJ I-NP vitamin NN I-NP D NN I-NP receptor NN I-NP were VBD B-VP examined VBN I-VP . . O Lymphocytes NNS B-NP activated VBN B-VP with IN B-PP the DT B-NP OKT3 NN I-NP antibody NN I-NP to TO B-PP the DT B-NP T-cell NN I-NP antigen NN I-NP receptor NN I-NP expressed VBD B-VP fewer JJR B-NP binding VBG I-NP sites NNS I-NP as IN B-SBAR compared VBN B-VP to TO B-PP lymphocytes NNS B-NP that WDT B-NP were VBD B-VP activated VBN I-VP by IN B-PP the DT B-NP polyclonal JJ I-NP activator NN I-NP phytohemagglutinin NN I-NP ( ( O PHA NN B-NP ) ) O . . O However RB B-ADVP COMMA COMMA O combination NN B-NP of IN B-PP OKT3 NN B-NP and CC O phorbol NN B-NP myristate NN I-NP acetate NN I-NP produced VBD B-VP a DT B-NP concentration NN I-NP of IN B-PP binding VBG B-NP sites NNS I-NP similar JJ B-ADJP to TO B-PP the DT B-NP PHA-activated JJ I-NP cells NNS I-NP . . O The DT B-NP receptor NN I-NP from IN B-PP OKT3 NN B-NP and CC O OKT3 NN B-ADJP + CC I-ADJP phorbol NN I-ADJP myristate NN I-ADJP acetate-activated JJ I-ADJP lymphocytes NNS B-NP exhibited VBD B-VP decreased VBN B-NP binding NN I-NP to TO B-PP DNA-cellulose NN B-NP compared VBN B-VP to TO B-PP PHA-activated JJ B-NP lymphocytes NNS I-NP . . O In IN B-PP lymphocytes NNS B-NP activated VBN B-VP either CC B-PP by IN I-PP PHA NN B-NP or CC O OKT3 NN B-NP ( ( B-PP but CC I-PP not RB B-PP in IN I-PP resting VBG B-NP cells NNS I-NP ) ) O COMMA COMMA O a DT B-NP 50-kDa JJ I-NP species NNS I-NP cross-reacting VBG B-VP with IN B-PP a DT B-NP monoclonal JJ I-NP antibody NN I-NP against IN B-PP the DT B-NP intestinal JJ I-NP vitamin NN I-NP D NN I-NP receptor NN I-NP was VBD B-VP detected VBN I-VP . . O Finally RB B-ADVP COMMA COMMA O RNA NN B-NP from IN B-PP activated VBN B-NP lymphocytes NNS I-NP was VBD B-VP amplified VBN I-VP by IN B-PP polymerase NN B-NP chain NN I-NP reaction NN I-NP using VBG B-VP oligonucleotide NN B-NP primers NNS I-NP flanking VBG B-VP the DT B-NP 196 CD I-NP base NN I-NP pair NN I-NP long JJ I-NP region NN I-NP encoding VBG B-VP the DT B-NP DNA-binding JJ I-NP domain NN I-NP of IN B-PP the DT B-NP human JJ I-NP intestinal JJ I-NP receptor NN I-NP . . O The DT B-NP amplified VBN I-NP product NN I-NP showed VBD B-VP an DT B-NP identical JJ I-NP nucleotide NN I-NP sequence NN I-NP to TO B-PP the DT B-NP DNA-binding JJ I-NP domain NN I-NP of IN B-PP the DT B-NP human JJ I-NP intestinal JJ I-NP receptor NN I-NP . . O These DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR expression NN B-NP of IN B-PP the DT B-NP 1COMMA25-(OH)2D3 NN I-NP receptor NN I-NP in IN B-PP lymphocytes NNS B-NP is VBZ B-VP triggered VBN I-VP by IN B-PP distinct JJ B-NP and CC I-NP contingent JJ I-NP signals NNS I-NP COMMA COMMA O and CC O that IN B-SBAR the DT B-NP protein NN I-NP and CC O the DT B-NP mRNA NN I-NP encoding VBG B-VP it PRP B-NP are VBP B-VP identical JJ B-ADJP to TO B-PP the DT B-NP classical JJ I-NP vitamin NN I-NP D NN I-NP receptor NN I-NP . . O Cloning NN B-NP of IN B-PP murine JJ B-NP TCF-1 NN I-NP COMMA COMMA O a DT B-NP T NN I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP interacting VBG B-VP with IN B-PP functional JJ B-NP motifs NNS I-NP in IN B-PP the DT B-NP CD3-epsilon NN I-NP and CC I-NP T NN I-NP cell NN I-NP receptor NN I-NP alpha NN I-NP enhancers NNS I-NP . . O CD3-epsilon NN B-NP gene NN I-NP expression NN I-NP is VBZ B-VP confined VBN I-VP to TO B-PP the DT B-NP T NN I-NP cell NN I-NP lineage NN I-NP . . O We PRP B-NP have VBP B-VP recently RB I-VP identified VBN I-VP and CC O cloned VBN B-VP a DT B-NP human JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O TCF-1 NN B-NP COMMA COMMA O that WDT B-NP binds VBZ B-VP to TO B-PP a DT B-NP functional JJ I-NP element NN I-NP in IN B-PP the DT B-NP T NN I-NP lymphocyte-specific JJ I-NP enhancer NN I-NP of IN B-PP CD3-epsilon NN B-NP . . O In IN B-PP a DT B-NP panel NN I-NP of IN B-PP human JJ B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O TCF-1 NN B-NP expression NN I-NP was VBD B-VP restricted JJ B-ADJP to TO B-PP T NN B-NP lineage NN I-NP cells NNS I-NP . . O TCF-1 NN B-NP belonged VBD B-VP to TO B-PP a DT B-NP novel JJ I-NP family NN I-NP of IN B-PP genes NNS B-NP that WDT B-NP contain VBP B-VP the DT B-NP so-called JJ I-NP high JJ I-NP mobility NN I-NP group NN I-NP 1 CD I-NP ( ( I-NP HMG NN I-NP ) ) I-NP box NN I-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP the DT B-NP cloning NN I-NP of IN B-PP murine JJ B-NP TCF-1 NN I-NP . . O Two CD B-NP splice NN I-NP alternatives NNS I-NP were VBD B-VP identified VBN I-VP that WDT B-NP were VBD B-VP not RB I-VP previously RB I-VP observed VBN I-VP in IN B-PP human JJ B-NP TCF-1 NN I-NP . . O Murine JJ B-NP and CC I-NP human JJ I-NP TCF-1 NN I-NP displayed VBD B-VP a DT B-NP 95.5 CD I-NP % NN I-NP overall JJ I-NP amino NN I-NP acid NN I-NP homology NN I-NP . . O Recombinant JJ B-NP murine JJ I-NP and CC I-NP human JJ I-NP TCF-1 NN I-NP recognized VBD B-VP the DT B-NP same JJ I-NP sequence NN I-NP motif NN I-NP in IN B-PP the DT B-NP CD3-epsilon NN I-NP enhancer NN I-NP as IN B-SBAR judged VBN B-VP by IN B-PP gel NN B-NP retardation NN I-NP and CC O methylation NN B-NP interference NN I-NP assays NNS B-NP . . O With IN B-PP the DT B-NP murine JJ I-NP cDNA NN I-NP clones NNS I-NP several JJ B-NP aspects NNS I-NP of IN B-PP TCF-1 NN B-NP were VBD B-VP analyzed VBN I-VP . . O First RB B-ADVP COMMA COMMA O deletion NN B-NP analysis NN I-NP revealed VBD B-VP that IN B-SBAR a DT B-NP region NN I-NP of IN B-PP TCF-1 NN B-NP containing VBG B-VP the DT B-NP HMG NN I-NP box NN I-NP was VBD B-VP sufficient JJ B-ADJP for IN B-PP sequence-specific JJ B-NP binding NN I-NP . . O Second RB B-ADVP COMMA COMMA O by IN B-PP high JJ B-NP stringency NN I-NP Northern NN I-NP blotting NN I-NP and CC O in FW B-NP situ FW I-NP hybridization NN I-NP COMMA COMMA O TCF-1 NN B-NP expression NN I-NP was VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP confined VBN I-VP to TO B-PP the DT B-NP thymus NN I-NP and CC B-PP to TO B-PP the DT B-NP T NN I-NP cell NN I-NP areas NNS I-NP of IN B-PP the DT B-NP spleen NN I-NP . . O Third RB B-ADVP COMMA COMMA O TCF-1 NN B-NP bound VBD B-VP specifically RB B-ADVP to TO B-PP a DT B-NP functional JJ I-NP T NN I-NP cell-specific JJ I-NP element NN I-NP in IN B-PP the DT O T NN B-NP cell NN I-NP receptor NN I-NP alpha NN I-NP ( ( O TCR-alpha NN B-NP ) ) O enhancer NN B-NP . . O The DT B-NP T NN I-NP lineage-specific JJ I-NP expression NN I-NP and CC O the DT B-NP affinity NN I-NP for IN B-PP functional JJ B-NP motifs NNS I-NP in IN B-PP the DT O TCR-alpha NN B-NP and CC O CD3-epsilon NN B-NP enhancers NNS B-NP imply VBP B-VP an DT B-NP important JJ I-NP role NN I-NP for IN B-PP TCF-1 NN B-NP in IN B-PP the DT B-NP establishment NN I-NP of IN B-PP the DT B-NP mature JJ I-NP T NN I-NP cell NN I-NP phenotype NN I-NP . . O HIV NN B-NP enhancer NN I-NP activity NN I-NP perpetuated VBN B-VP by IN B-PP NF-kappa NN B-NP B NN I-NP induction NN I-NP on IN B-PP infection NN B-NP of IN B-PP monocytes NNS B-NP { ( O see VB B-VP comments NNS B-NP } ) O Permissiveness NN B-NP to TO B-PP replication NN B-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O differs VBZ B-VP in IN B-PP T NN B-NP lymphocytes NNS I-NP and CC O macrophages NNS B-NP . . O In IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O HIV NN B-NP transcription NN I-NP is VBZ B-VP poorly RB I-VP detected VBN I-VP in FW B-ADVP vivo FW I-ADVP . . O Cloned VBN B-NP COMMA COMMA I-NP normal JJ I-NP T NN I-NP lymphocytes NNS I-NP show VBP B-VP very RB O little JJ O COMMA COMMA O if IN B-SBAR any DT O COMMA COMMA O basal JJ B-NP activity NN I-NP of IN B-PP the DT B-NP HIV NN I-NP enhancer NN I-NP and CC O low JJ B-NP nuclear JJ I-NP expression NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O a DT B-NP potent JJ I-NP transcriptional JJ I-NP activator NN I-NP of IN B-PP the DT B-NP HIV NN I-NP enhancer NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O fixed JJ B-NP tissue NN I-NP macrophages NNS I-NP express VBP B-VP detectable JJ B-NP HIV NN I-NP proteins NNS I-NP COMMA COMMA O indicating VBG B-VP permanent JJ B-NP virus NN I-NP transcription NN I-NP . . O One CD B-NP explanation NN I-NP for IN B-PP the DT B-NP perpetuation NN I-NP of IN B-PP virus NN B-NP infection NN I-NP in IN B-PP macrophages NNS B-NP could MD B-VP be VB I-VP sustained JJ B-NP nuclear JJ I-NP NF-kappa NN I-NP B NN I-NP expression NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP U937 NN I-NP monocytic JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP fully RB B-ADJP permissive JJ I-ADJP to TO B-PP HIV NN B-NP replication NN I-NP COMMA COMMA O is VBZ B-VP known VBN I-VP to TO I-VP express VB I-VP only RB B-NP low JJ I-NP levels NNS I-NP of IN B-PP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP . . O We PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR chronic JJ B-NP HIV VBP I-NP infection NN I-NP results VBZ B-VP in IN B-PP both CC O induction NN B-NP of IN B-PP a DT B-NP nuclear JJ I-NP factor NN I-NP with IN B-PP antigenic JJ B-NP properties NNS I-NP indistinguishable JJ B-ADJP from IN B-PP those DT B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O permanently RB B-NP increased VBN I-NP HIV NN I-NP enhancer NN I-NP activity NN I-NP . . O This DT B-NP phenomenon NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP independent JJ B-ADJP of IN B-PP tumour NN B-NP necrosis NN I-NP factor NN I-NP COMMA COMMA O is VBZ B-VP associated VBN I-VP with IN B-PP HIV NN B-NP replication NN I-NP COMMA COMMA O and CC O is VBZ B-VP thus RB O likely JJ B-ADJP to TO B-VP explain VB I-VP at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP the DT B-NP perpetuation NN I-NP of IN B-PP HIV NN B-NP infection NN I-NP in IN B-PP monocytes NNS B-NP . . O Role NN B-NP for IN B-PP the DT B-NP Epstein-Barr JJ I-NP virus NN I-NP nuclear JJ I-NP antigen NN I-NP 2 CD I-NP in IN B-PP viral JJ B-NP promoter NN I-NP switching VBG I-NP during IN B-PP initial JJ B-NP stages NNS I-NP of IN B-PP infection NN B-NP . . O During IN B-PP latent JJ O Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O infection NN B-NP of IN B-PP human JJ B-NP B NN I-NP lymphocytes NNS I-NP COMMA COMMA O six CD B-NP viral JJ I-NP nuclear JJ I-NP antigen NN I-NP ( ( O EBNAs NNS B-NP ) ) O are VBP B-VP expressed VBN I-VP from IN B-PP long JJ B-NP primary JJ I-NP transcripts NNS I-NP by IN B-PP means NNS I-PP of IN I-PP alternative JJ B-NP splicing NN I-NP and CC O alternative JJ B-NP polyadenylylation NN I-NP sites NNS I-NP . . O These DT B-NP transcripts NNS I-NP initiate VBP B-VP from IN B-PP one CD B-NP of IN B-PP two CD B-NP promoters NNS I-NP COMMA COMMA O Cp NN B-NP or CC O Wp NN B-NP COMMA COMMA O that WDT B-NP function VBP B-VP in IN B-PP a DT B-NP mutually RB I-NP exclusive JJ I-NP fashion NN I-NP . . O Wp NN B-NP is VBZ B-VP exclusively RB I-VP utilized VBN I-VP during IN B-PP the DT B-NP initial JJ I-NP stages NNS I-NP of IN B-PP infection NN B-NP of IN B-PP primary JJ B-NP B NN I-NP lymphocytes NNS I-NP COMMA COMMA O followed VBN B-VP by IN B-PP a DT B-NP switch NN I-NP to TO B-PP Cp NN B-NP usage NN I-NP . . O These DT B-NP studies NNS I-NP have VBP B-VP been VBN I-VP extended VBN I-VP to TO I-VP show VB I-VP that IN B-SBAR ( ( B-LST i LS I-LST ) ) O a DT B-NP mutant JJ I-NP EBV NN I-NP strain NN I-NP lacking VBG B-VP the DT B-NP gene NN I-NP encoding VBG B-VP EBNA NN B-NP 2 CD I-NP fails VBZ B-VP to TO I-VP switch VB I-VP from IN B-PP Wp NN B-NP to TO B-PP Cp NN B-NP usage NN B-NP in IN B-PP primary JJ B-NP B NN I-NP lymphocytes NNS I-NP COMMA COMMA O although IN B-SBAR the DT B-NP virus NN I-NP contains VBZ B-VP a DT B-NP functional JJ I-NP Cp NN I-NP ; : O ( ( B-LST ii LS I-LST ) ) O a DT B-NP region NN I-NP from IN B-NP -429 CD I-NP to TO I-NP -245 CD I-NP base NN I-NP pairs NNS I-NP upstream JJ B-ADJP of IN B-PP Cp NN B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP Cp NN B-NP activity NN I-NP in IN B-PP B NN B-NP lymphocytes NNS I-NP COMMA COMMA O but CC O only RB B-PP in IN I-PP the DT B-NP context NN I-NP of IN B-PP upstream JJ B-NP and CC I-NP downstream JJ I-NP sequences NNS I-NP ; : O ( ( B-LST iii LS I-LST ) ) O this DT B-NP region NN I-NP contains VBZ B-VP an DT B-NP EBNA NN I-NP 2-dependent JJ I-NP enhancer NN I-NP ; : O and CC O ( ( B-LST iv LS I-LST ) ) O DNase NN B-NP I CD I-NP protection NN I-NP employing VBG B-VP nuclear JJ B-NP extracts NNS I-NP from IN B-PP B NN B-NP and CC O T NN B-NP lymphocytes NNS B-NP revealed VBD B-VP a DT B-NP B-cell-specific JJ I-NP footprint NN I-NP in IN B-PP the DT B-NP region NN I-NP of IN B-PP the DT B-NP EBNA NN I-NP 2-dependent JJ I-NP enhancer NN I-NP . . O These DT B-NP results NNS I-NP support VBP B-VP a DT B-NP model NN I-NP for IN B-PP viral JJ B-NP promoter NN I-NP switching NN I-NP during IN B-PP the DT B-NP initial JJ I-NP stages NNS I-NP of IN B-PP infection NN B-NP in IN B-PP which WDT B-NP Wp NN B-NP activity NN I-NP leads VBZ B-VP to TO B-PP the DT B-NP expression NN I-NP of IN B-PP EBNA NN B-NP 2 CD I-NP COMMA COMMA O followed VBN B-VP by IN B-PP activation NN B-NP of IN B-PP Cp NN B-NP through IN B-PP the DT B-NP EBNA NN I-NP 2-dependent JJ I-NP enhancer NN I-NP . . O Glucocorticoid NN B-NP receptor NN I-NP characteristics NNS I-NP in IN B-PP monocytes NNS B-NP of IN B-PP patients NNS B-NP with IN B-PP corticosteroid-resistant JJ B-NP bronchial JJ I-NP asthma NN I-NP . . O The DT B-NP mechanism NN I-NP of IN B-PP corticosteroid NN B-NP resistance NN I-NP in IN B-PP bronchial JJ B-NP asthma NN I-NP has VBZ B-VP been VBN I-VP studied VBN I-VP by IN B-PP determining VBG B-VP the DT B-NP rank NN I-NP order NN I-NP of IN B-PP potency NN B-NP for IN B-PP different JJ B-NP corticosteroids NNS I-NP in IN B-PP inhibiting VBG B-VP the DT B-NP generation NN I-NP of IN B-PP a DT B-NP 3 CD I-NP kD NN I-NP molecule NN I-NP from IN B-PP peripheral JJ B-NP blood NN I-NP monocytes NNS I-NP isolated VBN B-VP from IN B-PP corticosteroid-sensitive JJ O ( ( O CS JJ B-ADJP ) ) O and CC O corticosteroid-resistant JJ O ( ( O CR JJ B-ADJP ) ) O asthmatic JJ B-NP subjects NNS I-NP COMMA COMMA O which WDT B-NP augments VBZ B-VP leukotriene NN B-NP B4 NN I-NP ( ( O LTB4 NN B-NP ) ) O generation NN B-NP by IN B-PP human JJ B-NP neutrophils NNS I-NP ( ( O PMN NN B-NP ) ) O stimulated VBN B-VP by IN B-PP calcium NN B-NP ionophore NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O binding VBG B-NP studies NNS I-NP with IN B-PP ( ( B-NP 3H NN I-NP ) ) I-NP dexamethasone NN I-NP have VBP B-VP been VBN I-VP performed VBN I-VP to TO B-VP determine VB I-VP the DT B-NP dissociation NN I-NP constant NN I-NP ( ( O Kd NN B-NP ) ) O and CC O receptor NN B-NP numbers NNS I-NP ( ( O Ro NN B-NP ) ) O in IN B-PP the DT B-NP monocytes NNS I-NP of IN B-PP these DT B-NP two CD I-NP groups NNS I-NP of IN B-PP subjects NNS B-NP . . O The DT B-NP concentration NN I-NP of IN B-PP corticosteroid NN B-NP producing VBG B-VP 50 CD B-NP % NN I-NP inhibition NN I-NP ( ( O IC50 NN B-NP ) ) O was VBD B-VP 600 CD B-NP nM NN I-NP COMMA COMMA O 70 CD B-NP nM NN I-NP COMMA COMMA O and CC O 0.5 CD B-NP nM NN I-NP for IN B-PP hydrocortisone NN B-NP COMMA COMMA O methylprednisolone NN B-NP COMMA COMMA O and CC O dexamethasone NN B-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O in IN B-PP monocytes NNS B-NP from IN B-PP CS JJ B-NP individuals NNS I-NP . . O There EX B-NP was VBD B-VP only RB B-NP weak JJ I-NP inhibition NN I-NP of IN B-PP the DT B-NP generation NN I-NP of IN B-PP enhancing NN B-NP activity NN I-NP by IN B-PP the DT B-NP corticosteroids NNS I-NP in IN B-PP the DT B-NP CR JJ I-NP asthmatic JJ I-NP individuals NNS I-NP . . O The DT B-NP dexamethasone NN I-NP Kd NN I-NP was VBD B-VP 2.45 CD B-NP +\/- CC I-NP 0.58 CD I-NP nM NN I-NP ( ( O mean NN B-NP +\/- CC O SEM NN B-NP COMMA COMMA O n NN B-NP = JJ B-VP 6 CD B-NP ) ) O in IN B-PP the DT O CS JJ B-NP group NN B-NP and CC O 1.6 CD B-NP +\/- CC I-NP 0.35 CD I-NP nM NN I-NP ( ( O mean NN B-NP +\/- CC O SEM NN B-NP COMMA COMMA O n NN B-NP = JJ B-VP 6 CD B-NP ) ) O in IN B-PP the DT O CR JJ B-NP group NN B-NP of IN B-PP patients NNS B-NP ( ( O p NN B-NP = JJ B-VP 0.14 CD B-NP ) ) O . . O The DT B-NP Ro NN I-NP in IN B-PP the DT B-NP CS JJ I-NP group NN I-NP was VBD B-VP 3COMMA605 CD B-NP +\/- CC I-NP 984 CD I-NP binding VBG I-NP sites NNS I-NP per IN B-PP nucleus NN B-NP ( ( O mean NN B-NP +\/- CC O SEM NN B-NP COMMA COMMA O n NN B-NP = JJ B-VP 6 CD B-NP ) ) O and CC O 4COMMA757 CD B-NP +\/- CC I-NP 692 CD I-NP binding VBG I-NP sites NNS I-NP per IN B-PP nucleus NN B-NP ( ( O mean NN B-NP +\/- CC O SEM NN B-NP COMMA COMMA O n NN B-NP = JJ B-VP 6 CD B-NP ) ) O in IN B-PP the DT B-NP CR JJ I-NP group NN I-NP ( ( O p NN B-NP = JJ B-VP 0.23 CD B-NP ) ) O . . O These DT B-NP findings NNS I-NP indicate VBP B-VP that IN B-SBAR corticosteroid NN B-NP resistance NN I-NP in IN B-PP bronchial JJ B-NP asthma NN I-NP can MD B-VP not RB I-VP be VB I-VP explained VBN I-VP by IN B-PP abnormalities NNS B-NP in IN B-PP corticosteroid NN B-NP receptor NN I-NP characteristics NNS B-NP . . O Tissue-specific JJ B-NP expression NN I-NP of IN B-PP the DT B-NP platelet NN I-NP GPIIb NN I-NP gene NN I-NP . . O One CD B-NP of IN B-PP the DT B-NP major JJ I-NP objectives NNS I-NP in IN B-PP the DT B-NP study NN I-NP of IN B-PP thrombogenesis NN B-NP is VBZ B-VP to TO B-VP determine VB I-VP the DT B-NP mechanisms NNS I-NP by IN B-PP which WDT B-NP a DT B-NP hematopoietic JJ I-NP progenitor NN I-NP is VBZ B-VP activated VBN I-VP and CC O committed VBN B-VP to TO B-PP the DT B-NP megakaryocytic JJ I-NP lineage NN I-NP . . O Recent JJ B-NP development NN I-NP of IN B-PP primary JJ B-NP cultures NNS I-NP of IN B-PP human JJ B-NP megakaryocytes NNS I-NP and CC O the DT B-NP molecular JJ I-NP cloning NN I-NP of IN B-PP genes NNS B-NP that WDT B-NP are VBP B-VP specific JJ B-ADJP to TO B-PP this DT B-NP lineage NN I-NP offer VBP B-VP the DT B-NP possibility NN I-NP of IN B-PP getting VBG B-VP some DT B-NP insights NNS I-NP into IN B-PP the DT B-NP genetic JJ I-NP mechanisms NNS I-NP that WDT B-NP control VBP B-VP megakaryocytopoiesis NNS B-NP . . O One CD B-NP gene NN I-NP of IN B-PP interest NN B-NP is VBZ B-VP the DT O glycoprotein NN B-NP IIb NN I-NP ( ( O GPIIb NN B-NP ) ) O gene NN B-NP ; : O GPIIb NN B-NP COMMA COMMA O the DT B-NP alpha NN I-NP subunit NN I-NP of IN B-PP the DT B-NP platelet NN I-NP cytoadhesin NN I-NP GPIIb-IIIa NN I-NP COMMA COMMA O is VBZ B-VP produced VBN I-VP in IN B-PP megakaryocytes NNS B-NP at IN B-PP an DT B-NP early JJ I-NP stage NN I-NP of IN B-PP the DT B-NP differentiation NN I-NP COMMA COMMA O whereas IN O the DT B-NP other JJ I-NP subunit NN I-NP of IN B-PP this DT B-NP complex NN I-NP COMMA COMMA O GPIIIa NN B-NP COMMA COMMA O is VBZ B-VP expressed VBN I-VP in IN B-PP other JJ B-NP cells NNS I-NP . . O For IN B-PP these DT B-NP reasons NNS I-NP COMMA COMMA O the DT B-NP 5'-flanking JJ I-NP region NN I-NP of IN B-PP the DT B-NP GPIIb NN I-NP gene NN I-NP was VBD B-VP used VBN I-VP to TO B-VP identify VB I-VP the DT B-NP regions NNS I-NP that WDT B-NP interact VBP B-VP with IN B-PP DNA-binding JJ B-NP nuclear JJ I-NP factors NNS I-NP . . O A DT B-NP fragment NN I-NP extending VBG B-VP from IN B-PP -643 CD B-NP to TO B-PP +33 CD B-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP controlling VBG B-VP the DT B-NP tissue-specific JJ I-NP expression NN I-NP of IN B-PP the DT B-NP CAT NN I-NP gene NN I-NP in IN B-PP transfection NN B-NP experiments NNS I-NP . . O Within IN B-PP this DT B-NP region NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP identified VBN I-VP several JJ B-NP sequences NNS I-NP that WDT B-NP are VBP B-VP implicated VBN I-VP in IN B-PP DNA NN B-NP protein NN I-NP interactions NNS I-NP as IN B-SBAR shown VBN B-VP in IN B-PP DNAse NN B-NP I NN I-NP footprints NNS I-NP and CC O gel NN B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP . . O One CD B-NP region NN I-NP COMMA COMMA O centered VBN B-ADJP at IN B-PP -54 CD B-NP COMMA COMMA O is VBZ B-VP similar JJ B-ADJP to TO B-PP a DT B-NP nuclear JJ I-NP factor NN I-NP E1-binding JJ I-NP site NN I-NP COMMA COMMA O and CC O a DT B-NP region NN I-NP located JJ B-ADJP at IN B-PP position NN B-NP -233 CD I-NP contains VBZ B-VP a DT B-NP CCAAT NN I-NP motif NN I-NP . . O Two CD B-NP domains NNS I-NP centered VBN O at IN B-PP positions NNS B-NP -345 CD B-NP and CC O -540 CD B-NP COMMA COMMA B-ADJP respectively RB I-ADJP COMMA COMMA O bind VBP B-VP proteins NNS B-NP that WDT B-NP are VBP B-VP present JJ B-ADJP in IN B-PP megakaryocytic JJ B-NP cells NNS I-NP and CC O nonrelated JJ B-NP cells NNS I-NP as RB B-PP well RB B-ADVP . . O Finally RB B-ADVP COMMA COMMA O two CD B-NP other JJ I-NP domains NNS I-NP COMMA COMMA O located JJ B-ADJP at IN B-PP positions NNS B-NP -460 CD B-NP and CC O -510 CD B-NP COMMA COMMA O interact VBP B-VP with IN B-PP proteins NNS B-NP that WDT B-NP are VBP B-VP only RB B-ADJP present JJ I-ADJP in IN B-PP megakaryocytic JJ B-NP cells NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O deletion NN B-NP of IN B-PP the DT B-NP region NN I-NP containing VBG B-VP these DT B-NP two CD I-NP domains NNS I-NP results VBZ B-VP in IN B-PP a DT B-NP significant JJ I-NP decrease NN I-NP of IN B-PP the DT B-NP promoter NN I-NP activity NN I-NP . . O It PRP B-NP is VBZ B-VP very RB B-ADJP likely JJ I-ADJP that IN B-SBAR these DT B-NP domains NNS I-NP bind VBP B-VP megakaryocyte-specific JJ B-NP nuclear JJ I-NP proteins NNS I-NP acting VBG B-VP as IN B-PP positive JJ B-NP transcription NN I-NP factors NNS I-NP . . O Inhibition NN B-NP of IN B-PP protein NN B-NP phosphatases NNS I-NP by IN B-PP okadaic JJ B-NP acid NN I-NP induces VBZ B-VP AP1 NN B-NP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP . . O To TO B-VP examine VB I-VP the DT B-NP role NN I-NP of IN B-PP protein NN B-NP phosphatases NNS I-NP in IN B-PP T NN B-NP cell NN I-NP activation NN I-NP COMMA COMMA O Jurkat NN B-NP cells NNS I-NP were VBD B-VP treated VBN I-VP with IN B-PP okadaic JJ B-NP acid NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP type NN B-NP 1 CD I-NP and CC I-NP 2A NN I-NP phosphatases NNS I-NP COMMA COMMA O and CC O nuclear JJ B-NP extracts NNS I-NP were VBD B-VP examined VBN I-VP for IN B-PP the DT B-NP presence NN I-NP of IN B-PP AP1 NN B-NP as IN B-PP a DT B-NP measure NN I-NP of IN B-PP early JJ B-NP T NN I-NP cell NN I-NP activation NN I-NP . . O Okadaic JJ B-NP acid NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP a DT B-NP potent JJ I-NP inducer NN I-NP of IN B-PP AP1 NN B-NP . . O In IN B-PP contrast NN I-PP to TO I-PP phorbol NN B-NP esters NNS I-NP such JJ B-PP as IN I-PP phorbol NN B-NP myristate NN I-NP acetate NN I-NP ( ( O PMA NN B-NP ) ) O COMMA COMMA O the DT B-NP induction NN I-NP of IN B-PP AP1 NN B-NP by IN B-PP okadaic JJ B-NP acid NN I-NP occurs VBZ B-VP predominantly RB B-PP by IN I-PP transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT O jun NN B-NP and CC O fos NN B-NP family NN B-NP of IN B-PP proto-oncogenes NNS B-NP . . O Surprisingly RB B-ADVP COMMA COMMA O while IN B-SBAR the DT B-NP addition NN I-NP of IN B-PP phytohemagglutinin NN B-NP further RB B-ADVP enhanced VBD B-VP the DT B-NP induction NN I-NP of IN B-PP AP1 NN B-NP COMMA COMMA O the DT B-NP addition NN I-NP of IN B-PP PMA NN B-NP inhibited VBD B-VP it PRP B-NP . . O Okadaic JJ B-NP acid NN I-NP treatment NN I-NP was VBD B-VP found VBN I-VP to TO I-VP dramatically RB I-VP increase VB I-VP mRNA NN B-NP transcripts NNS I-NP of IN B-PP the DT B-NP jun NN I-NP family NN I-NP of IN B-PP proto-oncogenes NNS B-NP including VBG B-PP c-jun NN B-NP COMMA COMMA O junD NN B-NP COMMA COMMA O and CC O junB NN B-NP and CC O to TO B-PP a DT B-NP lesser JJR I-NP extent NN I-NP the DT B-NP fos NN I-NP family NN I-NP including VBG B-PP c-fos NN B-NP and CC O fra-1 NN B-NP . . O By IN B-PP comparison NN B-NP COMMA COMMA O PMA NN B-NP is VBZ B-VP a DT B-NP very RB I-NP inefficient JJ I-NP inducer NN I-NP of IN B-PP the DT B-NP jun NN I-NP gene NN I-NP family NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O Similar JJ B-ADJP to TO B-PP its PRP$ B-NP effect NN I-NP on IN B-PP the DT B-NP induction NN I-NP of IN B-PP AP1 NN B-NP by IN B-PP okadaic JJ B-NP acid NN I-NP COMMA COMMA O PMA NN B-NP inhibits VBZ B-VP the DT B-NP induction NN I-NP of IN B-PP c-jun NN B-NP mRNA NN I-NP by IN B-PP okadaic JJ B-NP acid NN I-NP . . O Transfection NN B-NP of IN B-PP c-jun NN B-NP promoter NN I-NP constructs NNS I-NP confirmed VBD B-VP the DT B-NP marked JJ I-NP difference NN I-NP between IN B-PP PMA NN B-NP and CC O okadaic JJ B-NP acid NN I-NP in IN B-PP inducing VBG B-VP c-jun NN B-NP transcription NN I-NP . . O The DT B-NP induction NN I-NP of IN B-PP AP1 NN B-NP by IN B-PP okadaic JJ B-NP acid NN I-NP suggests VBZ B-VP that IN B-SBAR protein NN B-NP phosphatases NNS I-NP 1 CD B-NP and CC O 2A NN B-NP ( ( O PP1 NN B-NP and CC O PP2A NN B-NP ) ) O may MD B-VP be VB I-VP involved VBN I-VP in IN B-PP T NN B-NP cell NN I-NP activation NN I-NP as IN B-PP important JJ B-NP negative JJ I-NP regulators NNS I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP AP1 NN I-NP . . O Demonstration NN B-NP of IN B-PP estrogen NN B-NP and CC O progesterone NN B-NP receptors NNS B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP Ki-67 NN B-NP and CC O p-145 NN B-NP antigens NNS B-NP in IN B-PP single JJ B-NP tumor NN I-NP cells NNS I-NP from IN B-PP blood NN B-NP and CC O pleural JJ B-ADJP effusions NNS B-NP using VBG B-VP a DT B-NP slide NN I-NP assay NN I-NP . . O We PRP B-NP describe VBP B-VP a DT B-NP slide NN I-NP assay NN I-NP that WDT B-NP allows VBZ B-VP the DT B-NP demonstration NN I-NP of IN B-PP antigens NNS B-NP localized JJ B-ADJP in IN B-PP the DT B-NP nucleus NN I-NP from IN B-PP isolated VBN B-NP white JJ I-NP blood NN I-NP cells NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP from IN B-PP single JJ B-NP tumor NN I-NP cells NNS I-NP derived VBN B-VP from IN B-PP malignant JJ B-NP effusions NNS I-NP . . O With IN B-PP the DT B-NP antibodies NNS I-NP Ki-67 NN B-NP and CC O anti-p-145 NN B-NP an DT B-NP increased VBN I-NP rate NN I-NP of IN B-PP nuclear JJ B-NP and CC I-NP nucleolar JJ I-NP staining NN I-NP resulted VBD B-VP in IN B-PP cells NNS B-NP from IN B-PP highly RB B-NP malignant JJ I-NP lymphomas NNS I-NP . . O An DT B-NP almost RB I-NP identical JJ I-NP reaction NN I-NP was VBD B-VP obtained VBN I-VP when WRB B-ADVP tumor NN B-NP cells NNS I-NP from IN B-PP malignant JJ B-NP effusions NNS I-NP were VBD B-VP tested VBN I-VP . . O Cells NNS B-NP isolated VBN B-VP from IN B-PP the DT B-NP blood NN I-NP of IN B-PP patients NNS B-NP with IN B-PP leukemic JJ B-NP spread NN I-NP of IN B-PP lymphomas NNS B-NP of IN B-PP low JJ B-NP malignancy NN I-NP yielded VBD B-VP a DT B-NP weak JJ I-NP staining NN I-NP comparable JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP normal JJ B-NP mesothelial JJ I-NP cells NNS I-NP from IN B-PP non-tumorous JJ B-NP cavity NN I-NP fluids NNS I-NP . . O The DT B-NP detection NN I-NP of IN B-PP estrogen NN B-NP and CC O progesterone NN B-NP receptors NNS B-NP ( ( O ER NN B-NP and CC O PR NN B-NP ) ) O localized JJ B-ADJP in IN B-PP the DT B-NP cell NN I-NP nucleus NN I-NP can MD B-VP be VB I-VP achieved VBN I-VP by IN B-PP the DT B-NP same JJ I-NP assay NN I-NP . . O The DT B-NP reaction NN I-NP is VBZ B-VP enhanced VBN I-VP by IN B-PP incubation NN B-NP of IN B-PP the DT B-NP tumor NN I-NP cells NNS I-NP for IN B-PP 30 CD B-NP min NN I-NP at IN B-PP 37 CD B-NP degrees NNS I-NP C NN I-NP prior RB B-PP to TO I-PP fixation NN B-NP . . O Pleural JJ B-NP effusions NNS I-NP from IN B-PP 20 CD B-NP patients NNS I-NP with IN B-PP breast NN B-NP cancer NN I-NP were VBD B-VP tested VBN I-VP . . O ER NN B-NP was VBD B-VP positive JJ B-ADJP in IN B-PP 13 CD B-NP and CC O PR NN B-NP was VBD B-VP positive JJ B-ADJP in IN B-PP 12 CD B-NP of IN B-PP the DT B-NP 20 CD I-NP samples NNS I-NP . . O In IN B-PP 5 CD B-NP cases NNS I-NP there EX B-NP was VBD B-VP a DT B-NP divergent JJ I-NP reaction NN I-NP with IN B-PP ER NN B-NP and CC O PR NN B-NP antibody NN B-NP . . O The DT B-NP hormone NN I-NP receptors NNS I-NP of IN B-PP the DT B-NP primary JJ I-NP tumor NN I-NP were VBD B-VP known VBN I-VP in IN B-PP 15 CD B-NP ( ( O ER NN B-NP ) ) O and CC O 14 CD B-NP ( ( O PR NN B-NP ) ) O patients NNS B-NP COMMA COMMA O respectively RB B-ADVP . . O In IN B-PP each DT B-NP cohort NN I-NP there EX B-NP was VBD B-VP only RB B-NP one CD I-NP case NN I-NP with IN B-PP a DT B-NP negative JJ I-NP reaction NN I-NP of IN B-PP the DT B-NP primary JJ I-NP tumor NN I-NP and CC O a DT B-NP positive JJ I-NP reaction NN I-NP with IN B-PP the DT B-NP isolated VBN I-NP tumor NN I-NP cells NNS I-NP from IN B-PP the DT B-NP pleural JJ I-NP effusions NNS I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP demonstration NN I-NP of IN B-PP hormone NN B-NP receptor NN I-NP proteins NNS I-NP in IN B-PP cells NNS B-NP from IN B-PP malignant JJ B-NP effusions NNS I-NP is VBZ B-VP possible JJ B-ADJP and CC O that IN B-SBAR there EX B-NP is VBZ B-VP a DT B-NP correlation NN I-NP with IN B-PP the DT B-NP status NN I-NP of IN B-PP the DT B-NP primary JJ I-NP site NN I-NP of IN B-PP cancer NN B-NP . . O Transforming VBG B-NP growth NN I-NP factor-beta NN I-NP suppresses VBZ B-VP human JJ B-NP B NN I-NP lymphocyte NN I-NP Ig NN I-NP production NN I-NP by IN B-PP inhibiting VBG B-VP synthesis NN B-NP and CC O the DT B-NP switch NN I-NP from IN B-PP the DT B-NP membrane NN I-NP form NN I-NP to TO B-PP the DT B-NP secreted JJ I-NP form NN I-NP of IN B-PP Ig NN O mRNA NN O . . O Transforming VBG B-NP growth NN I-NP factor-beta NN I-NP ( ( O TGF-beta NN B-NP ) ) O inhibits VBZ B-VP B NN B-NP cell NN I-NP Ig NN I-NP secretion NN I-NP and CC O reduces VBZ B-VP B NN B-NP cell NN I-NP membrane NN I-NP Ig NN I-NP expression NN I-NP . . O The DT B-NP addition NN I-NP of IN B-PP TGF-beta NN B-NP to TO B-PP human JJ B-NP B NN I-NP lymphocyte NN I-NP cultures NNS I-NP stimulated VBN B-VP with IN B-PP Staphylococcus FW B-NP aureus FW I-NP Cowan NN I-NP strain NN I-NP I NN I-NP and CC O IL-2 NN B-NP completely RB B-ADVP inhibited VBD B-VP B NN B-NP cell NN I-NP Ig NN I-NP secretion NN I-NP ( ( O greater JJR B-ADVP than IN B-PP 90 CD B-NP % NN I-NP ) ) O and CC O decreased VBD B-VP B NN O cell NN O surface NN O IgM NN B-NP COMMA COMMA O IgD NN B-NP COMMA COMMA O kappa NN B-NP L NN I-NP chain NN I-NP COMMA COMMA O and CC O lambda NN B-NP L NN I-NP chain NN I-NP expression NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O TGF-beta NN B-NP had VBD B-VP only RB B-NP minimal JJ I-NP effects NNS I-NP on IN B-PP two CD B-NP other JJ I-NP B NN I-NP cell NN I-NP membrane NN I-NP proteins NNS I-NP COMMA COMMA O HLA-DR NN B-NP and CC O CD20 NN B-NP . . O Internal JJ B-NP labeling NN I-NP with IN B-PP {35S}methionine NN B-NP and CC O immunoprecipitation NN B-NP with IN B-PP anti-IgM JJ B-NP COMMA COMMA I-NP anti-kappa JJ I-NP COMMA COMMA I-NP and CC I-NP anti-lambda JJ I-NP antibodies NNS I-NP revealed VBD B-VP a DT B-NP striking JJ I-NP reduction NN I-NP in IN B-PP kappa NN B-NP L NN I-NP chain NN I-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP TGF-beta NN B-NP . . O A DT B-NP less RBR I-NP pronounced JJ I-NP reduction NN I-NP in IN B-PP lambda NN B-NP L NN I-NP chain NN I-NP and CC O microH NN B-NP chain NN I-NP was VBD B-VP also RB I-VP noted VBN I-VP . . O Northern NN B-NP blot NN I-NP analysis NN I-NP of IN B-PP RNA NN B-NP purified VBN B-VP from IN B-PP B NN B-NP cells NNS I-NP treated VBN B-VP with IN B-PP TGF-beta NN B-NP for IN B-PP varying VBG B-NP time NN I-NP intervals NNS I-NP revealed VBD B-VP a DT B-NP significant JJ I-NP decrease NN I-NP in IN B-PP steady JJ B-NP state NN I-NP kappa NN I-NP and CC I-NP lambda NN I-NP L NN I-NP chain NN I-NP mRNA NN I-NP levels NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O a DT B-NP significant JJ I-NP decrease NN I-NP in IN B-PP the DT B-NP switch NN I-NP from IN B-PP the DT B-NP membrane NN I-NP forms NNS I-NP of IN B-PP mu NN B-NP and CC O gamma NN B-NP to TO B-PP their PRP$ B-NP respective JJ I-NP secreted JJ I-NP forms NNS I-NP was VBD B-VP noted VBN I-VP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP TGF-beta NN B-NP . . O Nuclear JJ B-NP run-on JJ I-NP experiments NNS I-NP demonstrated VBD B-VP decreased VBN B-NP transcription NN I-NP of IN B-PP kappa NN B-NP L NN I-NP chain NN I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP TGF-beta NN B-NP on IN B-PP two CD B-NP transcriptional JJ I-NP regulatory JJ I-NP factors NNS I-NP COMMA COMMA O Oct-2 NN B-NP and CC O nuclear JJ B-NP factor NN I-NP ( ( O NF NN B-NP ) ) O kappa NN B-NP B NN I-NP COMMA COMMA O known VBN B-VP to TO I-VP be VB I-VP important JJ B-ADJP in IN B-PP Ig NN B-NP gene NN I-NP transcription NN I-NP were VBD B-VP examined VBN I-VP . . O Oct-2 NN B-NP mRNA NN I-NP levels NNS I-NP and CC O both DT B-NP Oct-2 NN B-NP and CC O NF-kappa NN B-NP B NN I-NP proteins NNS B-NP in IN B-PP nuclear JJ B-NP extracts NNS I-NP were VBD B-VP not RB I-VP altered VBN I-VP by IN B-PP treatment NN B-NP with IN B-PP TGF-beta NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O levels NNS B-NP of IN B-PP the DT B-NP transcriptional JJ I-NP factor NN I-NP AP-1 NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP not RB I-VP known VBN I-VP to TO I-VP be VB I-VP important JJ B-ADJP in IN B-PP B NN B-NP cell NN I-NP Ig NN I-NP production NN I-NP COMMA COMMA O were VBD B-VP reduced VBN I-VP by IN B-PP TGF-beta NN B-NP . . O These DT B-NP findings NNS I-NP demonstrate VBP B-VP that IN B-SBAR TGF-beta NN B-NP decreases VBZ B-VP B NN B-NP lymphocyte NN I-NP Ig NN I-NP secretion NN I-NP by IN B-PP inhibiting VBG B-VP the DT B-NP synthesis NN I-NP of IN B-PP Ig NN B-NP mRNA NN I-NP and CC O inhibiting VBG B-VP the DT B-NP switch NN I-NP from IN B-PP the DT B-NP membrane NN I-NP form NN I-NP to TO B-PP the DT B-NP secreted JJ I-NP forms NNS I-NP of IN B-PP mu NN B-NP and CC O gamma NN B-NP mRNA NN B-NP . . O The DT B-NP mechanism NN I-NP by IN B-PP which WDT B-NP TGF-beta NN B-NP inhibits VBZ B-VP Ig NN B-NP chain NN I-NP synthesis NN I-NP is VBZ B-VP unclear JJ B-ADJP although IN B-SBAR it PRP B-NP does VBZ B-VP not RB I-VP involve VB I-VP inhibition NN B-NP of IN B-PP the DT B-NP binding NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP or CC O Oct-2 NN B-NP to TO B-PP their PRP$ B-NP respective JJ I-NP target NN I-NP sequences NNS I-NP . . O Differentiation-associated JJ B-NP expression NN I-NP of IN B-PP the DT B-NP Epstein-Barr JJ I-NP virus NN I-NP BZLF1 NN I-NP transactivator NN I-NP protein NN I-NP in IN B-PP oral JJ B-NP hairy JJ I-NP leukoplakia NN I-NP . . O The DT B-NP BZLF1 NN I-NP protein NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O is VBZ B-VP a DT B-NP key JJ I-NP immediate-early JJ I-NP protein NN I-NP which WDT B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP disrupt VB I-VP virus NN B-NP latency NN I-NP in IN B-PP EBV-infected JJ B-NP B NN I-NP cells NNS I-NP . . O We PRP B-NP have VBP B-VP generated VBN I-VP a DT B-NP monoclonal JJ I-NP antibody NN I-NP COMMA COMMA O BZ1 NN B-NP COMMA COMMA O to TO B-PP BZLF1 NN B-NP which WDT B-NP reacts VBZ B-VP in IN B-PP immunohistology NN B-NP COMMA COMMA O immunoblotting NN B-NP COMMA COMMA O and CC O immunoprecipitation NN B-NP and CC O which WDT B-NP recognizes VBZ B-VP both CC O the DT B-NP active JJ I-NP COMMA COMMA I-NP dimeric JJ I-NP form NN I-NP and CC O the DT B-NP inactive JJ I-NP COMMA COMMA I-NP monomeric JJ I-NP form NN I-NP of IN B-PP the DT B-NP protein NN I-NP . . O Biopsies NNS B-NP of IN B-PP oral JJ B-NP hairy JJ I-NP leukoplakia NN I-NP COMMA COMMA O an DT B-NP AIDS-associated JJ I-NP lesion NN I-NP characterized VBN B-VP by IN B-PP high-level JJ B-NP EBV NN I-NP replication NN I-NP COMMA COMMA O were VBD B-VP examined VBN I-VP by IN B-PP immunohistochemistry NN B-NP using VBG B-VP the DT B-NP BZ1 NN I-NP monoclonal JJ I-NP antibody NN I-NP . . O A DT B-NP differentiation-associated JJ I-NP pattern NN I-NP of IN B-PP BZLF1 NN B-NP expression NN I-NP was VBD B-VP observed VBN I-VP COMMA COMMA O BZ1 NN B-NP reacting VBG B-VP with IN B-PP nuclei NNS B-NP of IN B-PP the DT B-NP upper JJ I-NP spinous JJ I-NP layer NN I-NP of IN B-PP the DT B-NP lesion NN I-NP . . O This DT B-NP finding NN I-NP suggests VBZ B-VP that IN B-SBAR the DT B-NP BZLF1 NN I-NP promoter NN I-NP may MD B-VP be VB I-VP regulated VBN I-VP by IN B-PP the DT B-NP degree NN I-NP of IN B-PP squamous JJ B-NP differentiation NN I-NP . . O A DT B-NP comparison NN I-NP of IN B-PP in FW B-NP situ FW I-NP hybridization NN I-NP to TO B-PP EBV NN B-NP DNA NN I-NP and CC O viral JJ B-NP capsid NN I-NP antigen NN I-NP staining VBG I-NP with IN B-PP BZ1 NN B-NP reactivity NN I-NP suggested VBD B-VP that IN B-SBAR BZLF1 NN B-NP expression NN I-NP precedes VBZ B-VP rampant JJ B-NP virus NN I-NP replication NN I-NP . . O The DT B-NP inability NN I-NP to TO B-VP detect VB I-VP EBV NN B-NP in IN B-PP the DT B-NP lower RBR I-NP epithelial JJ I-NP layers NNS I-NP of IN B-PP oral JJ B-NP hairy JJ I-NP leukoplakia NN I-NP raises VBZ B-VP questions NNS B-NP concerning VBG B-PP the DT B-NP nature NN I-NP of IN B-PP EBV NN B-NP latency NN B-NP and CC O persistence NN B-NP in IN B-PP stratified JJ B-NP squamous JJ I-NP epithelium NN I-NP . . O Transactivation NN B-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP promoter NN I-NP by IN B-PP human JJ B-NP herpesvirus NN I-NP 6 CD I-NP ( ( O HHV-6 NN B-NP ) ) O strains VBZ B-NP GS NN B-NP and CC O Z-29 NN B-NP in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP and CC O identification NN B-NP of IN B-PP transactivating VBG B-NP HHV-6 NN I-NP ( ( I-NP GS NN I-NP ) ) I-NP gene NN I-NP fragments NNS I-NP . . O Human JJ B-NP herpesvirus NN I-NP 6 CD I-NP ( ( O HHV-6 NN B-NP ) ) O can MD B-VP activate VB I-VP the DT O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O promoter NN B-NP and CC O accelerate VB B-VP cytopathic JJ B-NP effects NNS I-NP in IN B-PP HIV-infected JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O This DT B-NP study NN I-NP examines VBZ B-VP the DT B-NP regions NNS I-NP of IN B-PP the DT B-NP HIV NN I-NP promoter NN I-NP required VBN B-VP for IN B-PP HHV-6 NN B-NP transactivation NN I-NP in IN B-PP a DT B-NP heterogeneous JJ I-NP population NN I-NP of IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP with IN B-PP or CC B-PP without IN B-PP antigenic JJ B-NP stimulation NN I-NP . . O Two CD B-NP different JJ I-NP strains NNS I-NP of IN B-PP HHV-6 NN B-NP COMMA COMMA O GS NN B-NP and CC O Z29 NN B-NP COMMA COMMA O transactivated VBD B-VP the DT B-NP HIV NN I-NP promoter NN I-NP . . O The DT B-NP GS NN I-NP strain NN I-NP transactivated VBD B-VP the DT B-NP promoter NN I-NP in IN B-PP both CC B-NP stimulated VBN I-NP and CC I-NP resting VBG I-NP T NN I-NP cells NNS I-NP COMMA COMMA O while IN B-SBAR the DT B-NP Z29 NN I-NP strain NN I-NP increased VBD B-VP HIV NN B-NP promoter NN I-NP activity NN I-NP only RB B-PP in IN I-PP stimulated VBN B-NP T NN I-NP cells NNS I-NP . . O Three CD B-NP DNA NN I-NP clones NNS I-NP containing VBG B-VP HHV-6 NN B-NP ( ( I-NP GS NN I-NP ) ) I-NP genomic JJ I-NP fragments NNS I-NP transactivated VBD B-VP the DT B-NP HIV NN I-NP promoter NN I-NP in IN B-PP cotransfected VBN B-NP T NN I-NP cells NNS I-NP . . O A DT B-NP 21.4-kb JJ I-NP DNA NN I-NP clone NN I-NP COMMA COMMA O pZVB70 NN B-NP COMMA COMMA O showed VBD B-VP the DT B-NP highest JJS I-NP transactivating NN I-NP ability NN I-NP COMMA COMMA O while IN B-SBAR two CD B-NP other JJ I-NP DNA NN I-NP fragments NNS I-NP COMMA COMMA O pZVB10 NN B-NP ( ( O 6.2 CD B-NP kb NN I-NP ) ) O and CC O pZVH14 NN B-NP ( ( O 8.7 CD B-NP kb NN I-NP ) ) O COMMA COMMA O showed VBD B-VP lower JJR B-NP activity NN I-NP . . O One CD B-NP of IN B-PP these DT B-NP clones NNS I-NP COMMA COMMA O pZVH14 NN B-NP COMMA COMMA O activated VBD B-VP the DT B-NP HIV NN I-NP promoter NN I-NP construct NN I-NP containing VBG B-VP a DT B-NP mutation NN I-NP in IN B-PP the DT B-NP NF NN I-NP kappa NN I-NP B NN I-NP site NN I-NP . . O However RB B-ADVP COMMA COMMA O this DT B-NP mutated VBN I-NP NF NN I-NP kappa NN I-NP B NN I-NP promoter NN I-NP was VBD B-VP not RB I-VP transactivated VBN I-VP during IN B-PP HHV-6 NN B-NP ( ( I-NP GS NN I-NP ) ) I-NP infection NN I-NP or CC B-PP after IN B-PP cotransfection NN B-NP with IN B-PP pZVB70 NN B-NP or CC O pZVB10 NN B-NP . . O These DT B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP NF NN I-NP kappa NN I-NP B NN I-NP sites NNS I-NP of IN B-PP the DT B-NP HIV NN I-NP promoter NN I-NP are VBP B-VP essential JJ B-ADJP for IN B-PP its PRP$ B-NP transactivation NN I-NP during IN B-PP HHV-6 NN B-NP ( ( I-NP GS NN I-NP ) ) I-NP infection NN I-NP . . O By IN B-PP increasing VBG B-VP HIV NN B-NP promoter NN I-NP activity NN I-NP in IN B-PP primary JJ B-NP T NN I-NP lymphocytes NNS I-NP COMMA COMMA O HHV-6 NN B-NP may MD B-VP consequently RB I-VP increase VB I-VP HIV NN B-NP replication NN I-NP COMMA COMMA O leading VBG B-VP to TO B-PP an DT B-NP increase NN I-NP in IN B-PP the DT B-NP cytopathic JJ I-NP effect NN I-NP on IN B-PP coinfected VBN B-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O The DT B-NP rhombotin NN I-NP family NN I-NP of IN B-PP cysteine-rich JJ B-NP LIM-domain JJ I-NP oncogenes NNS I-NP : : O distinct JJ B-NP members NNS I-NP are VBP B-VP involved VBN I-VP in IN B-PP T-cell NN B-NP translocations NNS I-NP to TO B-PP human JJ B-NP chromosomes NNS I-NP 11p15 NN B-NP and CC O 11p13 NN B-NP . . O A DT B-NP chromosomal NN I-NP translocation NN I-NP in IN B-PP a DT B-NP T-cell NN I-NP leukemia NN I-NP involving VBG B-VP the DT B-NP short JJ I-NP arm NN I-NP of IN B-PP human JJ B-NP chromosome NN I-NP 11 CD I-NP at IN B-PP band NN B-NP 11p15 NN I-NP disrupts VBZ B-VP the DT B-NP rhombotin NN I-NP gene NN I-NP . . O This DT B-NP gene NN I-NP encodes VBZ B-VP a DT B-NP protein NN I-NP with IN B-PP duplicated JJ B-NP cysteine-rich JJ I-NP regions NNS I-NP called VBN B-VP LIM NN B-NP domains NNS I-NP COMMA COMMA O which WDT B-NP show VBP B-VP homology NN B-NP to TO B-PP zinc-binding JJ B-NP proteins NNS I-NP and CC B-PP to TO B-PP iron-sulfur JJ B-NP centers NNS I-NP of IN B-PP ferredoxins NNS B-NP . . O Two CD B-NP homologues NNS I-NP of IN B-PP the DT B-NP rhombotin NN I-NP gene NN I-NP have VBP B-VP now RB I-VP been VBN I-VP isolated VBN I-VP . . O One CD B-NP of IN B-PP these DT B-NP COMMA COMMA O designated VBN B-VP Rhom-2 NN B-NP COMMA COMMA O is VBZ B-VP located JJ B-ADJP on IN B-PP human JJ B-NP chromosome NN I-NP 11 CD I-NP at IN B-PP band NN B-NP 11p13 NN I-NP COMMA COMMA O where WRB B-ADVP a DT B-NP cluster NN I-NP of IN B-PP T-cell NN B-NP leukemia-specific JJ I-NP translocations NNS I-NP occur VBP B-VP ; : O all DT B-NP translocation NN I-NP breakpoints NNS I-NP at IN B-PP 11p13 NN B-NP are VBP B-VP upstream JJ B-ADJP of IN B-PP the DT B-NP Rhom-2 NN I-NP gene NN I-NP . . O Human JJ O and CC O mouse NN B-NP Rhom-2 NN B-NP are VBP B-VP highly RB I-VP conserved VBN I-VP and CC O COMMA COMMA O like IN B-PP rhombotin NN B-NP COMMA COMMA O encode VBP B-VP two CD B-NP tandem JJ I-NP cysteine-rich JJ I-NP LIM NN I-NP domains NNS I-NP . . O Rhom-2 NN B-NP mRNA NN I-NP is VBZ B-VP expressed VBN I-VP in IN B-PP early JJ B-NP mouse NN I-NP development NN I-NP in IN B-PP central JJ B-NP nervous JJ I-NP system NN I-NP COMMA COMMA O lung NN B-NP COMMA COMMA O kidney NN B-NP COMMA COMMA O liver NN B-NP COMMA COMMA O and CC O spleen NN B-NP but CC O only RB B-NP very RB I-NP low JJ I-NP levels NNS I-NP occur VBP B-VP in IN B-PP thymus NN B-NP . . O The DT B-NP other JJ I-NP gene NN I-NP COMMA COMMA O designated VBN B-VP Rhom-3 NN B-NP COMMA COMMA O is VBZ B-VP not RB O on IN B-PP chromosome NN B-NP 11 CD I-NP but CC B-CONJP also RB I-CONJP retains VBZ B-VP homology NN B-NP to TO B-PP the DT B-NP LIM NN I-NP domain NN I-NP of IN B-PP rhombotin NN B-NP . . O Since IN B-SBAR the DT B-NP Rhom-2 NN I-NP gene NN I-NP is VBZ B-VP such JJ B-NP a DT I-NP common JJ I-NP site NN I-NP of IN B-PP chromosomal JJ B-NP damage NN I-NP in IN B-PP T-cell NN B-NP tumors NNS I-NP COMMA COMMA O the DT B-NP consistency NN I-NP of IN B-PP translocations NNS B-NP near IN B-PP the DT B-NP rhombotin NN I-NP gene NN I-NP was VBD B-VP further RB I-VP examined VBN I-VP . . O A DT B-NP second JJ I-NP translocation NN I-NP adjacent JJ B-ADJP to TO B-PP rhombotin NN B-NP was VBD B-VP found VBN B-VP and CC O at IN B-PP the DT B-NP same JJ I-NP position NN I-NP as IN B-PP in IN B-PP the DT B-NP previous JJ I-NP example NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O chromosome NN B-NP bands NNS I-NP 11p15 NN B-NP ( ( O rhombotin NN B-NP ) ) O and CC O 11p13 NN B-NP ( ( O Rhom-2 NN B-NP ) ) O are VBP B-VP consistent JJ B-NP sites NNS I-NP of IN B-PP chromosome NN B-NP translocation NN I-NP in IN B-PP T-cell NN B-NP leukemia NN I-NP COMMA COMMA O with IN B-SBAR the DT B-NP 11p15 NN I-NP target NN I-NP more RBR B-VP rarely RB I-VP involved VBN I-VP . . O The DT B-NP results NNS I-NP define VBP B-VP the DT B-NP rhombotin NN I-NP gene NN I-NP family NN I-NP as IN B-PP a DT B-NP class NN I-NP of IN B-PP T-cell NN B-NP oncogenes NNS I-NP with IN B-PP duplicated JJ B-NP cysteine-rich JJ I-NP LIM NN I-NP domains NNS I-NP . . O The DT B-NP human JJ I-NP myelomonocytic JJ I-NP cell NN I-NP line NN I-NP U-937 NN I-NP as IN B-PP a DT B-NP model NN I-NP for IN B-PP studying VBG B-VP alterations NNS B-NP in IN B-PP steroid-induced JJ B-NP monokine NN I-NP gene NN I-NP expression NN I-NP : : O marked JJ B-NP enhancement NN I-NP of IN B-PP lipopolysaccharide-stimulated JJ B-NP interleukin-1 NN I-NP beta NN I-NP messenger NN I-NP RNA NN I-NP levels NNS I-NP by IN B-PP 1COMMA25-dihydroxyvitamin NN B-NP D3 NN I-NP . . O The DT B-NP active JJ I-NP metabolite NN I-NP of IN B-PP vitamin NN B-NP D NN I-NP COMMA COMMA O 1COMMA25-dihydroxyvitamin NN B-NP D3 NN I-NP { ( O 1COMMA25-(OH)2D3 NN B-NP } ) O COMMA COMMA O is VBZ B-VP a DT B-NP potent JJ I-NP regulator NN I-NP of IN B-PP human JJ B-NP monocyte\/macrophage JJ I-NP function NN I-NP in FW B-ADVP vitro FW I-ADVP . . O To TO B-VP establish VB I-VP a DT B-NP model NN I-NP for IN B-PP 1COMMA25-(OH)2D3 NN B-NP regulation NN I-NP of IN B-PP human JJ B-NP monocyte NN I-NP monokine NN I-NP synthesis NN I-NP COMMA COMMA O three CD B-NP human JJ I-NP cell NN I-NP lines NNS I-NP ( ( O U-937 NN B-NP COMMA COMMA O THP-1 NN B-NP COMMA COMMA O and CC O HL-60 NN B-NP ) ) O were VBD B-VP examined VBN I-VP for IN B-PP : : O 1 LS B-LST ) ) O the DT B-NP presence NN I-NP of IN B-PP functional JJ B-NP 1COMMA25-(OH)2D3 NN I-NP receptors NNS I-NP ; : O 2 LS B-LST ) ) O the DT B-NP accumulation NN I-NP of IN B-PP interleukin-1 NN B-NP beta NN I-NP ( ( O IL-1 NN B-NP beta NN I-NP ) ) O mRNA NN B-NP and CC O IL-1 NN B-NP beta NN I-NP protein NN I-NP in IN B-PP response NN I-PP to TO I-PP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O ; : O and CC O 3 LS B-LST ) ) O the DT B-NP regulation NN I-NP of IN B-PP this DT B-NP response NN I-NP by IN B-PP 1COMMA25-(OH)2D3 NN B-NP . . O All DT B-NP three CD I-NP cell NN I-NP lines NNS I-NP expressed VBD B-VP vitamin NN B-NP D NN I-NP receptor NN I-NP and CC O had VBD B-VP increased VBN I-VP levels NNS B-NP of IN B-PP IL-1 NN B-NP beta NN I-NP mRNA NN I-NP in IN B-PP response NN I-PP to TO I-PP LPS NN B-NP . . O Preincubation NN B-NP of IN B-PP cells NNS B-NP with IN B-PP 1COMMA25-(OH)2D3 NN B-NP augmented VBD B-VP IL-1 NN B-NP beta NN I-NP mRNA NN I-NP levels NNS I-NP only RB B-PP in IN I-PP U-937 NN B-NP and CC O HL-60 NN B-NP cells NNS B-NP . . O From IN B-PP these DT B-NP data NNS I-NP COMMA COMMA O and CC O taking VBG B-VP into IN B-PP consideration NN B-NP their PRP$ B-NP state NN B-NP of IN B-PP differentiation NN B-NP and CC O relative JJ B-NP ease NN I-NP of IN B-PP culture NN B-NP COMMA COMMA O U-937 NN B-NP was VBD B-VP chosen VBN I-VP over IN B-PP HL-60 NN B-NP and CC O THP-1 NN B-NP as IN B-PP the DT B-NP cell NN I-NP line NN I-NP we PRP B-NP further RB B-ADVP characterized VBD B-VP . . O In IN B-PP U-937 NN B-NP cells NNS I-NP COMMA COMMA O optimum JJ B-NP time NN B-NP and CC O dose NN B-NP of IN B-PP pretreatment NN B-NP with IN B-PP 1COMMA25-(OH)2D3 NN B-NP were VBD B-VP determined VBN I-VP to TO I-VP be VB I-VP 12-24 CD B-NP h NN I-NP at IN B-PP a DT B-NP receptor NN I-NP saturating JJ I-NP concentration NN I-NP of IN B-PP 1COMMA25-(OH)2D3 NN B-NP ( ( O 10 CD B-NP nM NN I-NP ) ) O . . O Preincubation NN B-NP of IN B-PP cells NNS B-NP with IN B-PP 1COMMA25-(OH)2D3 NN B-NP had VBD B-VP no DT B-NP effect NN I-NP on IN B-PP the DT B-NP time NN I-NP course NN I-NP of IN B-PP IL-1 NN B-NP beta NN I-NP mRNA NN I-NP appearance NN I-NP in IN B-PP response NN I-PP to TO I-PP LPS NN B-NP . . O However RB B-ADVP COMMA COMMA O exposure NN B-NP of IN B-PP U-937 NN B-NP cells NNS I-NP to TO B-PP 1COMMA25-(OH)2D3 NN B-NP increased VBD B-VP by IN B-PP 200 CD B-NP % NN I-NP the DT B-NP level NN I-NP of IN B-PP IL-1 NN B-NP beta NN I-NP mRNA NN I-NP detected VBD B-VP and CC O decreased VBD B-VP by IN B-PP three CD B-NP orders NNS I-NP of IN B-PP magnitude NN B-NP the DT B-NP concentration NN I-NP of IN B-PP LPS NN B-NP required VBN B-VP to TO I-VP achieve VB I-VP steady JJ B-NP state NN I-NP mRNA NN I-NP levels NNS I-NP equivalent JJ B-ADJP to TO B-PP those DT B-NP observed VBN B-VP in IN B-PP U-937 NN B-NP cells NNS I-NP not RB B-VP preincubated VBN I-VP with IN B-PP the DT B-NP hormone.2+o NN I-NP Cortivazol NN B-NP mediated VBD I-NP induction NN I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP messenger NN I-NP ribonucleic JJ I-NP acid NN I-NP in IN B-PP wild-type JJ B-NP and CC I-NP dexamethasone-resistant JJ I-NP human JJ I-NP leukemic NN I-NP ( ( I-NP CEM NN I-NP ) ) I-NP cells NNS I-NP . . O Cortivazol NN B-NP is VBZ B-VP a DT B-NP phenylpyrazolo JJ I-NP glucocorticoid NN I-NP of IN B-PP high JJ B-NP potency NN I-NP and CC O unusual JJ B-NP structure NN I-NP . . O In IN B-PP both CC O wild-type JJ O and CC O highly RB O dexamethasone NN B-NP ( ( O dex NN B-NP ) ) O -resistant JJ B-NP clones NNS I-NP of IN B-PP the DT B-NP human JJ I-NP leukemic JJ I-NP cell NN I-NP line NN I-NP CEM NN I-NP COMMA COMMA O exposure NN B-NP to TO B-PP cortivazol NN B-NP leads VBZ B-VP to TO B-PP cell NN B-NP death NN I-NP . . O It PRP B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP recently RB B-ADVP that IN B-SBAR in IN B-PP wild-type JJ B-NP CEM NN I-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP a DT B-NP dex-resistant JJ I-NP COMMA COMMA I-NP glucocorticoid NN I-NP receptor NN I-NP ( ( I-NP GR NN I-NP ) ) I-NP -defective JJ I-NP clone NN I-NP ICR-27 NN I-NP TK-3 NN I-NP COMMA COMMA O dex NN B-NP induces VBZ B-VP GR NN B-NP mRNA NN I-NP . . O To TO B-VP test VB I-VP the DT B-NP hypothesis NN I-NP that IN B-SBAR cortivazol NN B-NP acts VBZ B-VP in IN B-PP dex-resistant JJ B-NP cells NNS I-NP by IN B-PP making VBG B-VP use NN B-NP of IN B-PP the DT B-NP residual JJ I-NP GR NN I-NP found VBN B-VP there RB B-ADVP COMMA COMMA O wild-type JJ B-NP and CC I-NP dex-resistant JJ I-NP clones NNS I-NP were VBD B-VP treated VBN I-VP with IN B-PP various JJ B-NP concentrations NNS I-NP of IN B-PP cortivazol NN B-NP and CC O induction NN B-NP of IN B-PP GR NN B-NP mRNA NN I-NP was VBD B-VP studied VBN I-VP . . O Cortivazol NN B-NP significantly RB B-ADVP induced VBD B-VP GR NN B-NP mRNA NN I-NP in IN B-PP the DT B-NP normal JJ I-NP CEM-C7 NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP two CD B-NP classes NNS I-NP of IN B-PP dex-resistant JJ B-NP clones NNS I-NP COMMA COMMA O although IN B-SBAR the DT B-NP dex-resistant JJ I-NP clones NNS I-NP needed VBD B-VP at IN B-NP least JJS I-NP 10 CD I-NP times NNS I-NP more JJR I-NP cortivazol NN I-NP than IN B-PP the DT B-NP normal JJ I-NP cells NNS I-NP for IN B-PP significant JJ B-NP GR NN I-NP mRNA NN I-NP induction NN I-NP . . O Increased VBN B-NP levels NNS I-NP of IN B-PP GR NN B-NP mRNA NN I-NP were VBD B-VP noticed VBN I-VP as RB B-ADVP early RB I-ADVP as IN B-PP 3 CD B-NP h NN I-NP after IN B-PP treatment NN B-NP . . O A DT B-NP general JJ I-NP correlation NN I-NP between IN B-PP induction NN B-NP of IN B-PP GR NN B-NP mRNA NN I-NP and CC O lysis NN B-NP of IN B-PP the DT B-NP normal JJ I-NP and CC I-NP dex-resistant JJ I-NP cells NNS I-NP was VBD B-VP found VBN I-VP . . O Positive JJ B-NP induction NN I-NP of IN B-PP GR NN B-NP mRNA NN I-NP might MD B-VP be VB I-VP one CD B-NP of IN B-PP the DT B-NP earliest JJS I-NP crucial JJ I-NP steps NNS I-NP in IN B-PP the DT B-NP lysis NN I-NP of IN B-PP normal JJ B-NP and CC I-NP dex-resistant JJ I-NP CEM NN I-NP cells NNS I-NP COMMA COMMA O or CC O might MD B-VP serve VB I-VP as IN B-PP a DT B-NP marker NN I-NP for IN B-PP the DT B-NP process NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP lysis NN I-NP pathway NN I-NP in IN B-PP the DT B-NP dex-resistant JJ I-NP cells NNS I-NP is VBZ B-VP defective JJ B-ADJP in IN B-PP that IN B-SBAR dex-resistant JJ B-NP clones NNS I-NP needed VBD B-VP significantly RB B-NP more JJR I-NP cortivazol NN I-NP than IN B-PP the DT B-NP normal JJ I-NP cells NNS I-NP for IN B-PP lysis NN B-NP of IN B-PP the DT B-NP cells NNS I-NP . . O Expression NN B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP on IN B-PP alveolar JJ B-NP lymphocytes NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP pulmonary JJ B-NP granulomatous JJ I-NP diseases NNS I-NP . . O 1COMMA25(OH)2D3 NN B-NP is VBZ B-VP known VBN I-VP to TO I-VP be VB I-VP produced VBN I-VP at IN B-PP sites NNS B-NP of IN B-PP granulomatous JJ B-NP reactions NNS I-NP . . O In IN B-SBAR order NN O to TO O characterize VB B-VP the DT B-NP cell NN I-NP types NNS I-NP that WDT B-NP are VBP B-VP targets NNS B-NP for IN B-PP this DT B-NP immunoregulatory JJ I-NP hormone NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP evaluated VBN I-VP the DT B-NP expression NN I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP on IN B-PP peripheral JJ B-NP blood NN I-NP T-lymphocytes NNS I-NP and CC O those DT B-NP recovered VBN B-VP from IN B-PP the DT B-NP lung NN I-NP by IN B-PP bronchoalveolar JJ B-NP lavage NN I-NP from IN B-PP patients NNS B-NP with IN B-PP pulmonary JJ B-NP granulomatous JJ I-NP diseases NNS I-NP ( ( O tuberculosis NN B-NP and CC O sarcoidosis NN B-NP ) ) O and CC B-PP from IN B-PP normal JJ B-NP control NN I-NP subjects NNS I-NP using VBG B-VP combined JJ B-NP autoradiographic JJ I-NP and CC I-NP immunohistochemical JJ I-NP techniques NNS I-NP . . O Lavage NN B-NP T-lymphocytes NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP tuberculosis NN B-NP or CC B-PP with IN B-PP sarcoidosis NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP those DT B-NP from IN B-PP normal JJ B-NP control NN I-NP subjects NNS I-NP COMMA COMMA O expressed VBD B-VP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP as IN B-SBAR demonstrated VBN B-VP by IN B-PP binding NN B-NP of IN B-PP {3H}1COMMA25(OH)2D3 NN B-NP COMMA COMMA O which WDT B-NP was VBD B-VP inhibited VBN I-VP by IN B-PP the DT B-NP presence NN I-NP of IN B-PP excess JJ B-NP unlabeled JJ I-NP 1COMMA25(OH)2D3 NN I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP by IN I-PP the DT B-NP presence NN I-NP of IN B-PP unlabeled JJ B-NP 25(OH)D3 NN I-NP ( ( O receptor-positive JJ B-NP lymphocytes NNS I-NP : : O sarcoidosis NN B-NP COMMA COMMA O 20 CD B-NP +\/- CC I-NP 12 CD I-NP % NN I-NP ; : O tuberculosis NN B-NP COMMA COMMA O 31 CD B-NP +\/- CC I-NP 17 CD I-NP % NN I-NP ) ) O . . O In IN B-PP contrast NN B-NP COMMA COMMA O blood NN B-NP lymphocytes NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP granulomatous JJ B-NP diseases NNS I-NP did VBD B-VP not RB I-VP express VB I-VP detectable JJ B-NP 1COMMA25(OH)2D3 NN I-NP receptors NNS I-NP . . O The DT B-NP percentage NN I-NP of IN B-PP lavage NN B-NP T-lymphocytes NNS I-NP expressing VBG B-VP 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP was VBD B-VP significantly RB B-ADJP greater JJR I-ADJP for IN B-PP patients NNS B-NP with IN B-PP tuberculosis NN B-NP presenting VBG B-VP with IN B-PP isolated VBN B-NP hilar JJ I-NP adenopathy JJ I-NP than IN B-PP for IN B-PP patients NNS B-NP with IN B-PP pulmonary JJ B-NP infiltrates NNS B-NP and\/or CC O cavities NNS B-NP . . O 1COMMA25(OH)2D3 NN B-NP receptors NNS I-NP were VBD B-VP expressed VBN I-VP to TO B-PP a DT B-NP greater JJR I-NP extent NN I-NP on IN B-PP CD8+ JJ B-NP T-lymphocytes NNS I-NP than IN B-PP on IN B-PP CD4+ JJ B-NP T-lymphocytes NNS I-NP in IN B-PP sarcoidosis NN B-NP COMMA COMMA O whereas IN O a DT B-NP greater JJR I-NP proportion NN I-NP of IN B-PP CD4+ JJ B-NP than IN B-PP of IN B-PP CD8+ JJ B-NP T-lymphocytes NNS B-NP from IN B-PP patients NNS B-NP with IN B-PP tuberculosis NN B-NP were VBD B-VP receptor-positive JJ B-ADJP . . O These DT B-NP findings NNS I-NP support VBP B-VP the DT B-NP conclusion NN I-NP that IN B-SBAR the DT B-NP interaction NN I-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP with IN B-PP its PRP$ B-NP receptor NN I-NP on IN B-PP T-lymphocytes NNS B-NP may MD B-VP play VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP granulomatous JJ B-NP reactions NNS I-NP COMMA COMMA O but CC O because IN B-SBAR these DT B-NP receptors NNS I-NP are VBP B-VP expressed VBN I-VP on IN B-PP different JJ B-NP lymphocyte NN I-NP populations NNS I-NP COMMA COMMA O the DT B-NP net JJ I-NP effect NN I-NP of IN B-PP this DT B-NP potent JJ I-NP immunoregulatory JJ I-NP molecule NN I-NP is VBZ B-VP likely RB B-ADJP different JJ I-ADJP in IN B-PP sarcoidosis NN B-NP and CC O tuberculosis NN B-NP . . O Inhibition NN B-NP of IN B-PP transcription NN B-NP factors NNS I-NP belonging VBG B-VP to TO B-PP the DT B-NP rel\/NF-kappa NN I-NP B NN I-NP family NN I-NP by IN B-PP a DT B-NP transdominant JJ I-NP negative JJ I-NP mutant NN I-NP . . O The DT B-NP KBF1 NN I-NP factor NN I-NP COMMA COMMA O which WDT B-NP binds VBZ B-VP to TO B-PP the DT B-NP enhancer NN I-NP A NN I-NP located JJ B-VP in IN B-PP the DT B-NP promoter NN I-NP of IN B-PP the DT B-NP mouse NN I-NP MHC NN I-NP class NN I-NP I CD I-NP gene NN I-NP H-2Kb NN I-NP COMMA COMMA O is VBZ B-VP indistinguishable JJ B-ADJP from IN B-PP the DT B-NP p50 NN I-NP DNA NN I-NP binding NN I-NP subunit NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP COMMA COMMA O which WDT B-NP regulates VBZ B-VP a DT B-NP series NN I-NP of IN B-PP genes NNS B-NP involved VBN B-VP in IN B-PP immune JJ B-NP and CC I-NP inflammatory JJ I-NP responses NNS I-NP . . O The DT B-NP KBF1\/p50 NN I-NP factor NN I-NP binds VBZ B-VP as IN B-PP a DT B-NP homodimer NN I-NP but CC O can MD B-VP also RB I-VP form VB I-VP heterodimers NNS B-NP with IN B-PP the DT B-NP products NNS I-NP of IN B-PP other JJ B-NP members NNS I-NP of IN B-PP the DT B-NP same JJ I-NP family NN I-NP COMMA COMMA O like IN B-PP the DT O c-rel NN B-NP and CC O v-rel NN B-NP ( ( B-NP proto NN I-NP ) ) I-NP oncogenes NNS I-NP . . O The DT B-NP dimerization NN I-NP domain NN I-NP of IN B-PP KBF1\/p50 NN B-NP is VBZ B-VP contained VBN I-VP between IN B-PP amino NN B-NP acids NNS I-NP 201 CD B-NP and CC O 367 CD B-NP . . O A DT B-NP mutant NN I-NP of IN B-PP KBF1\/p50 NN B-NP ( ( I-NP delta NN I-NP SP NN I-NP ) ) O COMMA COMMA O unable JJ B-ADJP to TO B-VP bind VB I-VP to TO B-PP DNA NN B-NP but CC O able JJ B-ADJP to TO B-VP form VB I-VP homo- JJ B-NP or CC O heterodimers NNS B-NP COMMA COMMA O has VBZ B-VP been VBN I-VP constructed VBN I-VP . . O This DT B-NP protein NN I-NP reduces VBZ B-VP or CC O abolishes VBZ B-VP in FW B-ADVP vitro FW I-ADVP the DT B-NP DNA NN I-NP binding NN I-NP activity NN I-NP of IN B-PP wild-type JJ B-NP proteins NNS I-NP of IN B-PP the DT B-NP same JJ I-NP family NN I-NP ( ( O KBF1\/p50 NN B-NP COMMA COMMA O c- NN B-NP and CC O v-rel NN B-NP ) ) O . . O This DT B-NP mutant JJ I-NP also RB B-ADVP functions NNS B-VP in FW B-ADVP vivo FW I-ADVP as IN B-PP a DT B-NP trans-acting JJ I-NP dominant JJ I-NP negative JJ I-NP regulator NN I-NP : : O the DT B-NP transcriptional JJ I-NP inducibility NN I-NP of IN B-PP the DT B-NP HIV NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP ( ( O which WDT B-NP contains VBZ B-VP two CD B-NP potential JJ I-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP sites NNS I-NP ) ) O by IN B-PP phorbol NN B-NP ester NN I-NP ( ( O PMA NN B-NP ) ) O is VBZ B-VP inhibited VBN I-VP when WRB B-ADVP it PRP B-NP is VBZ B-VP co-transfected VBN I-VP into IN B-PP CD4+ JJ B-NP T NN I-NP cells NNS I-NP with IN B-PP the DT B-NP delta NN I-NP SP NN I-NP mutant NN I-NP . . O Similarly RB B-ADVP the DT O basal JJ O as RB B-CONJP well RB I-CONJP as IN I-CONJP TNF NN B-NP or CC O IL1-induced JJ B-ADJP activity NN B-NP of IN B-PP the DT B-NP MHC NN I-NP class NN I-NP I CD I-NP H-2Kb NN I-NP promoter NN I-NP can MD B-VP be VB I-VP inhibited VBN I-VP by IN B-PP this DT B-NP mutant NN I-NP in IN B-PP two CD B-NP different JJ I-NP cell NN I-NP lines NNS I-NP . . O These DT B-NP results NNS I-NP constitute VBP B-VP the DT B-NP first JJ I-NP formal JJ I-NP demonstration NN I-NP that IN B-SBAR these DT B-NP genes NNS I-NP are VBP B-VP regulated VBN I-VP by IN B-PP members NNS B-NP of IN B-PP the DT B-NP rel\/NF-kappa NN I-NP B NN I-NP family NN I-NP . . O Human JJ B-NP erythroid JJ I-NP 5-aminolevulinate NN I-NP synthase NN I-NP : : O promoter NN B-NP analysis NN I-NP and CC O identification NN B-NP of IN B-PP an DT B-NP iron-responsive JJ I-NP element NN I-NP in IN B-PP the DT B-NP mRNA NN I-NP . . O 5-Aminolevulinate NN B-NP synthase NN I-NP ( ( O ALAS NN B-NP ) ) O catalyzes VBZ B-VP the DT B-NP first JJ I-NP step NN I-NP of IN B-PP the DT B-NP heme NN I-NP biosynthetic JJ I-NP pathway NN I-NP . . O cDNA NN B-NP clones NNS I-NP for IN B-PP the DT B-NP human JJ I-NP erythroid JJ I-NP ALAS NN I-NP isozyme NN I-NP were VBD B-VP isolated VBN I-VP from IN B-PP a DT B-NP fetal JJ I-NP liver NN I-NP library NN I-NP . . O It PRP B-NP can MD B-VP be VB I-VP deduced VBN I-VP that IN B-SBAR the DT B-NP erythroid JJ I-NP ALAS NN I-NP precursor NN I-NP protein NN I-NP has VBZ B-VP a DT B-NP molecular JJ I-NP weight NN I-NP of IN B-PP 64.6 CD B-NP kd NN I-NP COMMA COMMA O and CC O is VBZ B-VP similar JJ B-ADJP in IN B-PP size NN B-NP to TO B-PP the DT B-NP previously RB I-NP isolated VBN I-NP human JJ I-NP housekeeping JJ I-NP ALAS NN I-NP precursor NN I-NP of IN B-PP molecular JJ B-NP weight NN I-NP 70.6 CD I-NP kd NN I-NP . . O The DT B-NP mature JJ I-NP mitochondrial JJ I-NP forms NNS I-NP of IN B-PP the DT O erythroid JJ O and CC O housekeeping JJ B-NP ALAS NN B-NP isozymes NNS I-NP are VBP B-VP predicted VBN I-VP to TO I-VP have VB I-VP molecular JJ B-NP weights NNS I-NP of IN B-PP 59.5 CD B-NP kd NN I-NP and CC O 64.6 CD B-NP kd NN I-NP COMMA COMMA O respectively RB B-ADVP . . O The DT B-NP two CD I-NP isozymes NNS I-NP show VBP B-VP little JJ B-NP amino NN I-NP acid NN I-NP identity NN I-NP in IN B-PP their PRP$ B-NP N-terminal JJ I-NP signal NN I-NP sequences NNS I-NP but CC O have VBP B-VP considerable JJ B-NP sequence NN I-NP identity NN I-NP in IN B-PP the DT B-NP C-terminal JJ I-NP two-thirds CD I-NP of IN B-PP their PRP$ B-NP proteins NNS I-NP . . O An DT B-NP analysis NN I-NP of IN B-PP the DT B-NP immediate JJ I-NP promoter NN I-NP of IN B-PP the DT B-NP human JJ I-NP erythroid JJ I-NP ALAS NN I-NP gene NN I-NP revealed VBD B-VP several JJ B-NP putative JJ I-NP erythroid-specific JJ I-NP cis-acting JJ I-NP elements NNS I-NP including VBG B-PP both PDT O a DT B-NP GATA-1 NN I-NP and CC O an DT B-NP NF-E2 NN I-NP binding NN B-NP site NN I-NP . . O An DT O iron-responsive JJ B-NP element NN I-NP ( ( O IRE NN B-NP ) ) O motif NN B-NP has VBZ B-VP been VBN I-VP identified VBN I-VP in IN B-PP the DT B-NP 5'-untranslated JJ I-NP region NN I-NP of IN B-PP the DT B-NP human JJ I-NP erythroid JJ I-NP ALAS NN I-NP mRNA NN I-NP COMMA COMMA O but CC O is VBZ B-VP not RB O present JJ B-ADJP in IN B-PP the DT B-NP housekeeping JJ I-NP ALAS NN I-NP mRNA NN I-NP . . O Gel NN B-NP retardation NN I-NP experiments NNS I-NP established VBD B-VP that IN B-SBAR this DT B-NP IRE NN I-NP motif NN I-NP formed VBD B-VP a DT O protein-RNA JJ B-NP complex NN B-NP with IN B-PP cytosolic JJ B-NP extracts NNS I-NP from IN B-PP human JJ B-NP K562 NN I-NP cells NNS I-NP and CC O this DT B-NP binding NN I-NP was VBD B-VP strongly RB I-VP competed VBN I-VP with IN B-PP IRE NN B-NP transcripts NNS I-NP from IN B-PP ferritin NN B-NP or CC O transferrin NN B-NP receptor NN B-NP mRNAs NNS B-NP . . O A DT B-NP transcript NN I-NP of IN B-PP the DT B-NP ALAS NN I-NP IRE NN I-NP COMMA COMMA O mutated VBN B-VP in IN B-PP the DT B-NP conserved VBN I-NP loop NN I-NP of IN B-PP the DT B-NP IRE NN I-NP COMMA COMMA O did VBD B-VP not RB I-VP readily RB I-VP form VB I-VP this DT O protein-RNA JJ B-NP complex NN B-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP IRE NN I-NP motif NN I-NP in IN B-PP the DT B-NP ALAS NN I-NP mRNA NN I-NP is VBZ B-VP functional JJ B-ADJP and CC O imply VBP B-VP that IN B-SBAR translation NN B-NP of IN B-PP the DT B-NP mRNA NN I-NP is VBZ B-VP controlled VBN I-VP by IN B-PP cellular JJ B-NP iron NN I-NP availability NN I-NP during IN B-PP erythropoiesis NN B-NP . . O Human JJ B-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP gene NN I-NP regulation NN I-NP in IN B-PP phorbol NN B-NP ester NN I-NP stimulated VBD I-NP T NN I-NP and CC I-NP B NN I-NP cell NN I-NP lines NNS I-NP . . O The DT B-NP minimal JJ I-NP region NN I-NP of IN B-PP the DT B-NP human JJ I-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( I-NP TNF-alpha NN I-NP ) ) I-NP gene NN I-NP promoter NN I-NP necessary JJ B-ADJP for IN B-PP its PRP$ B-NP transcriptional JJ I-NP induction NN I-NP by IN B-PP phorbol NN B-NP esters NNS I-NP ( ( O PMA NN B-NP ) ) O in IN B-PP human JJ B-NP T NN I-NP and CC I-NP B NN I-NP lymphocyte NN I-NP cell NN I-NP lines NNS I-NP has VBZ B-VP been VBN I-VP localized JJ I-VP between IN B-PP -52 CD B-NP and CC O +89 CD B-NP nucleotides NNS B-NP ( ( O nt NN B-NP ) ) O relative JJ B-ADVP to TO B-PP the DT B-NP gene NN I-NP 's POS B-NP transcriptional JJ I-NP start NN I-NP site NN I-NP . . O Comparison NN B-NP of IN B-PP these DT B-NP sequences NNS I-NP to TO B-PP those DT B-NP required VBN B-VP to TO B-VP mediate VB I-VP virus NN B-NP or CC O lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O induction NN B-NP of IN B-PP the DT B-NP gene NN I-NP reveal VB B-VP significant JJ B-NP differences NNS I-NP COMMA COMMA O and CC O thus RB O COMMA COMMA O the DT B-NP sequence NN I-NP requirements NNS I-NP for IN B-PP PMA NN B-NP induction NN I-NP are VBP B-VP distinct JJ B-ADJP from IN B-PP those DT B-NP that WDT B-NP mediate VBP B-VP induction NN B-NP by IN B-PP virus NN B-NP or CC O LPS NN B-NP . . O Although IN B-SBAR three CD B-NP sites NNS I-NP in IN B-PP the DT B-NP TNF-alpha NN I-NP promoter NN I-NP ( ( O kappa NN B-NP 1 CD I-NP COMMA COMMA O kappa NN B-NP 2 CD I-NP COMMA COMMA O and CC O kappa NN B-NP 3 CD I-NP ) ) O specifically RB B-ADVP bind VBP B-VP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP in IN B-PP lymphoid JJ B-NP nuclear JJ I-NP extracts NNS I-NP COMMA COMMA O TNF-alpha NN B-NP mRNA NN I-NP induction NN I-NP by IN B-PP PMA NN B-NP does VBZ B-VP not RB I-VP correlate VB I-VP with IN B-PP NF-kappa NN B-NP B NN I-NP binding NN I-NP activities NNS I-NP displayed VBN B-VP by IN B-PP different JJ B-NP T NN I-NP and CC I-NP B NN I-NP cell NN I-NP lines NNS I-NP . . O Moreover RB B-ADVP COMMA COMMA O kappa NN B-NP 1 CD I-NP - : O kappa NN B-NP 3 CD I-NP can MD B-VP each DT O be VB B-VP deleted VBN I-VP from IN B-PP the DT B-NP TNF-alpha NN I-NP promoter NN I-NP with IN B-PP little JJ B-NP effect NN I-NP on IN B-PP the DT B-NP gene NN I-NP 's POS B-NP inducibility NN I-NP by IN B-PP PMA NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O TNF-alpha NN B-NP mRNA NN I-NP induction NN I-NP by IN B-PP PMA NN B-NP COMMA COMMA O like IN B-PP its PRP$ B-NP induction NN I-NP by IN B-PP virus NN B-NP and CC O LPS NN B-NP COMMA COMMA O is VBZ B-VP not RB I-VP primarily RB I-VP mediated VBN I-VP by IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O but CC B-CONJP rather RB I-CONJP is VBZ B-VP mediated VBN I-VP through IN B-PP other JJ B-NP sequences NNS B-NP and CC O protein NN B-NP factors NNS I-NP . . O Surprisingly RB B-ADVP COMMA COMMA O multimers NNS B-NP of IN B-PP kappa NN B-NP 1 CD I-NP - : O kappa NN B-NP 3 CD I-NP can MD B-VP confer VB I-VP PMA NN B-NP inducibility NN I-NP on IN B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP in IN B-PP a DT B-NP B NN B-NP ( ( O Raji NN B-NP ) ) O COMMA COMMA O but CC B-CONJP not RB I-CONJP a DT B-NP T NN B-NP ( ( O HUT78 NN B-NP ) ) O cell NN B-NP line NN I-NP . . O However WRB O they PRP B-NP are VBP B-VP not RB O functional JJ B-ADJP on IN B-PP a DT B-NP truncated VBN I-NP TNF-alpha NN I-NP promoter NN I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR promoter NN B-NP context NN I-NP and CC O cell NN B-NP type NN I-NP specificity NN I-NP influence VBP B-VP the DT B-NP PMA NN I-NP inducible JJ I-NP function NN I-NP of IN B-PP these DT B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP sites NNS I-NP . . O Towards IN B-PP a DT B-NP molecular JJ I-NP understanding NN I-NP of IN B-PP T-cell NN B-NP differentiation NN I-NP Lymphoid JJ B-NP differentiation NN I-NP is VBZ B-VP one CD B-NP of IN B-PP the DT B-NP best RBS I-NP studied VBN I-NP examples NNS I-NP of IN B-PP mammalian JJ B-NP development NN I-NP . . O Here RB B-ADVP Hans NNP B-NP Clevers NNP I-NP and CC O Michael NNP B-NP Owen NNP I-NP describe VBP B-VP how WRB B-ADVP the DT B-NP cloning NN I-NP of IN B-PP the DT B-NP genes NNS I-NP that WDT B-NP encode VBP B-VP T-cell-specific JJ I-VP membrane NN I-VP proteins NNS I-VP allows VBZ B-VP the DT B-NP identification NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP that WDT B-NP control VBP B-VP the DT B-NP expression NN I-NP of IN B-PP these DT B-NP T-cell NN I-NP genes NNS I-NP . . O Such JJ B-NP transcription NN I-NP factors NNS I-NP play VBP B-VP a DT B-NP key JJ I-NP role NN I-NP in IN B-PP the DT B-NP development NN I-NP of IN B-PP the DT B-NP mature JJ I-NP T-cell NN I-NP phenotype NN I-NP by IN B-PP functioning VBG B-VP as IN B-PP ' `` O master JJ B-NP regulators NNS I-NP of IN B-PP T-cell NN B-NP differentiation NN I-NP ' '' O . . O Regulation NN B-NP of IN B-PP jun NN B-NP and CC I-NP fos NN I-NP gene NN I-NP expression NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP by IN B-PP the DT B-NP macrophage NN I-NP colony-stimulating JJ I-NP factor NN I-NP . . O The DT B-NP macrophage NN B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O M-CSF NN B-NP ) ) O is VBZ B-VP required VBN I-VP for IN B-PP the DT B-NP growth NN B-NP and CC O differentiation NN B-NP of IN B-PP mononuclear JJ B-NP phagocytes NNS I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP signaling NN I-NP events NNS I-NP responsible JJ B-ADJP for IN B-PP these DT B-NP effects NNS I-NP remain VBP B-VP unclear JJ B-ADJP . . O The DT B-NP present JJ I-NP studies NNS I-NP have VBP B-VP examined VBN I-VP the DT B-NP effects NNS I-NP of IN B-PP M-CSF NN B-NP on IN B-PP potential JJ B-NP signaling NN I-NP pathways NNS I-NP involving VBG B-VP expression NN B-NP of IN B-PP the DT O jun NN B-NP and CC O fos NN B-NP early JJ B-NP response NN I-NP genes NNS I-NP . . O Low JJ B-NP levels NNS I-NP of IN B-PP c-jun NN B-NP transcripts NNS I-NP were VBD B-VP detectable JJ B-ADJP in IN B-PP resting VBG B-NP human JJ I-NP peripheral JJ I-NP blood NN I-NP monocytes NNS I-NP . . O Treatment NN B-NP of IN B-PP these DT B-NP cells NNS I-NP with IN B-PP 10(3) CD B-NP units\/ml NNS I-NP human JJ I-NP recombinant JJ I-NP M-CSF NN I-NP was VBD B-VP associated VBN I-VP with IN B-PP rapid JJ B-NP and CC I-NP transient JJ I-NP increases NNS I-NP in IN B-PP c-jun NN B-NP mRNA NN I-NP levels NNS I-NP . . O Nuclear JJ B-NP run-on JJ I-NP assays NNS I-NP and CC O mRNA NN B-NP stability NN I-NP studies NNS I-NP demonstrated VBD B-VP that IN B-SBAR M-CSF NN B-NP regulates VBZ B-VP c-jun NN B-NP expression NN I-NP by IN B-PP both CC O an DT B-NP increase NN I-NP in IN B-PP transcription NN B-NP rate NN I-NP and CC O a DT B-NP prolongation NN I-NP in IN B-PP the DT B-NP half-life NN I-NP of IN B-PP c-jun NN B-NP transcripts NNS I-NP . . O M-CSF NN B-NP treatment NN I-NP was VBD B-VP also RB I-VP associated VBN I-VP with IN B-PP a DT B-NP rapid JJ I-NP induction NN I-NP of IN B-PP the DT B-NP jun-B NN I-NP gene NN I-NP COMMA COMMA O although IN B-SBAR expression NN B-NP of IN B-PP this DT B-NP gene NN I-NP was VBD B-VP prolonged JJ I-VP compared VBN B-VP to TO B-PP that DT B-NP of IN B-PP c-jun NN B-NP . . O We PRP B-NP further RB B-ADVP demonstrate VBP B-VP that IN B-SBAR M-CSF NN B-NP increases VBZ B-VP c-fos NN B-NP mRNA NN I-NP levels NNS I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP through IN B-PP control NN B-NP at IN B-PP both CC B-NP the DT I-NP transcriptional JJ I-NP and CC I-NP posttranscriptional JJ I-NP levels NNS I-NP . . O Maximal JJ B-NP induction NN I-NP of IN B-PP the DT B-NP c-fos NN I-NP gene NN I-NP was VBD B-VP followed VBN I-VP by IN B-PP that DT B-NP for IN B-PP the DT B-NP fos-B NN I-NP gene NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O M-CSF-induced JJ B-NP expression NN I-NP of IN B-PP the DT B-NP fos-related JJ I-NP gene NN I-NP COMMA COMMA O fra-1 NN B-NP COMMA COMMA O was VBD B-VP delayed VBN I-VP compared VBN B-VP to TO B-PP that DT B-NP for IN B-PP both DT B-NP c-fos NN B-NP and CC O fos-B NN B-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O the DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR M-CSF NN B-NP treatment NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP differential JJ B-NP activation NN I-NP of IN B-PP multiple JJ B-NP members NNS I-NP of IN B-PP the DT B-NP jun\/fos NN I-NP family NN I-NP and CC O that IN B-SBAR expression NN B-NP of IN B-PP these DT B-NP genes NNS I-NP could MD B-VP contribute VB I-VP to TO B-PP nuclear JJ B-NP signaling NN I-NP mechanisms NNS I-NP that WDT B-NP regulate VBP B-VP a DT B-NP specific JJ I-NP program NN I-NP of IN B-PP monocyte NN B-NP differentiation NN I-NP . . O Cloning NN B-NP of IN B-PP a DT B-NP human JJ I-NP homeobox NN I-NP gene NN I-NP that WDT B-NP resembles VBZ B-VP a DT B-NP diverged JJ I-NP Drosophila NN I-NP homeobox NN I-NP gene NN I-NP and CC O is VBZ B-VP expressed VBN I-VP in IN B-PP activated VBN B-NP lymphocytes NNS I-NP . . O A DT B-NP new JJ I-NP homeobox NN I-NP gene NN I-NP COMMA COMMA O HB24 NN B-NP COMMA COMMA O has VBZ B-VP been VBN I-VP isolated VBN I-VP from IN B-PP a DT B-NP human JJ I-NP B-lymphocyte NN I-NP cDNA NN I-NP library NN I-NP . . O Northern JJ B-NP blot NN I-NP analysis NN I-NP of IN B-PP polyadenylated JJ B-NP RNA NN I-NP purified VBN B-VP from IN B-PP activated VBN B-NP human JJ I-NP B NN I-NP cells NNS I-NP revealed VBD B-VP a DT B-NP single JJ I-NP mRNA NN I-NP transcript NN I-NP of IN B-PP approximately RB B-NP 2.3 CD I-NP kb NN I-NP . . O Two CD B-NP cDNA NN I-NP clones NNS I-NP were VBD B-VP sequenced VBN I-VP and CC O provided VBN B-VP 2COMMA250 CD B-NP nucleotides NNS B-NP ( ( O nt NN B-NP ) ) O of IN B-PP DNA NN B-NP sequence NN I-NP information NN I-NP . . O There EX B-NP is VBZ B-VP a DT B-NP single JJ I-NP methionine NN I-NP codon-initiated JJ I-NP open JJ I-NP reading NN I-NP frame NN I-NP of IN B-PP 1COMMA458 CD B-NP nt NN I-NP in IN B-PP frame NN B-NP with IN B-PP a DT B-NP homeobox NN I-NP and CC O a DT B-NP CAX NN I-NP repeat NN I-NP COMMA COMMA O and CC O the DT B-NP open JJ I-NP reading NN I-NP frame NN I-NP is VBZ B-VP predicted VBN I-VP to TO I-VP encode VB I-VP a DT B-NP protein NN I-NP of IN B-PP 51COMMA659 CD B-NP daltons NNS I-NP . . O When WRB B-ADVP the DT B-NP homeodomain NN I-NP from IN B-PP HB24 NN B-NP was VBD B-VP compared VBN I-VP to TO B-PP known JJ O mammalian JJ O and CC O Drosophila NN B-NP homeodomains NNS B-NP it PRP B-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP only RB B-ADJP moderately RB I-ADJP conserved VBN I-ADJP COMMA COMMA O but CC O when WRB B-ADVP it PRP B-NP was VBD B-VP compared VBN I-VP to TO B-PP a DT B-NP highly RB I-NP diverged JJ I-NP Drosophila FW I-NP homeodomain NN I-NP COMMA COMMA O H2.0 NN B-NP COMMA COMMA O it PRP B-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP 80 CD B-NP % NN I-NP identical JJ B-ADJP . . O The DT B-NP HB24 NN I-NP mRNA NN I-NP was VBD B-VP absent JJ B-ADJP or CC O present JJ B-ADJP at IN B-PP low JJ B-NP levels NNS I-NP in IN B-PP normal JJ B-NP B NN B-NP and CC O T NN B-NP lymphocytes NNS B-NP ; : O however RB B-ADVP COMMA COMMA O with IN B-PP the DT B-NP appropriate JJ I-NP activation NN I-NP signal NN I-NP HB24 NN B-NP mRNA NN I-NP was VBD B-VP induced VBN I-VP within IN B-PP several JJ B-NP hours NNS I-NP even RB B-PP in IN I-PP the DT I-PP presence NN I-PP of IN I-PP cycloheximide NN B-NP . . O Characterization NN B-NP of IN B-PP HB24 NN B-NP expression NN I-NP in IN B-PP lymphoid JJ B-NP and CC O select JJ B-NP developing VBG I-NP tissues NNS I-NP was VBD B-VP performed VBN I-VP by IN B-PP in FW B-NP situ FW I-NP hybridization NN I-NP . . O Positive JJ B-NP hybridization NN I-NP was VBD B-VP found VBN I-VP in IN B-PP thymus NN B-NP COMMA COMMA O tonsil NN B-NP COMMA COMMA O bone NN B-NP marrow NN I-NP COMMA COMMA O developing VBG B-NP vessels NNS I-NP COMMA COMMA B-PP and CC I-PP in IN B-PP fetal JJ B-NP brain NN I-NP . . O HB24 NN B-NP is VBZ B-VP likely JJ B-ADJP to TO B-VP have VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP lymphocytes NNS B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP certain JJ B-NP developing VBG I-NP tissues NNS I-NP . . O Severe JJ B-NP 5-fluorouracil NN I-NP toxicity NN I-NP secondary JJ B-ADJP to TO B-PP dihydropyrimidine NN B-NP dehydrogenase NN I-NP deficiency NN I-NP . . O A DT B-NP potentially RB I-NP more RBR I-NP common JJ I-NP pharmacogenetic JJ I-NP syndrome NN I-NP . . O This DT B-NP study NN I-NP describes VBZ B-VP the DT B-NP inheritance NN I-NP of IN B-PP a DT B-NP defect NN I-NP in IN B-PP pyrimidine NN B-NP catabolism NN I-NP and CC O its PRP$ B-NP association NN I-NP with IN B-PP drug-induced JJ B-NP toxicity NN I-NP in IN B-PP a DT B-NP patient NN I-NP receiving VBG B-VP 5-fluorouracil NN B-NP ( ( O FUra NN B-NP ) ) O as IN B-PP adjuvant JJ B-NP chemotherapy NN I-NP for IN B-PP breast NN B-NP carcinoma NN I-NP . . O The DT B-NP study NN I-NP population NN I-NP included VBD B-VP the DT B-NP affected VBN I-NP patient NN I-NP ( ( O proband NN B-NP ) ) O COMMA COMMA O nine CD B-NP of IN B-PP her PRP$ B-NP blood NN I-NP relatives NNS I-NP COMMA COMMA O and CC O seven CD B-NP healthy JJ I-NP volunteers NNS I-NP . . O The DT B-NP activity NN I-NP of IN B-PP dihydropyrimidine NN B-NP dehydrogenase NN I-NP ( ( O DPD NN B-NP ) ) O COMMA COMMA O the DT B-NP initial JJ I-NP enzyme NN I-NP of IN B-PP pyrimidine NN B-NP ( ( O and CC O FUra NN B-NP ) ) O catabolism NN B-NP COMMA COMMA O in IN B-PP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP was VBD B-VP measured VBN I-VP in IN B-PP each DT B-NP subject NN I-NP by IN B-PP a DT B-NP specific JJ I-NP radiometric JJ I-NP assay NN I-NP using VBG B-VP FUra NN B-NP as IN B-PP the DT B-NP substrate NN I-NP . . O The DT B-NP proband NN I-NP had VBD B-VP no DT B-NP detectable JJ I-NP DPD NN I-NP activity NN I-NP . . O When WRB B-ADVP enzyme NN B-NP levels NNS I-NP in IN B-PP the DT B-NP proband NN B-NP and CC O relatives NNS B-NP were VBD B-VP compared VBN I-VP with IN B-PP that DT B-NP in IN B-PP controls NNS B-NP COMMA COMMA O an DT B-NP autosomal JJ I-NP recessive JJ I-NP pattern NN I-NP of IN B-PP inheritance NN B-NP was VBD B-VP demonstrated VBN I-VP . . O This DT B-NP is VBZ B-VP the DT B-NP third JJ I-NP patient NN I-NP with IN B-PP severe JJ B-NP FUra NN I-NP toxicity NN I-NP secondary JJ B-ADJP to TO B-PP an DT B-NP alteration NN I-NP in IN B-PP pyrimidine NN B-NP catabolism NN I-NP and CC O the DT B-NP second NN I-NP from IN B-PP our PRP$ B-NP clinic NN I-NP population NN I-NP suggesting VBG B-VP that IN B-SBAR the DT B-NP frequency NN I-NP of IN B-PP this DT B-NP genetic JJ I-NP defect NN I-NP may MD B-VP be VB I-VP greater JJR B-ADJP than IN B-SBAR previously RB B-ADVP thought VBN B-VP . . O Monitoring VBG B-VP DPD NN B-NP activity NN I-NP may MD B-VP be VB I-VP important JJ B-ADJP in IN B-PP the DT B-NP management NN I-NP of IN B-PP patients NNS B-NP experiencing VBG B-VP severe JJ B-NP toxicity NN I-NP secondary JJ B-ADJP to TO B-PP FUra NN B-NP chemotherapy NN I-NP . . O Characterization NN B-NP of IN B-PP an DT B-NP immediate-early JJ I-NP gene NN I-NP induced VBN B-VP in IN B-PP adherent JJ B-NP monocytes NNS I-NP that WDT B-NP encodes VBZ B-VP I NN B-NP kappa NN I-NP B-like JJ I-NP activity NN I-NP . . O We PRP B-NP have VBP B-VP cloned VBN I-VP a DT B-NP group NN I-NP of IN B-PP cDNAs NNS B-NP representing VBG B-VP mRNAs NNS B-NP that WDT B-NP are VBP B-VP rapidly RB I-VP induced VBN I-VP following VBG B-PP adherence NN B-NP of IN B-PP human JJ B-NP monocytes NNS I-NP . . O One CD B-NP of IN B-PP the DT B-NP induced VBN I-NP transcripts NNS I-NP ( ( O MAD-3 NN B-NP ) ) O encodes VBZ B-VP a DT B-NP protein NN I-NP of IN B-PP 317 CD B-NP amino NN I-NP acids NNS I-NP with IN B-PP one CD B-NP domain NN I-NP containing VBG B-VP five CD B-NP tandem JJ I-NP repeats NNS I-NP of IN B-PP the DT B-NP cdc10\/ankyrin JJ I-NP motif NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP 60 CD B-NP % NN I-NP similar JJ B-ADJP ( ( O 46 CD B-NP % NN I-NP identical JJ B-ADJP ) ) O to TO B-PP the DT B-NP ankyrin NN I-NP repeat NN I-NP region NN I-NP of IN B-PP the DT B-NP precursor NN I-NP of IN B-PP NF-kappa NN B-NP B\/KBF1 NN I-NP p50 NN I-NP . . O The DT B-NP C-terminus NN I-NP has VBZ B-VP a DT B-NP putative JJ I-NP protein NN I-NP kinase NN I-NP C NN I-NP phosphorylation NN I-NP site NN I-NP . . O In FW B-ADVP vitro FW I-ADVP translated VBN B-NP MAD-3 NN I-NP protein NN I-NP was VBD B-VP found VBN I-VP to TO I-VP specifically RB I-VP inhibit VB I-VP the DT B-NP DNA-binding JJ I-NP activity NN I-NP of IN B-PP the DT B-NP p50\/p65 NN I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP but CC B-CONJP not RB I-CONJP that DT B-NP of IN B-PP the DT B-NP p50\/p50 NN I-NP KBF1 NN I-NP factor NN I-NP or CC B-PP of IN B-PP other JJ B-NP DNA-binding JJ I-NP proteins NNS I-NP . . O The DT B-NP MAD-3 NN I-NP cDNA NN I-NP encodes VBZ B-VP an DT B-NP I NN I-NP kappa NN I-NP B-like JJ I-NP protein NN I-NP that WDT B-NP is VBZ B-VP likely JJ B-ADJP to TO B-VP be VB I-VP involved VBN I-VP in IN B-PP regulation NN B-NP of IN B-PP transcriptional JJ B-NP responses NNS I-NP to TO B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O including VBG B-PP adhesion-dependent JJ B-NP pathways NNS I-NP of IN B-PP monocyte NN B-NP activation NN I-NP . . O Reactive JJ B-NP oxygen NN I-NP intermediates NNS I-NP as IN B-PP apparently RB B-ADJP widely RB I-ADJP used VBN I-ADJP messengers NNS O in IN B-PP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP NF-kappa NN B-NP B NN I-NP transcription NN I-NP factor NN I-NP and CC O HIV-1 NN B-NP . . O Hydrogen NN B-NP peroxide NN I-NP and CC O oxygen NN B-NP radicals NNS B-NP are VBP B-VP agents NNS B-NP commonly RB B-VP produced VBN I-VP during IN B-PP inflammatory JJ B-NP processes NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR micromolar JJ B-NP concentrations NNS I-NP of IN B-PP H2O2 NN B-NP can MD B-VP induce VB I-VP the DT B-NP expression NN B-NP and CC O replication NN B-NP of IN B-PP HIV-1 NN B-NP in IN B-PP a DT B-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP . . O The DT B-NP effect NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP which WDT B-NP is VBZ O potently RB B-ADVP and CC O rapidly RB B-ADVP activated VBN B-VP by IN O an DT B-NP H2O2 NN I-NP treatment NN I-NP of IN B-PP cells NNS B-NP from IN B-PP its PRP$ B-NP inactive JJ I-NP cytoplasmic JJ I-NP form NN I-NP . . O N-acetyl-L-cysteine NN B-NP ( ( O NP NN B-NP ) ) O COMMA COMMA O a DT B-NP well RB I-NP characterized VBN I-NP antioxidant NN I-NP which WDT B-NP counteracts VBZ B-VP the DT B-NP effects NNS I-NP of IN B-PP reactive JJ B-NP oxygen NN I-NP intermediates NNS I-NP ( ( O ROI NN B-NP ) ) O in IN B-PP living VBG B-NP cells NNS I-NP COMMA COMMA O prevented VBD B-VP the DT B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP by IN B-PP H2O2 NN B-NP . . O NP NN B-NP and CC O other JJ B-NP thiol JJ I-NP compounds NNS I-NP also RB B-ADVP blocked VBD B-VP the DT B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP by IN B-PP cycloheximide NN B-NP COMMA COMMA O double-stranded JJ B-NP RNA NN I-NP COMMA COMMA O calcium NN B-NP ionophore NN I-NP COMMA COMMA O TNF-alpha NN B-NP COMMA COMMA O active JJ B-NP phorbol NN I-NP ester NN I-NP COMMA COMMA O interleukin-1 NN B-NP COMMA COMMA O lipopolysaccharide NN B-NP and CC O lectin NN B-NP . . O This DT B-NP suggests VBZ B-VP that IN B-SBAR diverse JJ B-NP agents NNS I-NP thought VBN B-VP to TO I-VP activate VB I-VP NF-kappa NN B-NP B NN I-NP by IN B-PP distinct JJ B-NP intracellular JJ I-NP pathways NNS I-NP might MD B-VP all RB I-VP act VB I-VP through IN B-PP a DT B-NP common JJ I-NP mechanism NN I-NP involving VBG B-VP the DT B-NP synthesis NN I-NP of IN B-PP ROI NN B-NP . . O ROI NN B-NP appear VBP B-VP to TO I-VP serve VB I-VP as IN B-PP messengers NNS B-NP mediating VBG B-VP directly RB B-ADVP or CC B-ADVP indirectly RB B-ADVP the DT B-NP release NN I-NP of IN B-PP the DT B-NP inhibitory JJ I-NP subunit NN I-NP I NN I-NP kappa NN I-NP B NN I-NP from IN B-PP NF-kappa NN B-NP B NN I-NP . . O HTLV-1 NN B-NP Tax NN I-NP induces VBZ B-VP expression NN B-NP of IN B-PP various JJ B-NP immediate JJ I-NP early JJ I-NP serum NN I-NP responsive JJ I-NP genes NNS I-NP . . O Human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HTLV-1 NN B-NP ) ) O is VBZ B-VP an DT B-NP etiological JJ I-NP agent NN I-NP of IN B-PP adult JJ B-NP T-cell NN I-NP leukemia NN I-NP ( ( O ATL NN B-NP ) ) O . . O We PRP B-NP showed VBD B-VP here RB B-ADVP by IN B-PP mobility-shift NN B-NP assay NN I-NP that IN B-SBAR T-cell NN B-NP lines NNS I-NP transformed VBN B-VP with IN B-PP the DT B-NP virus NN I-NP contained VBD B-VP high JJ B-NP levels NNS I-NP of IN B-PP AP-1 NN B-NP activities NNS I-NP . . O Consistent JJ B-ADJP with IN B-PP this DT B-NP result NN I-NP COMMA COMMA O these DT B-NP cell NN I-NP lines NNS I-NP expressed VBD B-VP increased VBN B-NP levels NNS I-NP of IN B-PP mRNAs NNS B-NP encoding VBG B-VP the DT B-NP AP-1 NN I-NP proteins NNS I-NP COMMA COMMA O c-Fos NN B-NP COMMA COMMA O Fra-1 NN B-NP COMMA COMMA O c-Jun NN B-NP COMMA COMMA O JunB NN B-NP COMMA COMMA O and CC O JunD NN B-NP . . O Previously RB B-ADVP COMMA COMMA O transcription NN B-NP of IN B-PP the DT B-NP c-fos NN I-NP gene NN I-NP has VBZ B-VP been VBN I-VP reported VBN I-VP to TO I-VP be VB I-VP transactivated VBN I-VP by IN B-PP the DT B-NP viral JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O Tax1 NN B-NP . . O By IN B-PP using VBG B-VP the DT B-NP human JJ I-NP T-cell NN I-NP line NN I-NP ( ( O JPX-9 NN B-NP ) ) O COMMA COMMA O in IN B-PP which WDT B-NP expression NN B-NP of IN B-PP the DT B-NP Tax1 NN I-NP is VBZ B-VP inducible JJ B-ADJP COMMA COMMA O we PRP B-NP showed VBD B-VP that IN B-SBAR expression NN B-NP of IN B-PP mRNAs NNS B-NP for IN B-PP Fra-1 NN B-NP COMMA COMMA O c-Jun NN B-NP COMMA COMMA O and CC O JunD NN B-NP was VBD B-VP also RB I-VP transactivated VBN I-VP by IN B-PP Tax1 NN B-NP . . O Moreover RB B-ADVP COMMA COMMA O Tax1 NN B-NP activated VBD B-VP expression NN B-NP of IN B-PP two CD B-NP other JJ I-NP transcription NN I-NP factors NNS I-NP having VBG B-VP zinc NN B-NP finger NN I-NP motifs NNS I-NP COMMA COMMA O Egr-1 NN B-NP and CC O Egr-2 NN B-NP COMMA COMMA O in IN B-PP the DT B-NP same JJ I-NP cells NNS I-NP . . O The DT B-NP Tax1-inducible JJ I-NP transcription NN I-NP factors NNS I-NP identified VBN B-VP here RB B-ADVP are VBP B-VP encoded VBN I-VP by IN B-PP the DT B-NP members NNS I-NP of IN B-PP immediate JJ B-NP early JJ I-NP genes NNS I-NP under IN B-PP the DT B-NP control NN I-NP of IN B-PP growth NN B-NP signals NNS I-NP . . O Thus RB O COMMA COMMA O Tax1 NN B-NP was VBD B-VP suggested VBN I-VP to TO I-VP replace VB I-VP growth NN B-NP signals NNS I-NP COMMA COMMA O at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP COMMA COMMA O by IN B-PP this DT B-NP mechanism NN I-NP . . O Contribution NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O Sp1 NN B-NP binding NN B-NP motifs NNS I-NP to TO B-PP the DT B-NP replicative JJ I-NP capacity NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP : : O distinct JJ B-NP patterns NNS I-NP of IN B-PP viral JJ B-NP growth NN I-NP are VBP B-VP determined VBN I-VP by IN B-PP T-cell NN B-NP types NNS I-NP . . O Starting VBG B-VP with IN B-PP a DT B-NP replication-incompetent JJ I-NP molecular JJ I-NP clone NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP COMMA COMMA O lacking VBG B-VP all PDT O the DT O NF-kappa NN B-NP B NN I-NP and CC O Sp1 NN B-NP binding NN B-NP sites NNS I-NP present JJ B-ADJP in IN B-PP the DT B-NP native JJ I-NP long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O COMMA COMMA O proviruses NNS B-NP containing VBG B-VP reconstructed VBN B-NP LTRs NNS I-NP with IN B-PP individual JJ B-NP or CC O combinations NNS B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O Sp1 NN B-NP elements NNS B-NP were VBD B-VP generated VBN I-VP and CC O evaluated VBN B-VP for IN B-PP their PRP$ B-NP capacity NN I-NP to TO B-VP produce VB I-VP virus NN B-NP progeny NN I-NP following VBG B-PP transfection-cocultivation NN B-NP . . O Virus NN B-NP stocks NNS I-NP obtained VBN B-VP from IN B-PP these DT B-NP experiments NNS I-NP exhibited VBD B-VP a DT B-NP continuum NN I-NP of IN B-PP replicative JJ B-NP capacities NNS I-NP in IN B-PP different JJ B-NP human JJ I-NP T-cell NN I-NP types NNS I-NP depending VBG B-PP on IN B-PP which WDT B-NP element NN I-NP ( ( I-NP s NNS I-NP ) ) O was VBD B-VP present JJ B-ADJP in IN B-PP the DT B-NP LTR NN I-NP . . O For IN B-PP example NN B-NP COMMA COMMA O in IN B-PP experiments NNS B-NP involving VBG B-VP proviral JJ B-NP clones NNS I-NP with IN B-PP LTRs NNS B-NP containing VBG B-VP one CD B-NP or CC I-NP two CD I-NP NF-kappa NN I-NP B NN I-NP elements NNS I-NP ( ( O and CC O no DT B-NP Sp1 NN I-NP binding NN I-NP sites NNS I-NP ) ) O COMMA COMMA O a DT B-NP hierarchy NN I-NP of IN B-PP cellular JJ B-NP permissivity NN I-NP to TO B-PP virus NN B-NP replication NN I-NP ( ( O peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP = JJ B-VP MT4 NN B-NP greater JJR B-ADJP than IN B-PP H9 NN B-NP greater JJR B-ADJP than IN B-PP CEM NN B-NP greater JJR B-ADJP than IN B-PP Jurkat NN B-NP ) ) O was VBD B-VP observed VBN I-VP . . O Of IN B-PP note NN B-NP was VBD B-VP the DT B-NP associated VBN I-NP emergence NN I-NP of IN B-PP second-site JJ B-NP LTR NN I-NP revertants NNS I-NP which WDT B-NP involved VBD B-VP an DT B-NP alteration NN I-NP of IN B-PP the DT B-NP TATA NN I-NP box NN I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP LTR NN I-NP possesses VBZ B-VP functional JJ B-NP redundancy NN I-NP which WDT B-NP ensures VBZ B-VP virus NN B-NP replication NN I-NP in IN B-PP different JJ B-NP T-cell NN I-NP types NNS I-NP and CC O is VBZ B-VP capable JJ B-ADJP of IN B-PP changing VBG B-VP depending VBG B-PP on IN B-PP the DT B-NP particular JJ I-NP combination NN I-NP of IN B-PP transcriptional JJ B-NP factors NNS I-NP present JJ B-ADJP . . O Enhancement NN B-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP 1 CD I-NP replication NN I-NP in IN B-PP monocytes NNS B-NP by IN B-PP 1COMMA25-dihydroxycholecalciferol NN B-NP . . O Human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O expression NN B-NP and CC O replication NN B-NP are VBP B-VP under IN B-PP tight JJ B-NP regulatory JJ I-NP control NN I-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR 1COMMA25-dihydroxycholecalciferol NN B-NP { ( O 1COMMA25-(OH)2D3 NN B-NP } ) O enhances VBZ B-VP the DT B-NP replication NN I-NP of IN B-PP monocyte- NN B-NP and CC O lymphocyte-tropic JJ B-ADJP strains NNS B-NP of IN B-PP HIV-1 NN B-NP up IN B-PP to TO I-PP 10COMMA000-fold RB B-ADVP in IN B-PP monocyte NN B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O peripheral JJ B-NP blood NN I-NP monocytes NNS I-NP COMMA COMMA O and CC O unfractionated JJ B-NP peripheral JJ I-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP . . O 1COMMA25(OH)2D3 NN B-NP is VBZ B-VP therefore RB B-ADVP one CD B-NP of IN B-PP the DT B-NP most RBS I-NP potent JJ I-NP regulators NNS I-NP of IN B-PP HIV-1 NN B-NP replication NN I-NP described VBN B-VP to TO B-PP date NN B-NP . . O Precursors NNS B-NP of IN B-PP 1COMMA25(OH)2D3 NN B-NP enhance VBP B-VP HIV-1 NN B-NP replication NN I-NP in IN B-PP proportion NN I-PP to TO I-PP their PRP$ B-NP affinity NN I-NP for IN B-PP the DT B-NP 1COMMA25(OH)2D3 NN I-NP intracellular JJ I-NP receptor NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR 1COMMA25(OH)2D3 NN B-NP influences VBZ B-VP HIV-1 NN B-NP replication NN I-NP by IN B-PP mechanisms NNS B-NP involving VBG B-VP this DT B-NP receptor NN I-NP . . O These DT B-NP studies NNS I-NP may MD B-VP have VB I-VP important JJ B-NP implications NNS I-NP for IN B-PP the DT B-NP design NN I-NP of IN B-PP effective JJ B-NP therapy NN I-NP of IN B-PP HIV-1 NN B-NP infection NN I-NP . . O Inhibition NN B-NP of IN B-PP HIV-1 NN B-NP replication NN I-NP and CC O NF-kappa NN B-NP B NN I-NP activity NN I-NP by IN B-PP cysteine NN B-NP and CC O cysteine NN B-NP derivatives NNS I-NP . . O HIV-1 NN B-NP proviral JJ I-NP DNA NN I-NP contains VBZ B-VP two CD B-NP binding VBG I-NP sites NNS I-NP for IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP . . O HIV-1-infected JJ B-NP individuals NNS I-NP have VBP B-VP COMMA COMMA O on IN B-PP average NN B-NP COMMA COMMA O abnormally RB B-NP high JJ I-NP levels NNS I-NP of IN B-PP tumour NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF NN B-NP alpha NN I-NP ) ) O and CC O abnormally RB B-NP low JJ I-NP plasma NN I-NP cysteine NN I-NP levels NNS I-NP . . O We PRP B-NP therefore RB B-ADVP investigated VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP cysteine NN B-NP and CC O related JJ B-NP thiols NNS I-NP on IN B-PP HIV-1 NN B-NP replication NN I-NP and CC O NF-kappa NN B-NP B NN I-NP expression NN I-NP . . O The DT B-NP experiments NNS I-NP in IN B-PP this DT B-NP report NN I-NP show VBP B-VP that IN B-SBAR cysteine NN B-NP or CC O N-acetylcysteine NN B-NP ( ( O NP NN B-NP ) ) O raise VBP B-VP the DT B-NP intracellular JJ I-NP glutathione NN I-NP ( ( I-NP GSH NN I-NP ) ) I-NP level NN I-NP and CC O inhibit VBP B-VP HIV-1 NN B-NP replication NN I-NP in IN B-PP persistently RB O infected JJ O Molt-4 NN B-NP and CC O U937 NN B-NP cells NNS B-NP . . O However RB B-ADVP COMMA COMMA O inhibition NN B-NP of IN B-PP HIV-1 NN B-NP replication NN I-NP appears VBZ B-VP not RB I-VP to TO I-VP be VB I-VP directly RB I-VP correlated VBN I-VP with IN B-PP GSH NN B-NP levels NNS I-NP . . O Cysteine NN B-NP and CC O NP NN B-NP also RB B-ADVP inhibit VBP B-VP NF-kappa NN B-NP B NN I-NP activity NN I-NP as IN B-SBAR determined VBN B-VP by IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP and CC O chloramphenicol NN B-NP acetyl-transferase NN I-NP ( ( O CAT NN B-NP ) ) O gene NN B-NP expression NN I-NP under IN B-PP control NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP binding NN I-NP sites NNS I-NP in IN B-PP uninfected JJ B-NP cells NNS I-NP . . O This DT B-NP suggests VBZ B-VP that IN B-SBAR the DT B-NP cysteine NN I-NP deficiency NN I-NP in IN B-PP HIV-1-infected JJ B-NP individuals NNS I-NP may MD B-VP cause VB I-VP an DT B-NP over-expression NN I-NP of IN B-PP NF-kappa NN B-NP B-dependent JJ I-NP genes NNS I-NP and CC O enhance VB B-VP HIV-1 NN B-NP replication NN I-NP . . O NP NN B-NP may MD B-VP be VB I-VP considered VBN I-VP for IN B-PP the DT B-NP treatment NN I-NP of IN B-PP HIV-1-infected JJ B-NP individuals NNS I-NP . . O Glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP systemic JJ B-NP lupus NN I-NP erythematosus NN I-NP . . O Glucocorticosteroids NNS B-NP remain VBP B-VP the DT B-NP major JJ I-NP treatment NN I-NP modality NN I-NP for IN B-PP systemic JJ B-NP lupus NN I-NP erythematosus NN I-NP ( ( O SLE NN B-NP ) ) O COMMA COMMA O but CC O their PRP$ B-NP mechanism NN I-NP of IN B-PP action NN B-NP is VBZ B-VP unclear JJ B-ADJP . . O Over IN B-PP the DT B-NP past JJ I-NP decade NN I-NP it PRP B-NP has VBZ B-VP become VBN I-VP clear JJ B-ADJP that IN B-SBAR glucocorticosteroid NN B-NP receptors NNS I-NP play VBP B-VP a DT B-NP significant JJ I-NP role NN I-NP in IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP glucocorticosteroid NN B-NP action NN I-NP . . O We PRP B-NP studied VBD B-VP glucocorticosteroid NN B-NP receptor NN I-NP density NN B-NP and CC O affinity NN B-NP on IN B-PP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP by IN B-PP the DT B-NP glucocorticosteroid NN I-NP binding NN I-NP assay NN I-NP in IN B-PP 33 CD B-NP patients NNS I-NP with IN B-PP SLE NN B-NP who WP B-NP had VBD B-VP taken VBN I-VP no DT B-NP glucocorticosteroid NN I-NP for IN B-PP the DT B-NP previous JJ I-NP 6 CD I-NP months NNS I-NP and CC B-PP in IN B-PP 32 CD B-NP healthy JJ I-NP controls NNS I-NP . . O Patients NNS B-NP ' POS B-NP disease NN I-NP activity NN I-NP was VBD B-VP measured VBN I-VP by IN B-PP the DT B-NP SLE NN I-NP Disease NN I-NP Activity NN I-NP Index NN I-NP ( ( O SLEDAI NN B-NP ) ) O . . O Glucocorticosteroid NN B-NP receptors NNS I-NP on IN B-PP leukocytes NNS B-NP of IN B-PP patients NNS B-NP with IN B-PP SLE NN O were VBD B-VP significantly RB B-ADJP higher JJR I-ADJP than IN B-PP in IN B-PP healthy JJ B-NP controls NNS I-NP ( ( O 4419 CD B-NP +\/- CC I-NP 306 CD I-NP vs CC O 3369 CD B-NP +\/- CC I-NP 196 CD I-NP COMMA COMMA O p NN B-NP less JJR B-ADJP than IN B-PP 0.005 CD B-NP ) ) O . . O The DT B-NP binding NN I-NP affinity NN I-NP was VBD B-VP not RB O different JJ B-ADJP between IN B-PP patients NNS B-NP and CC O controls NNS B-NP . . O There EX B-NP was VBD B-VP no DT B-NP correlation NN I-NP between IN B-PP glucocorticosteroid NN B-NP receptor NN I-NP number NN I-NP and CC O SLE NN B-NP disease NN I-NP activity NN I-NP . . O { ( O Changes NNS B-NP in IN B-PP leucocytic JJ B-NP estrogen NN I-NP receptor NN I-NP levels NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP gynecomastia NN B-NP } ) O The DT B-NP number NN I-NP of IN B-PP estrogen NN B-NP receptor NN I-NP ( ( O ER NN B-NP ) ) O in IN B-PP human JJ B-NP peripheral JJ I-NP leucocytes NNS I-NP in IN B-PP 13 CD B-NP men NNS I-NP with IN B-PP gynecomastia NNS B-NP were VBD B-VP measured VBN I-VP by IN B-PP radioligand NN B-NP binding NN I-NP method NN I-NP . . O The DT B-NP results NNS I-NP were VBD B-VP compared VBN I-VP with IN B-PP those DT B-NP of IN B-PP 13 CD B-NP sex- NN I-NP and CC I-NP age-matched JJ I-NP healthy JJ I-NP subjects NNS I-NP . . O It PRP B-NP was VBD B-VP found VBN I-VP that IN B-SBAR the DT B-NP number NN I-NP of IN B-PP ER NN B-NP in IN B-PP leucocytes NNS B-NP was VBD B-VP significantly RB I-VP increased VBN I-VP in IN B-PP gynecomastia NN B-NP ( ( O Rs NN B-NP of IN B-PP leucocytes NNS B-NP were VBD B-VP 1054 CD B-NP +\/- CC I-NP 254 CD I-NP sites\/cell NN I-NP ) ) O . . O It PRP B-NP suggested VBD B-VP that IN B-SBAR increase NN B-NP of IN B-PP ER NN B-NP levels NNS I-NP play VBP B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP gynecomastia NN B-NP . . O { ( O Changes NNS B-NP in IN B-PP levels NNS B-NP of IN B-PP leucocytic JJ B-NP estrogen NN I-NP receptor NN I-NP in IN B-PP patients NNS B-NP with IN B-PP menopausal JJ B-NP type NN I-NP II CD I-NP diabetes NNS I-NP and CC O its PRP$ B-NP significance NN I-NP } ) O The DT B-NP number NN I-NP of IN B-PP estrogen NN B-NP receptors NNS I-NP ( ( O ER NN B-NP ) ) O in IN B-PP human JJ B-NP peripheral JJ I-NP leucocytes NNS I-NP in IN B-PP 12 CD B-NP women NNS I-NP with IN B-PP menopausal JJ B-NP type NN I-NP II CD I-NP diabetes NNS I-NP was VBD B-VP measured VBN I-VP with IN B-PP radio-ligand JJ B-NP binding NN I-NP method NN I-NP . . O The DT B-NP results NNS I-NP were VBD B-VP compared VBN I-VP with IN B-PP those DT B-NP of IN B-PP 12 CD B-NP menopausal JJ I-NP women NNS I-NP without IN B-PP diabetes NNS B-NP and CC O 12 CD B-NP normal JJ I-NP women NNS I-NP of IN B-PP childbearing JJ B-NP age NN I-NP . . O It PRP B-NP was VBD B-VP found VBN I-VP that IN B-SBAR the DT B-NP number NN I-NP of IN B-PP ER NN B-NP in IN B-PP the DT B-NP patients NNS I-NP was VBD B-VP significantly RB I-VP decreased VBN I-VP . . O Our PRP$ B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR decrease NN B-NP of IN B-PP ER NN B-NP level NN I-NP in IN B-PP leukocytes NNS B-NP may MD B-VP be VB I-VP related JJ B-ADJP to TO B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP type NN B-NP II CD I-NP diabetes NNS I-NP in IN B-PP menopausal JJ B-NP period NN I-NP . . O Lymphocyte NN B-NP glucocorticoid NN I-NP receptor NN I-NP binding NN I-NP during IN B-PP depression NN B-NP and CC B-PP after IN B-PP clinical JJ B-NP recovery NN I-NP . . O Lymphocyte NN B-NP glucocorticoid NN I-NP receptor NN I-NP binding NN I-NP parameters NNS I-NP were VBD B-VP studied VBN I-VP in IN B-PP 15 CD B-NP severely RB I-NP depressed JJ I-NP patients NNS I-NP during IN B-PP depression NN B-NP and CC B-PP after IN B-PP clinical JJ B-NP recovery NN I-NP COMMA COMMA O and CC O in IN B-PP 15 CD B-NP healthy JJ I-NP controls NNS I-NP . . O There EX B-NP was VBD B-VP no DT B-NP difference NN I-NP in IN B-PP glucocorticoid NN B-NP receptor NN I-NP number NN B-NP or CC O affinity NN B-NP between IN B-PP depressed JJ B-NP patients NNS I-NP and CC O recovered JJ B-NP or CC I-NP control NN I-NP subjects NNS I-NP . . O Afternoon NN O ACTH NN B-NP and CC O cortisol NN B-NP concentrations NNS B-NP did VBD B-VP not RB I-VP differ VB I-VP significantly RB B-ADVP between IN B-PP the DT B-NP three CD I-NP groups NNS I-NP . . O No DT B-NP relationship NN I-NP could MD B-VP be VB I-VP established VBN I-VP between IN B-PP glucocorticoid NN B-NP receptor NN I-NP binding NN I-NP and CC O antidepressant JJ B-NP medication NN I-NP . . O These DT B-NP data NNS I-NP support VBP B-VP the DT B-NP view NN I-NP of IN B-PP an DT B-NP impaired JJ I-NP ligand-induced JJ I-NP plasticity NN I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP regulation NN I-NP rather RB B-CONJP than IN I-CONJP the DT B-NP hypothesis NN I-NP of IN B-PP decreased VBN B-NP glucocorticoid NN I-NP receptor NN I-NP numbers NNS I-NP during IN B-PP depression NN B-NP . . O Nuclear JJ B-NP association NN I-NP of IN B-PP a DT B-NP T-cell NN I-NP transcription NN I-NP factor NN I-NP blocked VBN B-VP by IN B-PP FK-506 NN B-NP and CC O cyclosporin NN B-NP A NN I-NP { ( O see VB B-VP comments NNS B-NP } ) O Cyclosporin NN B-NP A NN I-NP and CC O FK506 NN B-NP inhibit VBP B-VP T- NN O and CC O B-cell NN B-ADJP activation NN B-NP and CC O other JJ B-NP processes NNS I-NP essential JJ B-ADJP to TO B-PP an DT B-NP effective JJ I-NP immune JJ I-NP response NN I-NP . . O In IN B-PP T NN B-NP lymphocytes NNS I-NP these DT B-NP drugs NNS I-NP disrupt VBP B-VP an DT B-NP unknown JJ I-NP step NN I-NP in IN B-PP the DT B-NP transmission NN I-NP of IN B-PP signals NNS B-NP from IN B-PP the DT B-NP T-cell NN I-NP antigen NN I-NP receptor NN I-NP to TO B-PP cytokine NN B-NP genes NNS I-NP that WDT B-NP coordinate VBP B-VP the DT B-NP immune JJ I-NP response NN I-NP . . O The DT B-NP putative JJ I-NP intracellular JJ I-NP receptors NNS I-NP for IN B-PP FK506 NN B-NP and CC O cyclosporin NN B-NP are VBP B-VP cis-trans JJ B-NP prolyl JJ I-NP isomerases NNS I-NP . . O Binding NN B-NP of IN B-PP the DT B-NP drug NN I-NP inhibits VBZ B-VP isomerase NN B-NP activity NN I-NP COMMA COMMA O but CC O studies NNS B-NP with IN B-PP other JJ B-NP prolyl JJ I-NP isomerase NN I-NP inhibitors NNS I-NP and CC O analysis NN B-NP of IN B-PP cyclosporin-resistant JJ B-NP mutants NNS I-NP in IN B-PP yeast NN B-NP suggest VBP B-VP that IN B-SBAR the DT B-NP effects NNS I-NP of IN B-PP the DT B-NP drug NN I-NP result VBP B-VP from IN B-PP the DT B-NP formation NN I-NP of IN B-PP an DT B-NP inhibitory JJ I-NP complex NN I-NP between IN B-PP the DT B-NP drug NN I-NP and CC O isomerase NN B-NP COMMA COMMA B-PP and CC I-PP not RB B-PP from IN I-PP inhibition NN B-NP of IN B-PP isomerase NN B-NP activity NN I-NP . . O A DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O NF-AT NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP early JJ B-NP T-cell NN I-NP gene NN I-NP activation NN I-NP COMMA COMMA O seems VBZ B-VP to TO I-VP be VB I-VP a DT B-NP specific JJ I-NP target NN I-NP of IN B-PP cyclosporin NN B-NP A NN I-NP and CC O FK506 NN B-NP action NN B-NP because IN B-SBAR transcription NN B-NP directed VBN B-VP by IN B-PP this DT B-NP protein NN I-NP is VBZ B-VP blocked VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP treated VBN B-VP with IN B-PP these DT B-NP drugs NNS I-NP COMMA COMMA O with IN B-PP little JJ B-NP or CC I-NP no DT I-NP effect NN I-NP on IN B-PP other JJ B-NP transcription NN I-NP factors NNS I-NP such JJ B-PP as IN I-PP AP-1 NN B-NP and CC O NF-kappa NN B-NP B NN I-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR NF-AT NN B-NP is VBZ B-VP formed VBN I-VP when WRB B-ADVP a DT B-NP signal NN I-NP from IN B-PP the DT B-NP antigen NN I-NP receptor NN I-NP induces VBZ B-VP a DT B-NP pre-existing JJ I-NP cytoplasmic JJ I-NP subunit NN I-NP to TO B-VP translocate VB I-VP to TO B-PP the DT B-NP nucleus NN I-NP and CC O combine VB B-VP with IN B-PP a DT B-NP newly RB I-NP synthesized VBN I-NP nuclear JJ I-NP subunit NN I-NP of IN B-PP NF-AT NN B-NP . . O FK506 NN B-NP and CC O cyclosporin NN B-NP A NN I-NP block VBP B-VP translocation NN B-NP of IN B-PP the DT B-NP cytoplasmic JJ I-NP component NN I-NP without IN B-PP affecting VBG B-VP synthesis NN B-NP of IN B-PP the DT B-NP nuclear JJ I-NP subunit NN I-NP . . O Regulation NN B-NP of IN B-PP M-CSF NN B-NP expression NN I-NP by IN B-PP M-CSF NN B-NP : : O role NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP and CC O transcription NN B-NP factor NN I-NP NF NN I-NP kappa NN I-NP B NN I-NP . . O Macrophage-colony-stimulating JJ B-NP factor NN I-NP ( ( O M-CSF NN B-NP ) ) O COMMA COMMA O also RB B-VP referred VBN I-VP to TO B-PP as IN B-PP CSF-1 NN B-NP COMMA COMMA O regulates VBZ B-VP the DT B-NP survival NN B-NP COMMA COMMA O growth NN B-NP COMMA COMMA O differentiation NN B-NP and CC O functional JJ B-NP activity NN I-NP of IN B-PP monocytes NNS B-NP by IN B-PP binding VBG B-VP to TO B-PP a DT B-NP single JJ I-NP class NN I-NP of IN B-PP high-affinity JJ B-NP cell NN I-NP surface NN I-NP receptors NNS I-NP COMMA COMMA O known VBN B-VP to TO I-VP be VB I-VP the DT B-NP product NN I-NP of IN B-PP the DT B-NP c-fms NN I-NP protooncogene NN I-NP . . O The DT B-NP detection NN I-NP of IN B-PP both CC O M-CSF NN B-NP and CC O c-fms NN B-NP expression NN B-NP by IN B-PP cells NNS B-NP of IN B-PP the DT B-NP monocyte NN I-NP lineage NN I-NP has VBZ B-VP suggested VBN I-VP that IN B-SBAR M-CSF NN B-NP may MD B-VP act VB I-VP by IN B-PP an DT B-NP autocrine JJ I-NP mechanism NN I-NP . . O Interestingly RB B-ADVP COMMA COMMA O it PRP B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP that IN B-SBAR M-CSF NN B-NP can MD B-VP induce VB I-VP the DT B-NP expression NN I-NP of IN B-PP its PRP$ B-NP own JJ I-NP gene NN I-NP . . O Although IN B-SBAR sensitivity NN B-NP to TO B-PP M-CSF NN B-NP can MD B-VP be VB I-VP modulated VBN I-VP by IN B-PP regulation NN B-NP of IN B-PP receptor NN B-NP expression NN B-NP and CC O function NN B-NP COMMA COMMA O M-CSF NN B-NP responsiveness NN I-NP is VBZ B-VP largely RB I-VP determined VBN I-VP at IN B-PP a DT B-NP postreceptor NN I-NP level NN I-NP . . O To TO B-PP date NN B-NP COMMA COMMA O little JJ B-NP is VBZ B-VP known VBN I-VP about IN B-PP the DT B-NP intracellular JJ I-NP pathway NN I-NP of IN B-PP M-CSF NN B-NP signal NN I-NP transduction NN I-NP . . O We PRP B-NP have VBP B-VP therefore RB I-VP investigated VBN I-VP the DT B-NP changes NNS I-NP in IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O activity NN B-NP upon IN B-PP exposure NN B-NP of IN B-PP monocytes NNS B-NP to TO B-PP M-CSF NN B-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR M-CSF NN B-NP activates VBZ B-VP and CC O translocates VBZ B-VP PKC NN B-NP . . O Inhibition NN B-NP of IN B-PP PKC NN B-NP by IN B-PP the DT B-NP isoquinoline NN I-NP derivative JJ I-NP H7 NN I-NP abolishes VBZ B-VP induction NN B-NP of IN B-PP M-CSF NN B-NP by IN B-PP M-CSF NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O activation NN B-NP of IN B-PP PKC NN B-NP was VBD B-VP pertussis-toxin-sensitive JJ B-ADJP and CC O was VBD B-VP associated VBN I-VP with IN B-PP the DT B-NP detection NN I-NP of IN B-PP an DT B-NP NF NN I-NP kappa NN I-NP B NN I-NP protein NN I-NP in IN B-PP nuclear JJ B-NP extracts NNS I-NP of IN B-PP M-CSF-induced JJ B-NP blood NN I-NP monocytes NNS I-NP but CC B-PP not RB B-PP in IN I-PP monocytes NNS B-NP exposed VBN B-VP to TO B-PP medium NN B-NP treatment NN I-NP only RB B-ADVP . . O The DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR M-CSF NN B-NP induction NN I-NP of IN B-PP M-CSF NN B-NP involves VBZ B-VP G NN B-NP proteins NNS I-NP COMMA COMMA O PKC NN B-NP and CC O NF NN B-NP kappa NN I-NP B NN I-NP . . O NF-kappa NN B-NP B NN I-NP activation NN I-NP by IN B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP in IN B-PP the DT B-NP Jurkat NN I-NP T NN I-NP cell NN I-NP line NN I-NP is VBZ B-VP independent JJ B-ADJP of IN B-PP protein NN B-NP kinase NN I-NP A NN I-NP COMMA COMMA O protein NN B-NP kinase NN I-NP C NN I-NP COMMA COMMA O and CC O Ca(2+)-regulated JJ B-NP kinases NNS I-NP . . O NF-kappa NN B-NP B NN I-NP is VBZ B-VP a DT B-NP DNA-binding JJ I-NP regulatory JJ I-NP factor NN I-NP able JJ B-ADJP to TO B-VP control VB I-VP transcription NN B-NP of IN B-PP a DT B-NP number NN I-NP of IN B-PP genes NNS B-NP COMMA COMMA O including VBG B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O genes NNS B-NP . . O In IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP is VBZ B-VP activated VBN I-VP upon IN B-PP cellular JJ B-NP treatment NN I-NP by IN B-PP phorbol NN B-NP esters NNS I-NP and CC O the DT B-NP cytokine NN I-NP tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF NN B-NP alpha NN I-NP ) ) O . . O In IN B-PP the DT B-NP present JJ I-NP work NN I-NP COMMA COMMA O we PRP B-NP investigated VBD B-VP the DT B-NP molecular JJ I-NP events NNS I-NP leading VBG B-VP to TO B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP by IN B-PP TNF NN B-NP alpha NN I-NP in IN B-PP a DT B-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP ( ( O Jurkat NN B-NP ) ) O and CC O its PRP$ B-NP subclone JJ I-NP JCT6 NN I-NP COMMA COMMA O which WDT B-NP presents VBZ B-VP a DT B-NP deficiency NN I-NP in IN B-PP the DT B-NP PKA NN I-NP transduction NN I-NP pathway NN I-NP . . O We PRP B-NP found VBD B-VP that IN B-SBAR in IN B-PP both DT B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O both CC O phorbol NN B-NP ester NN I-NP and CC O TNF NN B-NP alpha NN I-NP were VBD B-VP able JJ B-ADJP to TO B-VP activate VB I-VP NF-kappa NN B-NP B NN I-NP . . O Phorbol NN B-NP activation NN I-NP was VBD B-VP positively RB I-VP modulated VBN I-VP by IN B-PP Ca2+ NN B-NP influx NN I-NP while IN B-SBAR TNF NN B-NP alpha NN I-NP activation NN I-NP was VBD B-VP not RB O . . O Furthermore RB B-ADVP COMMA COMMA O while IN B-SBAR PMA NN B-NP activation NN I-NP was VBD B-VP inhibited VBN I-VP by IN B-PP the DT B-NP PKC NN I-NP inhibitor NN I-NP staurosporin NN I-NP COMMA COMMA O the DT B-NP TNF NN I-NP alpha NN I-NP effect NN I-NP was VBD B-VP unchanged JJ B-ADJP . . O TNF NN B-NP alpha NN I-NP did VBD B-VP not RB I-VP activate VB I-VP cAMP NN B-NP production NN I-NP and CC O its PRP$ B-NP signal NN I-NP was VBD B-VP not RB I-VP modulated VBN I-VP by IN B-PP cAMP NN B-NP activators NNS I-NP . . O Moreover RB B-ADVP COMMA COMMA O cAMP NN B-NP activators NNS I-NP did VBD B-VP not RB I-VP activate VB I-VP NF-kappa NN B-NP B NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O TNF NN B-NP alpha-induced JJ I-NP NF-kappa NN I-NP B NN I-NP activation NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP mediated VBN I-VP by IN B-PP none NN B-NP of IN B-PP the DT B-NP major JJ I-NP signal-mediating JJ I-NP kinases NNS I-NP such JJ B-PP as IN I-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O COMMA COMMA O protein NN B-NP kinase NN I-NP A NN I-NP COMMA COMMA O or CC O Ca(2+)-regulated JJ B-NP kinases NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP found VBD B-VP that IN B-SBAR cytoplasmic JJ B-NP acidification NN I-NP facilitated VBD B-VP NF-kappa NN B-NP B NN I-NP activation NN I-NP by IN B-PP both CC O TNF NN B-NP alpha NN I-NP and CC O PKC NN B-NP COMMA COMMA O by IN B-PP a DT B-NP mechanism NN I-NP that WDT B-NP increases VBZ B-VP NF-kappa NN B-NP B\/I NN I-NP kappa NN I-NP B NN I-NP dissociation NN I-NP without IN B-PP affecting VBG B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP translocation NN I-NP step NN I-NP . . O NF-kappa NN B-NP B NN I-NP activity NN I-NP in IN B-PP T NN B-NP cells NNS I-NP stably RB B-VP expressing VBG I-VP the DT B-NP Tax NN I-NP protein NN I-NP of IN B-PP human JJ B-NP T NN I-NP cell NN I-NP lymphotropic JJ I-NP virus NN I-NP type NN I-NP I CD I-NP . . O The DT B-NP effect NN I-NP of IN B-PP constitutive JJ B-NP Tax NN I-NP expression NN I-NP on IN B-PP the DT B-NP interaction NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP with IN B-PP its PRP$ B-NP recognition NN I-NP sequence NN I-NP and CC B-PP on IN B-PP NF-kappa NN B-NP B-dependent JJ I-NP gene NN I-NP expression NN I-NP was VBD B-VP examined VBN I-VP in IN B-PP T NN B-NP lymphoid JJ I-NP Jurkat NN I-NP cell NN I-NP lines NNS I-NP ( ( O 19D NN B-NP and CC O 9J NN B-NP ) ) O stably RB B-VP transformed VBN I-VP with IN B-PP a DT B-NP Tax NN I-NP expression NN I-NP vector NN I-NP . . O Tax NN B-NP expressing NN I-NP T NN I-NP cell NN I-NP lines NNS I-NP contained VBD B-VP a DT B-NP constitutive JJ I-NP level NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP binding NN I-NP activity NN I-NP COMMA COMMA O detectable JJ B-ADJP by IN B-PP mobility NN B-NP shift NN I-NP assay NN I-NP and CC O uv NN B-NP cross-linking NN I-NP using VBG B-VP a DT B-NP palindromic JJ I-NP NF-kappa NN I-NP B NN I-NP probe NN I-NP homologous JJ B-ADJP to TO B-PP the DT B-NP interferon NN I-NP beta NN I-NP PRDII NN I-NP site NN I-NP . . O In IN B-PP Jurkat NN B-NP and CC O NC2.10 NN B-NP induction NN B-NP with IN B-PP phorbol NN B-NP esters NNS I-NP resulted VBD B-VP in IN B-PP the DT B-NP appearance NN I-NP of IN B-PP new JJ B-NP DNA NN I-NP binding NN I-NP proteins NNS I-NP of IN B-PP 85 CD B-NP COMMA COMMA I-NP 75 CD I-NP COMMA COMMA I-NP and CC I-NP 54 CD I-NP kDa NN I-NP COMMA COMMA O whereas IN O in IN B-PP Tax NN B-NP expressing NN I-NP cells NNS I-NP the DT B-NP 85-kDa JJ I-NP protein NN I-NP and CC O a DT B-NP 92-kDa JJ I-NP DNA NN I-NP binding NN I-NP protein NN I-NP were VBD B-VP constitutively RB I-VP induced VBN I-VP . . O Expression NN B-NP of IN B-PP Tax NN B-NP protein NN I-NP in IN B-PP 19D NN B-NP and CC O 9J NN B-NP resulted VBD B-VP in IN B-PP transcription NN B-NP of IN B-PP the DT B-NP endogenous JJ I-NP NF-kappa NN I-NP B-dependent JJ I-NP granulocyte-macrophage JJ I-NP colony NN I-NP stimulating NN I-NP factor NN I-NP gene NN I-NP and CC O increased VBD B-NP basal JJ I-NP level NN I-NP expression NN I-NP of IN B-PP transfected VBN B-NP NF-kappa NN I-NP B-regulated JJ I-NP promoters NNS I-NP . . O Nonetheless RB B-ADVP transcription NN B-NP of IN B-PP both CC O the DT B-NP endogenous JJ I-NP and CC O the DT B-NP transfected VBN I-NP gene NN B-NP was VBD B-VP inducible JJ B-ADJP by IN B-PP PMA NN B-NP treatment NN I-NP . . O Tax NN B-NP expression NN I-NP in IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP may MD B-VP alter VB I-VP the DT B-NP stoichiometry NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP DNA NN I-NP binding NN I-NP proteins NNS I-NP and CC O thus RB O change VB B-VP the DT B-NP expression NN I-NP of IN B-PP NF-kappa NN B-NP B-regulated JJ I-NP promoters NNS I-NP . . O Regulation NN B-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP human JJ B-NP mononuclear JJ I-NP cells NNS I-NP : : O effects NNS B-NP of IN B-PP glucocorticoid NN B-NP treatment NN I-NP COMMA COMMA O Cushing NN B-NP 's POS B-NP disease NN I-NP and CC O ketoconazole NN B-NP . . O Glucocorticoid NN B-NP receptors NNS I-NP ( ( O GcR NN B-NP ) ) O were VBD B-VP determined VBN I-VP by IN B-PP a DT B-NP whole JJ I-NP cell NN I-NP assay NN I-NP in IN B-PP human JJ B-NP mononulear JJ I-NP leukocytes NNS I-NP ( ( O hMNL NN B-NP ) ) O from IN B-PP control NN B-NP subjects NNS I-NP COMMA COMMA O patients NNS B-NP receiving VBG B-VP glucocorticoid NN B-NP therapy NN I-NP for IN B-PP systemic JJ B-NP diseases NNS I-NP and CC O Cushing NN B-NP 's POS B-NP disease NN I-NP patients NNS B-NP with IN B-PP or CC B-PP without IN B-PP ketoconazole NN B-NP therapy NN I-NP . . O Prolonged JJ B-NP corticosteroid NN I-NP treatment NN I-NP resulted VBD B-VP in IN B-PP down-regulation NN B-NP of IN B-PP GcR NN B-NP COMMA COMMA O while IN B-SBAR the DT B-NP mean NN I-NP level NN I-NP of IN B-PP GcR NN B-NP in IN B-PP Cushing NN B-NP 's POS B-NP disease NN I-NP was VBD B-VP normal JJ B-ADJP . . O In IN B-PP this DT B-NP group NN I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O receptor NN B-NP levels NNS I-NP and CC O morning NN B-NP plasma NN I-NP cortisol NN I-NP values NNS I-NP showed VBD B-VP a DT B-NP negative JJ I-NP correlation NN I-NP COMMA COMMA O indicating VBG B-VP a DT B-NP subtle JJ I-NP down-regulatory JJ I-NP effect NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O GcR NN B-NP were VBD B-VP unaltered JJ B-ADJP after IN B-SBAR these DT B-NP patients NNS I-NP received VBD B-VP ketoconazole NN B-NP COMMA COMMA O in IN B-PP spite NN I-PP of IN I-PP a DT B-NP marked JJ I-NP reduction NN I-NP in IN B-PP morning NN B-NP plasma NN I-NP cortisol NN I-NP and CC O urinary JJ B-NP free JJ I-NP cortisol NN I-NP . . O We PRP B-NP also RB B-ADVP observed VBD B-VP that IN B-SBAR ketoconazole NN B-NP was VBD B-VP a DT B-NP weak JJ I-NP competitor NN I-NP of IN B-PP GcR NN B-NP in IN B-PP intact JJ B-NP cells NNS I-NP COMMA COMMA O although IN B-SBAR it PRP B-NP significantly RB B-ADVP inhibited VBD B-VP {3H} NN B-NP dexamethasone NN I-NP binding NN I-NP in IN B-PP cytosolic JJ B-NP preparations NNS I-NP from IN B-PP rat NN B-NP tissues NNS I-NP . . O The DT B-NP results NNS I-NP suggested VBD B-VP that IN B-SBAR GcR NN B-NP in IN B-PP hMNL NN B-NP are VBP B-VP down-regulated VBN I-VP by IN B-PP synthetic JJ B-NP steroids NNS I-NP given VBN B-VP in FW B-ADVP vivo FW I-ADVP COMMA COMMA O but CC O they PRP B-NP showed VBD B-VP very RB B-NP mild JJ I-NP down-regulation NN I-NP in IN B-PP hypercortisolemic JJ B-NP patients NNS I-NP suffering VBG B-VP from IN B-PP Cushing NN B-NP 's POS B-NP disease NN I-NP . . O Finally RB B-ADVP COMMA COMMA O we PRP B-NP did VBD B-VP not RB I-VP observed VBN I-VP either CC O up-regulation NN B-NP or CC O antagonism NN B-NP of IN B-PP GcR NN B-NP by IN B-PP ketoconazole NN B-NP treatment NN I-NP COMMA COMMA O at IN B-PP the DT B-NP time NN I-NP that IN B-ADVP cortisol NN B-NP levels NNS I-NP of IN B-PP patients NNS B-NP with IN B-PP Cushing NN B-NP 's POS B-NP disease NN I-NP were VBD B-VP reduced VBN I-VP . . O This DT B-NP indicates VBZ B-VP that IN B-SBAR the DT B-NP beneficial JJ I-NP effects NNS I-NP of IN B-PP ketoconazole NN B-NP in IN B-PP Cushing NN B-NP 's POS B-NP disease NN I-NP are VBP B-VP due JJ B-PP to TO B-PP adrenal JJ B-NP cortisol NN I-NP suppression NN I-NP and CC B-PP not RB B-PP to TO I-PP interaction NN B-NP with IN B-PP GcR NN B-NP of IN B-PP target NN B-NP cells NNS I-NP COMMA COMMA O and CC O that IN B-SBAR the DT B-NP process NN I-NP of IN B-PP GcR NN B-NP regulation NN I-NP in IN B-PP hMNL NN B-NP is VBZ B-VP a DT B-NP complex JJ I-NP phenomenon NN I-NP awaiting VBG B-VP further RBR B-NP elucidation NN I-NP . . O Glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP lymphocytes NNS B-NP in IN B-PP anorexia NN B-NP nervosa NN I-NP . . O OBJECTIVE NN B-NP : : O The DT B-NP aim NN I-NP was VBD B-VP to TO B-VP explore VB I-VP the DT B-NP down-regulation NN I-NP of IN B-PP the DT B-NP glucocorticoid NN I-NP receptors NNS I-NP during IN B-PP hypercortisolaemia NN B-NP in IN B-PP anorexia NN B-NP nervosa NN I-NP . . O DESIGN NN B-NP : : O Urine NN B-NP and CC O plasma NN B-NP samples NNS B-NP were VBD B-VP obtained VBN I-VP for IN B-PP cortisol NN B-NP determination NN I-NP and CC O blood NN B-NP lymphocytes NNS I-NP were VBD B-VP isolated VBN I-VP for IN B-PP receptor NN B-NP binding NN I-NP studies NNS I-NP . . O PATIENTS NNS B-NP : : O Sixteen CD B-NP anorexic JJ I-NP patients NNS I-NP COMMA COMMA O aged JJ B-ADJP 16-27 CD B-NP years NNS I-NP COMMA COMMA O with IN B-PP a DT B-NP mean NN I-NP +\/- CC I-NP SEM NN I-NP body NN I-NP mass NN I-NP index NN I-NP of IN B-PP 14.2 CD B-NP +\/- CC I-NP 2.0 CD I-NP ( ( O ranging VBG B-VP from IN B-PP 11.1 CD B-NP to TO B-PP 17.4 CD B-NP ) ) O COMMA COMMA O and CC O 15 CD B-NP normal JJ I-NP women NNS I-NP were VBD B-VP studied VBN I-VP . . O Six CD B-NP patients NNS I-NP were VBD B-VP reinvestigated VBN I-VP after IN B-PP a DT B-NP significant JJ I-NP weight NN I-NP gain NN I-NP . . O MEASUREMENTS NNS B-NP : : O The DT B-NP binding NN B-NP capacity NN B-NP and CC O affinity NN B-NP of IN B-PP the DT B-NP glucocorticoid NN I-NP receptors NNS I-NP were VBD B-VP measured VBN I-VP with IN B-PP dexamethasone NN B-NP as IN B-PP ligand NN B-NP on IN B-PP lymphocytes NNS B-NP . . O RESULTS NNS B-NP : : O In IN B-PP patients NNS B-NP COMMA COMMA O both DT B-NP total JJ I-NP and CC I-NP free JJ I-NP plasma NN I-NP cortisol NN I-NP concentrations NNS I-NP were VBD B-VP higher JJR B-ADJP than IN B-PP in IN B-PP the DT B-NP normal JJ I-NP women NNS I-NP COMMA COMMA O as IN B-SBAR was VBD O their PRP$ B-NP urinary JJ I-NP free JJ I-NP cortisol NN I-NP ; : O the DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP per IN B-PP cell NN B-NP ( ( O Ro NN B-NP ) ) O and CC O the DT B-NP binding NN I-NP affinity NN I-NP ( ( O Kd NN B-NP ) ) O for IN B-PP dexamethasone NN B-NP were VBD B-VP COMMA COMMA O however RB B-ADVP COMMA COMMA O not RB B-ADJP significantly RB I-ADJP different JJ I-ADJP ( ( O Ro NN B-NP : : O 7687 CD B-NP +\/- CC I-NP 1750 CD I-NP vs CC I-NP 7347 CD I-NP +\/- CC I-NP 1285 CD I-NP sites\/cell NN I-NP ; : O Kd NN B-NP : : O 7.7 CD B-NP +\/- CC I-NP 2.4 CD I-NP vs CC I-NP 7.4 CD I-NP +\/- CC I-NP 1.7 CD I-NP nM NN I-NP at IN B-PP 24 CD B-NP degrees NNS I-NP C NN I-NP ) ) O . . O After IN B-PP weight NN B-NP gain NN I-NP ( ( O 14 CD B-NP +\/- CC I-NP 2 CD I-NP to TO I-NP 16 CD I-NP +\/- CC I-NP 2 CD I-NP kg\/m2 NN I-NP ) ) O COMMA COMMA O receptor NN B-NP numbers NNS I-NP were VBD B-VP 8421 CD B-NP +\/- CC I-NP 2126 CD I-NP ( ( O pre JJ O ) ) O and CC O 9011 CD B-NP +\/- CC I-NP 500 CD I-NP ( ( O post JJ O ) ) O sites\/cell NN B-NP COMMA COMMA O which WDT B-NP are VBP B-VP not RB O significantly RB B-ADJP different JJ I-ADJP ( ( O P NN B-NP greater JJR B-ADJP than IN B-PP 0.2 CD B-NP ) ) O ; : O the DT B-NP Kd NN I-NP was VBD B-VP unchanged JJ B-ADJP ( ( O 9.3 CD B-NP +\/- CC I-NP 2.6 CD I-NP vs CC I-NP 9.2 CD I-NP +\/- CC I-NP 2.4 CD I-NP nM NN I-NP ) ) O . . O CONCLUSIONS NNS B-NP Hypercortisolaemia NN B-NP does VBZ B-VP not RB I-VP down-regulate VB I-VP the DT B-NP lymphocyte NN I-NP glucocorticoid NN I-NP receptors NNS I-NP in IN B-PP anorexia NN B-NP nervosa NN I-NP and CC O a DT B-NP post-receptor JJ I-NP defect NN I-NP might MD B-VP be VB I-VP involved VBN I-VP in IN B-PP peripheral JJ B-NP tissue NN I-NP resistance NN I-NP to TO B-PP the DT B-NP effects NNS I-NP of IN B-PP glucocorticoid NN B-NP hormones NNS I-NP in IN B-PP undernutrition NN B-NP . . O Tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP mRNA NN I-NP accumulation NN I-NP in IN B-PP human JJ B-NP myelomonocytic JJ I-NP cell NN I-NP lines NNS I-NP . . O Role NN B-NP of IN B-PP transcriptional JJ B-NP regulation NN I-NP by IN B-PP DNA NN B-NP sequence NN I-NP motifs NNS I-NP and CC O mRNA NN B-NP stabilization NN I-NP . . O The DT B-NP cytokine NN I-NP TNF NN I-NP mediates VBZ B-VP many JJ B-NP of IN B-PP the DT B-NP pathologic JJ I-NP signs NNS I-NP of IN B-PP cachexia NN B-NP COMMA COMMA O inflammation NN B-NP COMMA COMMA O and CC O sepsis NN B-NP . . O The DT B-NP current JJ I-NP work NN I-NP describes VBZ B-VP the DT B-NP regulation NN I-NP of IN B-PP TNF NN B-NP in IN B-PP human JJ B-NP myelomonocytic JJ I-NP cell NN I-NP lines NNS I-NP after IN B-PP PMA NN B-NP stimulation NN I-NP . . O The DT B-NP cell NN I-NP lines NNS I-NP exhibit VBP B-VP a DT B-NP low JJ I-NP level NN I-NP of IN B-PP constitutive JJ B-NP TNF NN I-NP mRNA NN I-NP expression NN I-NP . . O Within IN B-PP 2 CD B-NP to TO I-NP 4 CD I-NP h NN I-NP of IN B-PP PMA NN B-NP exposure NN I-NP COMMA COMMA O steady JJ B-NP state NN I-NP levels NNS I-NP of IN B-PP TNF NN B-NP mRNA NN I-NP are VBP B-VP markedly RB I-VP elevated JJ I-VP in IN B-PP all DT B-NP myelomonocytic JJ I-NP cell NN I-NP lines NNS I-NP studied VBN B-VP . . O This DT B-NP rise NN I-NP is VBZ B-VP due JJ B-PP to TO B-PP increased VBN B-NP mRNA NN I-NP stability NN I-NP COMMA COMMA O which WDT B-NP increased VBD B-VP by IN B-PP almost RB B-NP twofold RB I-NP COMMA COMMA B-PP and CC I-PP to TO B-PP an DT B-NP overall JJ I-NP increase NN I-NP in IN B-PP transcription NN B-NP COMMA COMMA O which WDT B-NP rises VBZ B-VP by IN B-PP more JJR B-NP than IN I-NP sixfold RB I-NP . . O At IN B-PP the DT B-NP level NN I-NP of IN B-PP the DT B-NP genomic JJ I-NP TNF NN I-NP gene NN I-NP COMMA COMMA O a DT B-NP DNase NN I-NP I CD I-NP hypersensitive JJ I-NP site NN I-NP is VBZ B-VP detected VBN I-VP within IN B-PP the DT B-NP TNF NN I-NP promoter NN I-NP between IN B-PP -200 CD B-NP to TO I-NP -100 CD I-NP bp NN I-NP relative JJ B-PP to TO I-PP the DT B-NP transcription NN I-NP initiation NN I-NP site NN I-NP . . O Although IN B-SBAR absent JJ B-ADJP in IN B-PP nonexpressing VBG B-NP erythroleukemia NN I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O the DT B-NP DNase NN I-NP I CD I-NP site NN I-NP is VBZ B-VP present JJ B-ADJP in IN B-PP uninduced JJ B-NP myelomonocytic JJ I-NP cell NN I-NP lines NNS I-NP and CC O is VBZ B-VP not RB I-VP changed VBN I-VP after IN B-PP PMA NN B-NP induction NN I-NP . . O The DT B-NP PMA NN I-NP induction NN I-NP of IN B-PP c-fos NN B-NP mRNA NN I-NP correlated VBD B-VP well RB B-ADVP with IN B-PP TNF NN B-NP gene NN I-NP induction NN I-NP ; : O expression NN B-NP of IN B-PP genes NNS B-NP encoding VBG B-VP other JJ B-NP proteins NNS I-NP in IN B-PP the DT B-NP AP-1 NN I-NP complex NN I-NP ( ( O junB NN B-NP and CC O junD NN B-NP ) ) O were VBD B-VP also RB I-VP induced VBN I-VP by IN B-PP PMA NN B-NP . . O The DT B-NP nuclear JJ I-NP extracts NNS I-NP from IN B-PP resting VBG B-NP and CC I-NP induced VBN I-NP ML-1 NN I-NP cells NNS I-NP contain VBP B-VP proteins NNS B-NP binding VBG B-VP specifically RB B-ADVP to TO B-PP the DT B-NP AP-1 NN B-NP COMMA COMMA O AP-2 NN B-NP COMMA COMMA O and CC O NF NN B-NP kappa NN I-NP B NN I-NP sequence NN I-NP located JJ B-ADJP within IN B-PP the DT B-NP TNF NN I-NP promoter NN I-NP . . O PMA NN B-NP induction NN I-NP increases VBZ B-VP the DT B-NP level NN I-NP of IN B-PP a DT B-NP number NN I-NP of IN B-PP specific JJ B-NP binding VBG I-NP complexes NNS I-NP relative JJ B-PP to TO I-PP the DT B-NP resting VBG I-NP cells NNS I-NP . . O The DT B-NP regulatory JJ I-NP mechanisms NNS I-NP of IN B-PP the DT B-NP human JJ I-NP and CC I-NP murine JJ I-NP TNF NN I-NP genes NNS I-NP are VBP B-VP discussed VBN I-VP . . O USF-related JJ B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O HIV-TF1 NN B-NP COMMA COMMA O stimulates VBZ B-VP transcription NN B-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus-1 NN I-NP . . O The DT B-NP transcription NN I-NP factor NN I-NP HIV-TF1 NN I-NP COMMA COMMA O which WDT B-NP binds VBZ B-VP to TO B-PP a DT B-NP region NN I-NP about IN B-NP 60 CD I-NP bp NN I-NP upstream JJ B-ADJP from IN B-PP the DT B-NP enhancer NN I-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus-1 NN I-NP ( ( O HIV-1 NN B-NP ) ) O COMMA COMMA O was VBD B-VP purified VBN I-VP from IN B-PP human JJ B-NP B NN I-NP cells NNS I-NP . . O HIV-TF1 NN B-NP had VBD B-VP a DT B-NP molecular JJ I-NP weight NN I-NP of IN B-PP 39COMMA000 CD B-NP . . O Binding NN B-NP of IN B-PP HIV-TF1 NN B-NP to TO B-PP the DT B-NP HIV NN I-NP long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O activated VBD B-VP transcription NN B-NP from IN B-PP the DT B-NP HIV NN I-NP promoter NN I-NP in FW B-ADVP vitro FW I-ADVP . . O The DT B-NP HIV-TF1-binding JJ I-NP site NN I-NP in IN B-PP HIV NN B-NP LTR NN I-NP was VBD B-VP similar JJ B-ADJP to TO B-PP the DT B-NP site NN I-NP recognized VBN B-VP by IN B-PP upstream JJ B-NP stimulatory JJ I-NP factor NN I-NP ( ( O USF NN B-NP ) ) O in IN B-PP the DT B-NP adenovirus NN I-NP major JJ I-NP late JJ I-NP promoter NN I-NP . . O DNA-binding JJ B-NP properties NNS I-NP of IN B-PP HIV-TF1 NN B-NP suggested VBD B-VP that IN B-SBAR HIV-TF1 NN B-NP might MD B-VP be VB I-VP identical JJ B-ADJP or CC O related JJ B-ADJP to TO B-PP USF NN B-NP . . O Interestingly RB B-ADVP COMMA COMMA O treatment NN B-NP of IN B-PP purified VBN B-NP HIV-TF1 NN I-NP by IN B-PP phosphatase NN B-NP greatly RB B-ADVP reduced VBD B-VP its PRP$ B-NP DNA-binding JJ I-NP activity NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR phosphorylation NN B-NP of IN B-PP HIV-TF1 NN B-NP was VBD B-VP essential JJ B-ADJP for IN B-PP DNA NN B-NP binding NN I-NP . . O The DT B-NP disruption NN I-NP of IN B-PP HIV-TF1-binding JJ B-NP site NN I-NP induced VBD B-VP a DT B-NP 60 CD B-NP % NN I-NP decrease NN B-NP in IN B-PP the DT B-NP level NN I-NP of IN B-PP transcription NN B-NP from IN B-PP the DT B-NP HIV NN I-NP promoter NN I-NP in FW B-ADVP vivo FW I-ADVP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR HIV-TF1 NN B-NP is VBZ B-VP involved VBN I-VP in IN B-PP transcriptional JJ B-NP regulation NN I-NP of IN B-PP HIV-1 NN B-NP . . O The DT B-NP effect NN I-NP of IN B-PP toremifene NN B-NP therapy NN I-NP on IN B-PP serum NN B-NP immunoglobulin NN I-NP levels NNS I-NP in IN B-PP breast NN B-NP cancer NN I-NP . . O Estrogens NNS B-NP and CC O anti-estrogens NNS B-NP enhance VBP B-VP the DT B-NP number NN I-NP of IN B-PP immunoglobulin NN B-NP ( ( I-NP Ig NN I-NP ) ) I-NP -secreting NN I-NP cells NNS I-NP in IN B-PP pokeweed NN B-NP mitogen NN I-NP ( ( I-NP PWM NN I-NP ) ) I-NP -stimulated JJ I-NP lymphocyte NN I-NP cultures NNS I-NP . . O Lymphocytes NNS B-NP from IN B-PP patients NNS B-NP who WP B-NP have VBP B-VP received VBN I-VP anti-estrogen NN B-NP therapy NN I-NP show VBP B-VP similar JJ B-NP enhancement NN I-NP of IN B-PP Ig-secreting JJ B-NP cells NNS I-NP after IN B-PP PWM NN B-NP stimulation NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP the DT B-NP effect NN I-NP of IN B-PP anti-estrogen NN B-NP ( ( I-NP toremifene NN I-NP ) ) I-NP therapy NN I-NP on IN B-PP serum NN B-NP immunoglobulin NN I-NP ( ( O IgA NN B-NP COMMA COMMA O IgM NN B-NP COMMA COMMA O IgG NN B-NP ) ) O levels NNS B-NP in IN B-PP breast NN B-NP cancer NN I-NP patients NNS I-NP was VBD B-VP investigated VBN I-VP . . O Serum NN B-NP Ig NN I-NP levels NNS I-NP were VBD B-VP followed VBN I-VP up RB B-NP to TO I-NP two CD I-NP years NNS I-NP after IN B-PP or CC B-PP during IN B-PP the DT B-NP therapy NN I-NP . . O An DT B-NP unexpected JJ I-NP finding NN I-NP was VBD B-VP that IN B-SBAR the DT B-NP Ig NN I-NP levels NNS I-NP decreased VBD B-VP during IN B-PP the DT B-NP follow-up JJ I-NP period NN I-NP . . O This DT B-NP decrease NN I-NP was VBD B-VP seen VBN I-VP in IN B-PP patients NNS B-NP who WP B-NP responded VBD B-VP to TO B-PP the DT B-NP therapy NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP those DT B-NP who WP B-NP did VBD B-VP not RB O . . O HIV1 NN B-NP infection NN I-NP of IN B-PP human JJ B-NP monocytes NNS B-NP and CC O macrophages NNS B-NP promotes VBZ B-VP induction NN B-NP or CC O translocation NN B-NP of IN B-PP NF-KB-related JJ B-NP factors NNS I-NP . . O In IN B-PP 1991 CD B-NP COMMA COMMA O we PRP B-NP demonstrated VBD B-VP COMMA COMMA O using VBG B-VP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP COMMA COMMA O that IN B-SBAR 3 CD B-NP different JJ I-NP factors NNS I-NP ( ( O termed VBN B-VP B1 NN B-NP COMMA COMMA O B2 NN B-NP and CC O B3 NN B-NP ) ) O with IN B-PP affinity NN B-NP for IN B-PP the DT B-NP KB-enhancer JJ I-NP target NN I-NP sequence NN I-NP were VBD B-VP specifically RB I-VP detected VBN I-VP in IN B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP HIV1-infected JJ B-NP monocytes NNS B-NP and CC O macrophages NNS B-NP . . O The DT B-NP B2 NN I-NP factor NN I-NP was VBD B-VP induced VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP these DT B-NP cells NNS I-NP only RB B-PP upon IN I-PP HIV1 NN B-NP infection NN I-NP . . O The DT B-NP B3 NN I-NP factor NN I-NP was VBD B-VP only RB B-ADJP slightly RB I-ADJP evident JJ I-ADJP in IN B-PP nuclei NNS B-NP of IN B-PP uninfected JJ B-NP cells NNS I-NP but CC O was VBD B-VP readily RB B-ADJP detectable JJ I-ADJP in IN B-PP nuclei NNS B-NP of IN B-PP infected JJ B-NP monocytes NNS I-NP . . O Its PRP$ B-NP expression NN I-NP remained VBD B-VP very RB B-ADJP low JJ I-ADJP in IN B-PP nuclei NNS B-NP of IN B-PP HIV1-infected JJ B-NP macrophages NNS I-NP . . O In IN B-PP this DT B-NP paper NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP B2 NN I-NP factor NN I-NP is VBZ B-VP expressed VBN I-VP in IN B-PP the DT B-NP cytosol NN I-NP of IN B-PP monocytes NNS B-NP and CC O macrophages NNS B-NP as IN B-PP a DT B-NP DNA-binding JJ I-NP protein NN I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR it PRP B-NP is VBZ B-VP not RB I-VP associated VBN I-VP with IN B-PP an DT B-NP inhibitor NN I-NP ( ( O IKB NN B-NP ) ) O . . O This DT B-NP factor NN I-NP remained VBD B-VP clustered VBN B-ADJP in IN B-PP the DT B-NP cytosol NN I-NP and CC O was VBD B-VP translocated VBN I-VP to TO B-PP the DT B-NP nuclei NNS I-NP only RB B-PP after IN I-PP HIV1 NN B-NP infection NN I-NP . . O The DT B-NP B3 NN I-NP factor NN I-NP is VBZ B-VP detected VBN I-VP in IN B-PP the DT B-NP cytosol NN I-NP only RB O when WRB B-ADVP cells NNS B-NP are VBP B-VP HIV1-infected JJ B-ADJP . . O The DT B-NP role NN I-NP of IN B-PP HIV1 NN B-NP infection NN I-NP in IN B-PP the DT B-NP expression NN I-NP and CC O the DT B-NP translocation NN I-NP of IN B-PP these DT B-NP factors NNS I-NP is VBZ B-VP discussed VBN I-VP . . O Induction NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP during IN B-PP monocyte NN B-NP differentiation NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP activation NN B-NP of IN B-PP HIV-gene JJ B-NP expression NN I-NP . . O Cells NNS B-NP of IN B-PP the DT B-NP monocyte-macrophage JJ I-NP lineage NN I-NP are VBP B-VP important JJ B-NP targets NNS I-NP of IN B-PP HIV NN B-NP infection NN I-NP . . O We PRP B-NP report VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP phenotypic JJ I-NP differentiation NN I-NP of IN B-PP monocyte NN B-NP cell NN I-NP lines NNS I-NP induced VBN B-VP by IN B-PP phorbol NN B-NP esters NNS I-NP or CC O tumour NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF NN B-NP alpha NN I-NP ) ) O is VBZ B-VP associated VBN I-VP with IN B-PP expression NN B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O . . O In IN B-PP parallel NN I-PP with IN I-PP such JJ B-NP differentiation NN I-NP COMMA COMMA O HIV NN B-NP transcription NN I-NP COMMA COMMA O monitored VBN B-VP using VBG B-VP an DT B-NP HIV NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP reporter NN I-NP gene NN I-NP construct NN I-NP COMMA COMMA O is VBZ B-VP activated VBN I-VP in IN B-PP such JJ B-NP cells NNS I-NP under IN B-PP the DT B-NP influence NN I-NP of IN B-PP enhanced VBN B-NP NF-kappa NN I-NP B NN I-NP expression NN I-NP . . O Also RB B-ADVP COMMA COMMA O in IN B-PP a DT B-NP promonocyte JJ I-NP cell NN I-NP line NN I-NP chronically RB B-ADJP infected VBN I-ADJP with IN B-PP HIV NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP expression NN I-NP and CC O HIV NN B-NP transcription NN I-NP were VBD B-VP enhanced VBN I-VP on IN B-PP stimulation NN B-NP with IN B-PP phorbol NN B-NP ester NN I-NP or CC O TNF NN B-NP alpha NN I-NP . . O Thus RB B-ADVP COMMA COMMA O stimulation NN B-NP of IN B-PP monocyte NN B-NP cell NN I-NP lines NNS I-NP by IN B-PP phorbol NN B-NP esters NNS I-NP or CC O TNF NN B-NP alpha NN I-NP induces VBZ B-VP cell NN B-NP differentiation NN I-NP and CC O activates VBZ B-VP HIV NN B-NP transcription NN I-NP . . O Such PDT B-NP a DT I-NP process NN I-NP may MD B-VP have VB I-VP fundamental JJ B-NP implications NNS I-NP in IN B-PP AIDS NN B-NP pathogenesis NN I-NP in FW B-ADVP vivo FW I-ADVP and CC O may MD B-VP be VB I-VP important JJ B-ADJP in IN B-PP disease NN B-NP progression NN I-NP induced VBN B-VP by IN B-PP opportunistic JJ B-NP infections NNS I-NP directly RB B-ADVP or CC O indirectly RB B-ADVP involving VBG B-VP macrophages NNS B-NP . . O A DT B-NP nuclear JJ I-NP factor NN I-NP NF-GM2 NN I-NP that WDT B-NP interacts VBZ B-VP with IN B-PP a DT B-NP regulatory JJ I-NP region NN I-NP of IN B-PP the DT B-NP GM-CSF NN I-NP gene NN I-NP essential JJ B-ADJP for IN B-PP its PRP$ B-NP induction NN I-NP in IN B-PP responses NNS I-PP to TO I-PP T-cell NN B-NP activation NN I-NP : : O purification NN B-NP from IN B-PP human JJ B-NP T-cell NN I-NP leukemia NN I-NP line NN I-NP Jurkat NN I-NP cells NNS I-NP and CC O similarity NN B-NP to TO B-PP NF-kappa NN B-NP B NN I-NP . . O Activation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP by IN B-PP antigen NN B-NP COMMA COMMA O lectin NN B-NP COMMA COMMA O or CC O a DT B-NP combination NN I-NP of IN B-PP phorbol-12-myristate NN B-NP acetate NN I-NP ( ( O PMA NN B-NP ) ) O and CC O calcium NN B-NP ionophore NN I-NP ( ( O A23187 NN B-NP ) ) O leads VBZ B-VP to TO B-PP the DT B-NP induction NN I-NP of IN B-PP genes NNS B-NP for IN B-PP a DT B-NP set NN I-NP of IN B-PP lymphokines NNS B-NP COMMA COMMA O including VBG B-PP granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O . . O We PRP B-NP demonstrated VBD B-VP in IN B-PP earlier JJR B-NP studies NNS I-NP that IN B-SBAR the DT B-NP upstream JJ I-NP region NN I-NP of IN B-PP the DT B-NP mouse NN I-NP GM-CSF NN I-NP promoter NN I-NP at IN B-PP positions NNS B-NP between IN B-PP -95 CD B-NP and CC O -73 CD B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP transcriptional JJ B-NP activation NN I-NP in IN B-PP response NN I-PP to TO I-PP PMA\/A23187 NN B-NP . . O This DT B-NP region NN I-NP contains VBZ B-VP two CD B-NP DNA-binding JJ I-NP motifs NNS I-NP COMMA COMMA O GM2 NN B-NP and CC O GC-box NN B-NP . . O The DT B-NP GM2 NN I-NP sequence NN I-NP ( ( O GGTAGTTCCC NN B-NP ) ) O is VBZ B-VP recognized VBN I-VP by IN B-PP an DT B-NP inducible JJ I-NP factor NN I-NP NF-GM2 NN I-NP ; : O the DT B-NP other JJ I-NP ( ( O CCGCCC NN B-NP ) ) O by IN B-PP constitutive JJ B-NP factors NNS I-NP A1 NN B-NP COMMA COMMA O A2 NN B-NP COMMA COMMA O and CC O B NN B-NP . . O To TO B-VP elucidate VB I-VP the DT B-NP mechanism NN I-NP of IN B-PP GM-CSF NN B-NP gene NN I-NP activation NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP purified VBN I-VP the DT B-NP inducible JJ I-NP factor NN I-NP NF-GM2 NN I-NP from IN B-PP the DT B-NP nuclear JJ I-NP extract NN I-NP of IN B-PP stimulated VBN B-NP Jurkat NN I-NP cells NNS I-NP on IN B-PP the DT I-PP basis NN I-PP of IN I-PP specific JJ B-NP DNA-binding JJ I-NP activity NN I-NP . . O The DT B-NP purified VBN I-NP NF-GM2 NN I-NP consists VBZ B-VP of IN B-PP 50 CD B-NP ( ( O p50 NN B-NP ) ) O and CC O 65 CD B-NP kDa NN B-NP ( ( O p65 NN B-NP ) ) O polypeptides NNS B-NP and CC O has VBZ B-VP a DT B-NP binding NN I-NP activity NN I-NP specific JJ B-ADJP for IN B-PP both CC O the DT O GM-CSF NN B-NP and CC O immunoglobulin NN B-NP kappa NN I-NP ( ( O GGAAAGTCCC NN B-NP ) ) O enhancers NNS B-NP . . O Electrophoretically RB B-NP purified VBN I-NP p50 NN I-NP alone RB B-ADVP can MD B-VP form VB I-VP a DT B-NP protein-DNA JJ I-NP complex NN I-NP COMMA COMMA O but CC O in IN B-PP the DT B-NP mixture NN I-NP COMMA COMMA O p50 NN B-NP associates VBZ B-VP preferentially RB B-ADVP with IN B-PP p65 NN B-NP to TO B-VP form VB I-VP the DT B-NP NF-GM2 NN I-NP complex NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O p65 NN B-NP gave VBD B-VP per FW B-ADVP se FW I-ADVP COMMA COMMA O with IN B-PP low JJ B-NP affinity NN I-NP COMMA COMMA O a DT B-NP protein-DNA JJ I-NP complex NN I-NP that WDT B-NP migrated VBD B-VP more RBR B-ADVP slowly RB I-ADVP than IN B-PP native JJ B-NP NF-GM2 NN I-NP complex NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O an DT B-NP antiserum NN I-NP against IN B-PP KBF1 NN B-NP ( ( O identical JJ B-ADJP to TO B-PP 50 CD B-NP kDa NN I-NP NF-kappa NN I-NP B NN I-NP protein NN I-NP ) ) O reacted VBD B-VP with IN B-PP the DT B-NP p50 NN I-NP of IN B-PP NF-GM2 NN B-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP NF-GM2 NN I-NP polypeptide NN I-NP can MD B-VP not RB I-VP be VB I-VP immunologically RB I-VP differentiated VBN I-VP from IN B-PP the DT B-NP 50 CD I-NP kDa NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O The DT B-NP purified VBN I-NP NF-GM2 NN I-NP activated VBD B-VP in FW B-NP vitro FW I-NP transcription NN I-NP from IN B-PP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP COMMA COMMA O while IN B-SBAR it PRP B-NP failed VBD B-VP to TO I-VP stimulate VB I-VP transcription NN B-NP from IN B-PP the DT B-NP GM-CSF NN I-NP promoter NN I-NP harboring VBG B-VP the DT B-NP GM2 NN I-NP sequence NN I-NP . . O This DT B-NP suggests VBZ B-VP that IN B-SBAR the DT B-NP activation NN I-NP mechanism NN I-NP of IN B-PP the DT B-NP GM-CSF NN I-NP gene NN I-NP through IN B-PP the DT B-NP GM2\/GC-box JJ I-NP sequence NN I-NP is VBZ B-VP different JJ B-ADJP from IN B-PP that DT B-NP of IN B-PP genes NNS B-NP carrying VBG B-VP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP alone RB B-ADVP . . O Glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP normal JJ B-NP leukocytes NNS I-NP : : O effects NNS B-NP of IN B-PP age NN B-NP COMMA COMMA O gender NN B-NP COMMA COMMA O season NN B-NP COMMA COMMA O and CC O plasma NN B-NP cortisol NN I-NP concentrations NNS I-NP . . O We PRP B-NP measured VBD B-VP glucocorticoid NN B-NP receptors NNS I-NP ( ( O GR NN B-NP ) ) O in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP ( ( O MNL NN B-NP ) ) O isolated VBN B-VP from IN B-PP peripheral JJ B-NP blood NN I-NP of IN B-PP 145 CD B-NP apparently RB I-NP healthy JJ I-NP volunteers NNS I-NP ( ( O 86 CD B-NP men NNS I-NP and CC O 59 CD B-NP women NNS I-NP ) ) O . . O An DT B-NP age-related JJ I-NP decrease NN I-NP in IN B-PP the DT B-NP number NN I-NP of IN B-PP GR NN B-NP was VBD B-VP suggested VBN I-VP between IN B-PP subjects NNS B-NP younger JJR B-ADJP than IN B-PP 20 CD B-NP years NNS I-NP and CC O elderly JJ B-NP subjects NNS I-NP ; : O there EX B-NP was VBD B-VP no DT B-NP apparent JJ I-NP seasonal JJ I-NP variation NN I-NP in IN B-PP GR NN B-NP . . O Gender NN B-NP difference NN I-NP in IN B-PP the DT B-NP number NN I-NP of IN B-PP GR NN B-NP was VBD B-VP not RB O significant JJ B-ADJP COMMA COMMA O although IN B-SBAR women NNS B-NP showed VBD B-VP slightly RB B-NP fewer JJR I-NP GR NN I-NP . . O Eight CD B-NP patients NNS I-NP with IN B-PP dermatomyositis\/polymyositis NN B-NP were VBD B-VP examined VBN I-VP to TO B-VP determine VB I-VP whether IN B-SBAR the DT B-NP number NN I-NP of IN B-PP GR NN B-NP in IN B-PP MNL NN B-NP could MD B-VP be VB I-VP down-regulated VBN I-VP by IN B-PP their PRP$ B-NP cognate JJ I-NP ligands NNS I-NP . . O The DT B-NP number NN I-NP of IN B-PP GR NN B-NP in IN B-PP MNL NN B-NP from IN B-PP these DT B-NP patients NNS I-NP was VBD B-VP significantly RB I-VP decreased VBN I-VP one CD B-NP month NN I-NP after IN B-PP the DT B-NP initiation NN I-NP of IN B-PP prednisolone NN B-NP therapy NN I-NP . . O However RB B-ADVP COMMA COMMA O in IN B-PP normal JJ B-NP subjects NNS I-NP COMMA COMMA O the DT B-NP GR NN I-NP in IN B-PP MNL NN B-NP did VBD B-VP not RB I-VP demonstrate VB I-VP circadian JJ B-NP variation NN I-NP COMMA COMMA O in IN B-PP contrast NN I-PP to TO I-PP concentrations NNS B-NP of IN B-PP plasma NN B-NP cortisol NN I-NP . . O Anti-CD2 JJ B-NP receptor NN I-NP antibodies NNS I-NP activate VBP B-VP the DT B-NP HIV NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP . . O The DT B-NP CD2 NN I-NP T NN I-NP lymphocyte NN I-NP glycoprotein NN I-NP surface NN I-NP molecule NN I-NP mediates VBZ B-VP both CC O cell NN B-NP to TO I-NP cell NN I-NP adhesion NN I-NP and CC O T NN B-NP cell NN I-NP activation NN I-NP COMMA COMMA O two CD B-NP processes NNS I-NP that WDT B-NP are VBP B-VP involved VBN I-VP in IN B-PP the DT B-NP spread NN I-NP of IN B-PP HIV NN B-NP infection NN I-NP . . O Treatment NN B-NP of IN B-PP chronically RB B-NP HIV-infected JJ I-NP PBMC NN I-NP with IN B-PP anti-CD2 JJ B-NP mAb NN I-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP induce VB I-VP the DT B-NP expression NN I-NP of IN B-PP infectious JJ B-NP virus NN I-NP from IN B-PP these DT B-NP cultures NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP investigated VBD B-VP the DT B-NP mechanisms NNS I-NP whereby WRB B-ADVP anti-CD2 JJ B-NP antibodies NNS I-NP stimulate VBP B-VP viral JJ B-NP production NN I-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR treatment NN B-NP of IN B-PP transiently RB B-NP transfected VBN I-NP T NN I-NP lymphocytes NNS I-NP with IN B-PP anti-CD2 JJ B-NP antibodies NNS I-NP results VBZ B-VP in IN B-PP activation NN B-NP of IN B-PP the DT B-NP HIV NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O CAT NN B-NP assays NNS I-NP using VBG B-VP mutated VBN B-NP HIV NN I-NP long JJ I-NP terminal JJ I-NP repeat-CAT NN I-NP constructs NNS I-NP and CC O gel NN B-NP shift NN I-NP assays NNS I-NP demonstrate VBP B-VP that IN B-SBAR this DT B-NP activation NN I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP enhancer NN I-NP . . O These DT B-NP studies NNS I-NP suggest VBP B-VP that IN B-SBAR interaction NN B-NP of IN B-PP CD2 NN B-NP with IN B-PP its PRP$ B-NP natural JJ I-NP ligand NN I-NP COMMA COMMA O LFA-3 NN B-NP COMMA COMMA O may MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP regulation NN B-NP of IN B-PP HIV NN B-NP expression NN I-NP . . O Nuclear JJ B-NP transcription NN I-NP factors NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP elements NNS B-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP . . O Induction NN B-NP requirements NNS I-NP in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O Prior JJ B-NP studies NNS I-NP have VBP B-VP identified VBN I-VP several JJ B-NP elements NNS I-NP that WDT B-NP contribute VBP B-VP to TO B-PP the DT B-NP activity NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP in IN B-PP the DT B-NP stimulated VBN I-NP T NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O Jurkat NN B-NP . . O The DT B-NP sites NNS I-NP and CC O their PRP$ B-NP corresponding JJ I-NP nuclear JJ I-NP binding VBG I-NP factors NNS I-NP include VBP B-VP : : O NF-kappa NN B-NP B NN I-NP COMMA COMMA O AP-1 NN B-NP COMMA COMMA O AP-3 NN B-NP COMMA COMMA O OCT-1 NN B-NP COMMA COMMA O and CC O NF-AT NN B-NP . . O The DT B-NP latter JJ I-NP " `` O nuclear JJ B-NP factor NN I-NP for IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP " '' O likely RB B-ADVP contributes VBZ B-VP to TO B-PP the DT B-NP tissue NN I-NP specificity NN I-NP of IN B-PP IL-2 NN B-NP gene NN I-NP expression NN I-NP . . O Using VBG B-VP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP studied VBN I-VP these DT B-NP transcription NN B-NP factors NNS I-NP in IN B-PP primary JJ B-NP T NN I-NP cells NNS I-NP from IN B-PP human JJ B-NP blood NN I-NP to TO B-VP verify VB I-VP their PRP$ B-NP presence NN I-NP in IN B-PP a DT B-NP physiologic JJ I-NP setting NN I-NP and CC O to TO B-VP identify VB I-VP the DT B-NP signals NNS I-NP that WDT B-NP stimulate VBP B-VP factor NN B-NP activity NN I-NP . . O All DT B-NP factors NNS I-NP are VBP B-VP induced VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP T NN B-NP cells NNS I-NP upon IN B-PP activation NN B-NP with IN B-PP mitogens NNS B-NP but CC B-PP not RB B-PP with IN I-PP exogenous JJ B-NP IL-2 NN I-NP growth NN I-NP factor NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP signaling NN I-NP requirements NNS I-NP and CC O sensitivity NN B-NP to TO B-PP protein NN B-NP synthesis NN I-NP inhibitors NNS I-NP differ VBP B-VP considerably RB B-ADVP . . O Only RB B-NP the DT I-NP activities NNS I-NP for IN B-PP NF-AT NN B-NP and CC O AP-1 NN B-NP sites NNS B-NP require VBP B-VP two CD B-NP signals NNS I-NP for IN B-PP optimal JJ B-NP induction NN I-NP COMMA COMMA O i.e. FW B-PP COMMA COMMA O PMA NN B-NP plus CC O either CC O lectin NN B-NP or CC O antibody NN B-NP to TO B-PP the DT O CD3 NN B-NP or CC O CD28 NN B-NP surface NN B-NP molecules NNS I-NP . . O Other JJ B-NP factors NNS I-NP are VBP B-VP induced VBN I-VP by IN B-PP lectin NN B-NP COMMA COMMA O antibody NN B-NP COMMA COMMA O and\/or CC O PMA NN B-NP alone RB B-ADVP . . O After IN B-PP appropriate JJ B-NP stimulation NN I-NP COMMA COMMA O both CC O NF-AT NN B-NP and CC O AP-1 NN B-NP are VBP B-VP peculiarly RB B-ADJP sensitive JJ I-ADJP to TO B-PP the DT B-NP protein NN I-NP synthesis NN I-NP inhibitor NN I-NP anisomycin NN I-NP . . O Our PRP$ B-NP data NNS I-NP correlate VBP B-VP the DT B-NP activity NN I-NP of IN B-PP NF-AT NN B-NP and CC O AP-1 NN B-NP in IN B-PP gel NN B-NP shift NN I-NP assays NNS I-NP with IN B-PP the DT B-NP two CD I-NP signals NNS I-NP requirements NNS I-NP for IN B-PP IL-2 NN B-NP gene NN I-NP expression NN I-NP . . O An DT B-NP erythroid JJ I-NP specific JJ I-NP enhancer NN I-NP upstream JJ B-ADJP to TO B-PP the DT B-NP gene NN I-NP encoding VBG B-VP the DT B-NP cell-type JJ I-NP specific JJ I-NP transcription NN I-NP factor NN I-NP GATA-1 NN I-NP . . O The DT B-NP transcription NN I-NP factor NN I-NP GATA-1 NN I-NP is VBZ B-VP expressed VBN I-VP in IN B-PP a DT B-NP subset NN I-NP of IN B-PP hemopoietic JJ B-NP cells NNS I-NP COMMA COMMA O where WRB B-ADVP it PRP B-NP mediates VBZ B-VP the DT B-NP cell-type JJ I-NP specific JJ I-NP expression NN I-NP of IN B-PP several JJ B-NP genes NNS I-NP . . O We PRP B-NP have VBP B-VP cloned VBN I-VP the DT O mouse NN B-NP and CC O human JJ B-NP GATA-1 NN B-NP genes NNS I-NP . . O A DT B-NP region NN I-NP upstream JJ B-ADJP to TO B-PP the DT B-NP first JJ I-NP exon NN I-NP COMMA COMMA O and CC O highly RB B-VP conserved VBN I-VP between IN B-PP mouse NN B-NP and CC O man NN B-NP COMMA COMMA O acts VBZ B-VP as IN B-PP an DT B-NP erythroid JJ I-NP specific JJ I-NP enhancer NN I-NP in IN B-PP transient JJ B-NP assays NNS I-NP COMMA COMMA O if IN B-SBAR linked VBN B-VP to TO B-PP the DT B-NP GATA-1 NN I-NP or CC B-PP to TO B-PP the DT B-NP SV40 NN I-NP promoter NN B-NP . . O The DT B-NP activity NN I-NP of IN B-PP the DT B-NP enhancer NN I-NP is VBZ B-VP almost RB B-ADJP completely RB I-ADJP dependent JJ I-ADJP on IN B-PP the DT B-NP integrity NN I-NP of IN B-PP a DT B-NP dimeric JJ I-NP GATA-1 NN I-NP binding NN I-NP site NN I-NP . . O Demonstration NN B-NP of IN B-PP a DT B-NP 1COMMA25-dihydroxyvitamin NN I-NP D3-responsive JJ I-NP protein NN I-NP in IN B-PP human JJ B-NP lymphocytes NNS I-NP : : O immunologic JJ B-NP crossreactivity NN I-NP and CC O inverse JJ B-NP regulation NN I-NP with IN B-PP the DT B-NP vitamin NN I-NP D NN I-NP receptor NN I-NP . . O Using VBG B-VP Western NN B-NP blot NN I-NP analysis NN I-NP with IN B-PP a DT B-NP monoclonal JJ I-NP antibody NN I-NP recognizing VBG B-VP a DT B-NP 17-amino NN I-NP acid NN I-NP epitope NN I-NP of IN B-PP the DT O 1COMMA25-dihydroxyvitamin NN B-NP D3 NN I-NP { ( O 1COMMA25(OH)2D3 NN B-NP } ) O receptor NN B-NP COMMA COMMA O we PRP B-NP have VBP B-VP detected VBN I-VP two CD B-NP crossreacting VBG I-NP proteins NNS I-NP in IN B-PP activated VBN B-NP normal JJ I-NP human JJ I-NP lymphocytes NNS I-NP . . O The DT B-NP smaller JJR I-NP of IN B-PP the DT B-NP two CD I-NP proteins NNS I-NP ( ( O 50 CD B-NP kDa NN I-NP ) ) O was VBD B-VP indistinguishable JJ B-ADJP from IN B-PP the DT B-NP classical JJ I-NP 1COMMA25(OH)2D3 NN I-NP receptor NN I-NP and CC O COMMA COMMA O similar JJ B-ADJP to TO B-PP the DT B-NP classical JJ I-NP 1COMMA25(OH)2D3 NN I-NP receptor NN I-NP COMMA COMMA O was VBD B-VP upregulated VBN B-VP in IN B-PP a DT B-NP dose-dependent JJ I-NP fashion NN I-NP by IN B-PP 1COMMA25(OH)2D3 NN B-NP . . O The DT B-NP larger JJR I-NP crossreacting VBG I-NP protein NN I-NP exhibited VBD B-VP an DT B-NP electrophoretic JJ I-NP mobility NN I-NP of IN B-PP 80 CD B-NP kDa NN I-NP COMMA COMMA O was VBD B-VP localized JJ I-VP in IN B-PP the DT B-NP cell NN I-NP cytosol NN I-NP COMMA COMMA O and CC O appeared VBD B-VP to TO I-VP be VB I-VP specific JJ B-ADJP for IN B-PP activated VBN B-NP lymphocytes NNS I-NP since IN B-SBAR it PRP B-NP was VBD B-VP not RB I-VP detected VBN I-VP in IN B-PP several JJ B-NP other JJ I-NP human JJ I-NP cells NNS I-NP including VBG B-PP monocytes NNS B-NP . . O More RBR B-ADVP strikingly RB I-ADVP COMMA COMMA O the DT B-NP 80-kDa JJ I-NP protein NN I-NP was VBD B-VP downregulated VBN I-VP in IN B-PP a DT B-NP dose-dependent JJ I-NP fashion NN I-NP by IN B-PP 1COMMA25(OH)2D3 NN B-NP ; : O this DT B-NP effect NN I-NP was VBD B-VP independent JJ B-ADJP of IN B-PP the DT B-NP mode NN I-NP of IN B-PP lymphocyte NN B-NP activation NN I-NP and CC O specific JJ B-ADJP for IN B-PP the DT B-NP 1COMMA25(OH)2D3 NN I-NP metabolite NN I-NP of IN B-PP vitamin NN B-NP D3 NN I-NP . . O However RB B-ADVP COMMA COMMA O two CD B-NP potent JJ I-NP immunosuppressive JJ I-NP agents NNS I-NP COMMA COMMA O glucocorticoids NNS B-NP and CC O cyclosporin NN B-NP A DT I-NP COMMA COMMA O also RB B-ADVP inhibited VBD B-VP the DT B-NP 80-kDa JJ I-NP protein NN I-NP . . O T-helper-cell JJ B-NP determinants NNS I-NP in IN B-PP protein NN B-NP antigens NNS I-NP are VBP B-VP preferentially RB B-ADVP located JJ I-ADVP in IN B-PP cysteine-rich JJ B-NP antigen NN I-NP segments NNS I-NP resistant JJ B-ADJP to TO B-PP proteolytic JJ B-NP cleavage NN I-NP by IN B-PP cathepsin NN B-NP B NN B-NP COMMA COMMA O L NN B-NP COMMA COMMA O and CC O D NN B-NP . . O We PRP B-NP report VBP B-VP on IN B-PP a DT B-NP computer NN I-NP algorithm NN I-NP capable JJ B-ADJP of IN B-PP predicting VBG B-VP the DT B-NP location NN I-NP of IN B-PP T-helper-cell NN B-NP epitopes NNS I-NP in IN B-PP protein NN B-NP antigen NN B-NP ( ( O Ag NN B-NP ) ) O by IN B-PP analysing VBG B-VP the DT B-NP Ag NN I-NP amino NN I-NP acid NN I-NP sequence NN I-NP . . O The DT B-NP algorithm NN I-NP was VBD B-VP constructed VBN I-VP with IN B-PP the DT B-NP aim NN I-NP of IN B-PP identifying VBG B-VP segments NNS B-NP in IN B-PP Ag NN B-NP which WDT B-NP are VBP B-VP resistant JJ B-ADJP to TO B-PP proteolytic JJ B-NP degradation NN I-NP by IN B-PP the DT B-NP enzymes NNS I-NP cathepsin NN I-NP B NN B-NP COMMA COMMA O L NN B-NP COMMA COMMA O and CC O D NN B-NP . . O These DT B-NP are VBP B-VP prominent JJ B-NP enzymes NNS I-NP in IN B-PP the DT B-NP endocytic JJ I-NP pathway NN I-NP through IN B-PP which WDT B-NP soluble JJ B-NP protein NN I-NP Ag NN I-NP enter VBP B-VP APC NN B-NP COMMA COMMA O and CC O resistant JJ B-NP segments NNS I-NP in IN B-PP Ag NN B-NP may MD B-VP COMMA COMMA O therefore RB B-ADVP COMMA COMMA O be VB B-VP expected VBN I-VP to TO I-VP contain VB I-VP more JJR B-NP T-cell NN I-NP determinants NNS I-NP than IN B-PP susceptible JJ B-NP segments NNS I-NP . . O From IN B-PP information NN B-NP available JJ B-ADJP in IN B-PP the DT B-NP literature NN I-NP on IN B-PP the DT B-NP substrate JJ I-NP specificity NN I-NP of IN B-PP the DT B-NP three CD I-NP enzymes NNS I-NP COMMA COMMA O it PRP B-NP is VBZ B-VP clear JJ B-ADJP that IN B-SBAR a DT B-NP cysteine NN I-NP is VBZ B-VP not RB I-VP accepted VBN I-VP in IN B-PP any DT B-NP of IN B-PP the DT O S2 NN B-NP COMMA COMMA O S1 NN B-NP COMMA COMMA O S1' NN B-NP COMMA COMMA O and CC O S2' NN B-NP subsites NNS B-NP of IN B-PP cathepsin NN B-NP B NN B-NP and CC O L NN B-NP COMMA COMMA B-PP and CC I-PP not RB B-PP in IN I-PP the DT O S1 NN B-NP and CC O S1' NN B-NP subsites NNS B-NP of IN B-PP cathepsin NN B-NP D NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O we PRP B-NP have VBP B-VP noticed VBN I-VP that IN B-SBAR cysteine-containing JJ B-NP T-cell NN I-NP determinants NNS I-NP in IN B-PP a DT B-NP number NN I-NP of IN B-PP protein NN B-NP Ag NN I-NP are VBP B-VP particularly RB B-ADJP rich JJ I-ADJP in IN B-PP the DT B-NP amino NN I-NP acids NNS I-NP alanine NN B-NP COMMA COMMA O glycine NN B-NP COMMA COMMA O lysine NN B-NP COMMA COMMA O leucine NN B-NP COMMA COMMA O serine NN B-NP COMMA COMMA O threonine NN B-NP COMMA COMMA O and CC O valine NN B-NP . . O By IN B-PP searching VBG B-VP protein NN B-NP Ag NN I-NP for IN B-PP clusters NNS B-NP of IN B-PP amino NN B-NP acids NNS I-NP containing VBG B-VP cysteine NN B-NP and CC O two CD B-NP of IN B-PP the DT B-NP other JJ I-NP amino NN I-NP acids NNS I-NP we PRP B-NP were VBD B-VP able JJ B-ADJP to TO B-VP predict VB I-VP 17 CD B-NP out IN I-NP of IN I-NP 23 CD I-NP empirically RB I-NP known VBN I-NP T-cell NN I-NP determinants NNS I-NP in IN B-PP the DT B-NP Ag NN I-NP with IN B-PP a DT B-NP relatively RB I-NP low JJ I-NP number NN I-NP of IN B-PP false JJ O ( ( O positive JJ B-ADJP ) ) O predictions NNS B-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP present VBP B-VP a DT B-NP new JJ I-NP principle NN I-NP for IN B-PP searching VBG B-VP Ag NN B-NP for IN B-PP potential JJ B-NP amphipatic JJ I-NP alpha-helical JJ I-NP protein NN I-NP segments NNS I-NP . . O Such JJ B-NP segments NNS I-NP accord VBP B-VP well RB B-ADVP with IN B-PP empirically RB B-NP known JJ I-NP T-cell NN I-NP determinants NNS I-NP and CC O our PRP$ B-NP algorithm NN I-NP produces VBZ B-VP a DT B-NP lower JJR I-NP number NN I-NP of IN B-PP false JJ B-NP positive JJ I-NP predictions NNS I-NP than IN B-PP the DT B-NP principle NN I-NP based VBN B-PP on IN B-PP discrete JJ B-NP Fourier NN I-NP transformations NNS I-NP previously RB B-VP described VBN I-VP . . O A DT B-NP human JJ I-NP putative JJ I-NP lymphocyte NN I-NP G0\/G1 NN I-NP switch NN I-NP gene NN I-NP containing VBG B-VP a DT B-NP CpG-rich JJ I-NP island NN I-NP encodes VBZ B-VP a DT B-NP small JJ I-NP basic JJ I-NP protein NN I-NP with IN B-PP the DT B-NP potential NN I-NP to TO B-VP be VB I-VP phosphorylated VBN I-VP . . O Genes NNS B-NP actively RB B-VP involved VBN I-VP in IN B-PP the DT B-NP G0\/G1 NN I-NP switch NN I-NP ( ( O G0S NN B-NP genes NNS I-NP ) ) O may MD B-VP be VB I-VP differentially RB I-VP expressed VBN I-VP during IN B-PP the DT B-NP lectin-induced JJ I-NP switch NN I-NP of IN B-PP lymphocytes NNS B-NP from IN B-PP the DT B-NP G0 NN I-NP to TO B-PP the DT B-NP G1 NN I-NP phases NNS I-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP . . O This DT B-NP paper NN I-NP presents VBZ B-VP studies NNS B-NP of IN B-PP G0S2 NN B-NP COMMA COMMA O a DT B-NP member NN I-NP of IN B-PP a DT B-NP set NN I-NP of IN B-PP putative JJ B-NP G0S NN I-NP genes NNS I-NP COMMA COMMA O for IN B-PP which WDT B-NP cDNAs NNS B-NP were VBD B-VP cloned VBN I-VP and CC O selected VBN B-VP on IN B-PP the DT I-PP basis NN I-PP of IN I-PP differential JJ B-NP cDNA NN I-NP hybridization NN I-NP . . O G0S2 NN B-NP mRNA NN I-NP increases VBZ B-VP transiently RB B-ADVP within IN B-PP 1-2 CD B-NP hr NN I-NP of IN B-PP the DT B-NP addition NN I-NP of IN B-PP lectin NN B-NP or CC O cycloheximide NN B-NP to TO B-PP cultured VBN B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP . . O Comparison NN B-NP of IN B-PP a DT B-NP nearly RB I-NP full-length JJ I-NP cDNA NN I-NP sequence NN I-NP with IN B-PP the DT B-NP corresponding JJ I-NP genomic JJ I-NP sequence NN I-NP reveals VBZ B-VP one CD B-NP small JJ I-NP intron NN I-NP and CC O an DT B-NP open JJ I-NP reading NN I-NP frame NN I-NP in IN B-PP the DT B-NP second JJ I-NP exon NN I-NP . . O The DT B-NP derived VBN I-NP 103-amino-acid JJ I-NP basic JJ I-NP protein NN I-NP has VBZ B-VP two CD B-NP potential JJ I-NP alpha-helical JJ I-NP domains NNS I-NP separated VBN B-VP by IN B-PP a DT B-NP hydrophobic JJ I-NP region NN I-NP with IN B-PP the DT B-NP potential NN I-NP to TO B-VP generate VB I-VP turns NNS B-NP and CC O assume VB B-VP a DT B-NP beta-sheet JJ I-NP conformation NN I-NP . . O Consistent JJ B-ADJP with IN B-PP involvement NN B-NP in IN B-PP the DT B-NP G0\/G1 NN I-NP switch NN I-NP COMMA COMMA O the DT B-NP protein NN I-NP contains VBZ B-VP potential JJ B-NP sites NNS I-NP for IN B-PP phosphorylation NN B-NP by IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP and CC O casein NN B-NP kinase NN I-NP II CD I-NP . . O The DT B-NP gene NN I-NP contains VBZ B-VP a DT B-NP CpG-rich JJ I-NP island NN I-NP suggesting VBG B-VP expression NN B-NP in IN B-PP the DT B-NP germ NN I-NP line NN I-NP . . O An DT B-NP upstream JJ I-NP segment NN I-NP contains VBZ B-VP tandem JJ B-NP dinucleotide NN I-NP repeats NNS I-NP (CT)19\/(CA)16 NN I-NP . . O There EX B-NP is VBZ B-VP a DT B-NP suitably RB I-NP located JJ I-NP TATA NN I-NP box NN I-NP COMMA COMMA O but CC O potential JJ B-NP sites NNS I-NP for IN B-PP CCAAT-box NN B-NP binding NN I-NP factors NNS I-NP are VBP B-VP far RB B-ADJP upstream JJ I-ADJP COMMA COMMA O embedded JJ B-ADJP in IN B-PP a DT B-NP 42-nucleotide JJ I-NP repeat NN I-NP element NN I-NP . . O Potential JJ B-NP sites NNS I-NP for IN B-PP transcription NN B-NP factors NNS I-NP AP1 NN B-NP COMMA COMMA O AP2 NN B-NP COMMA COMMA O and CC O AP3 NN B-NP are VBP B-VP consistent JJ B-ADJP with IN B-PP rapid JJ B-NP transcriptional JJ I-NP activation NN I-NP in IN B-PP response NN I-PP to TO I-PP inducing VBG B-NP agents NNS I-NP . . O Synergism NN B-NP between IN B-PP two CD B-NP distinct JJ I-NP elements NNS I-NP of IN B-PP the DT B-NP HTLV-I NN I-NP enhancer NN I-NP during IN B-PP activation NN B-NP by IN B-PP the DT B-NP trans-activator NN I-NP of IN B-PP HTLV-I NN B-NP . . O We PRP B-NP have VBP B-VP conducted VBN I-VP functional JJ B-NP studies NNS I-NP of IN B-PP the DT B-NP enhancer NN I-NP elements NNS I-NP of IN B-PP human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP ( ( O HTLV-I NN B-NP ) ) O using VBG B-VP the DT B-NP human JJ I-NP T-cell NN I-NP lines NNS I-NP Jurkat NN B-NP and CC O MOLT NN B-NP 4 CD I-NP COMMA COMMA O which WDT B-NP are VBP B-VP negative JJ B-ADJP for IN B-PP HTLV-I NN B-NP COMMA COMMA O and CC O MT-2 NN B-NP and CC O TL-Mor NN B-NP COMMA COMMA O which WDT B-NP carry VBP B-VP the DT B-NP proviral JJ I-NP genome NN I-NP of IN B-PP HTLV-I NN B-NP . . O Two CD B-NP distinct JJ I-NP elements NNS I-NP have VBP B-VP been VBN I-VP implicated VBN I-VP in IN B-PP function NN B-NP of IN B-PP the DT B-NP HTLV-I NN I-NP enhancer NN I-NP . . O One CD B-NP is VBZ B-VP the DT O 21-base-pair JJ O ( ( O bp NN B-NP ) ) O core NN B-NP element NN I-NP that WDT B-NP is VBZ B-VP responsible JJ B-ADJP for IN B-PP trans-activation NN B-NP by IN B-PP the DT B-NP HTLV-I NN I-NP trans-activator NN I-NP p40tax NN I-NP and CC O that WDT B-NP has VBZ B-VP the DT B-NP ability NN I-NP to TO B-VP bind VB I-VP to TO B-PP cyclic-AMP NN B-NP responsive JJ I-NP element NN I-NP binding NN I-NP factor NN I-NP ( ( I-NP CREB NN I-NP ) ) I-NP -like JJ I-NP factor NN I-NP ( ( I-NP s NNS I-NP ) ) O . . O The DT B-NP other JJ I-NP is VBZ B-VP a DT B-NP region NN I-NP interposed VBN B-ADJP between IN B-PP the DT B-NP 21-bp JJ I-NP elements NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR a DT B-NP subfragment NN I-NP ( ( O C26 NN B-NP ) ) O in IN B-PP the DT B-NP region NN I-NP between IN B-PP the DT B-NP 21-bp JJ I-NP elements NNS I-NP is VBZ B-VP involved VBN I-VP in IN B-PP trans-activation NN B-NP by IN B-PP p40tax NN B-NP COMMA COMMA O possibly RB B-PP through IN I-PP binding NN B-NP to TO B-PP an DT B-NP NF-kappa NN I-NP B-like JJ I-NP nuclear JJ I-NP factor NN B-NP or CC O factors NNS B-NP . . O Formation NN B-NP of IN B-PP the DT B-NP protein-DNA JJ I-NP complex NN I-NP with IN B-PP the DT B-NP C26 NN I-NP subfragment NN I-NP was VBD B-VP positively RB I-VP affected VBN I-VP by IN B-PP p40tax NN B-NP . . O The DT B-NP C26 NN I-NP element NN I-NP conferred VBD B-VP partial JJ B-NP responsiveness NN I-NP to TO B-PP p40tax NN B-NP when WRB B-ADVP linked VBN B-VP to TO B-PP one CD B-NP copy NN I-NP of IN B-PP the DT B-NP 21-bp JJ I-NP element NN I-NP that WDT B-NP COMMA COMMA O by IN B-PP itself PRP B-NP COMMA COMMA O showed VBD B-VP little JJ B-NP activation NN I-NP in IN B-PP response NN I-PP to TO I-PP p40tax NN B-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP C26 NN I-NP element NN I-NP alone RB B-ADVP COMMA COMMA O even RB B-ADVP when WRB I-ADVP repeated VBN B-VP COMMA COMMA O could MD B-VP not RB I-VP be VB I-VP activated VBN I-VP by IN B-PP p40tax NN B-NP COMMA COMMA O unlike IN B-PP other JJ B-NP NF-kappa NN I-NP B-binding JJ I-NP elements NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP C26 NN I-NP element NN I-NP itself PRP B-NP was VBD B-VP profoundly RB I-VP activated VBN I-VP upon IN B-PP stimulation NN B-NP with IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP . . O These DT B-NP findings NNS I-NP therefore RB B-ADVP suggest VBP B-VP that IN B-SBAR the DT B-NP HTLV-I NN I-NP enhancer NN I-NP contains VBZ B-VP multiple JJ B-NP functional JJ I-NP elements NNS I-NP COMMA COMMA O including VBG B-PP binding VBG B-NP sites NNS I-NP for IN B-PP at IN B-NP least JJS I-NP CREB- NN I-NP and CC I-NP NF-kappa NN I-NP B-like JJ I-NP factors NNS I-NP COMMA COMMA O which WDT B-NP synergistically RB B-ADVP cooperate VBP B-VP in IN B-PP activation NN B-NP of IN B-PP the DT B-NP HTLV-I NN I-NP enhancer NN I-NP in IN B-PP response NN I-PP to TO I-PP p40tax NN B-NP . . O Our PRP$ B-NP results NNS I-NP also RB B-ADVP demonstrate VBP B-VP that IN B-SBAR TPA-dependent JJ B-NP activation NN I-NP of IN B-PP the DT B-NP HTLV-I NN I-NP enhancer NN I-NP may MD B-VP be VB I-VP mediated VBN I-VP through IN B-PP the DT B-NP C26 NN I-NP element NN I-NP . . O v-erbA NN B-NP overexpression NN I-NP is VBZ B-VP required VBN I-VP to TO I-VP extinguish VB I-VP c-erbA NN B-NP function NN I-NP in IN B-PP erythroid JJ B-NP cell NN I-NP differentiation NN I-NP and CC O regulation NN B-NP of IN B-PP the DT B-NP erbA NN I-NP target NN I-NP gene NN I-NP CAII NN I-NP . . O The DT B-NP v-erbA NN I-NP oncoprotein NN I-NP represents VBZ B-VP a DT B-NP retrovirus-transduced JJ I-NP oncogenic JJ I-NP version NN I-NP of IN B-PP the DT B-NP thyroid NN I-NP hormone NN I-NP ( ( I-NP T3\/T4 NN I-NP ) ) I-NP receptor NN I-NP c-erbA NN I-NP ( ( I-NP type NN I-NP alpha NN I-NP ) ) O . . O It PRP B-NP contributes VBZ B-VP to TO B-PP virus-induced JJ B-NP erythroleukemia NN I-NP by IN B-PP efficiently RB B-ADVP arresting VBG B-VP differentiation NN B-NP of IN B-PP red JJ B-NP cell NN I-NP progenitors NNS I-NP and CC B-PP by IN B-PP suppressing VBG B-VP transcription NN B-NP of IN B-PP erythrocyte-specific JJ B-NP genes NNS I-NP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR v-erbA NN B-NP and CC O c-erbA NN B-NP bind VBP B-VP directly RB B-ADVP to TO B-PP sequences NNS B-NP within IN B-PP the DT B-NP promoter NN I-NP of IN B-PP the DT B-NP erythrocyte-specific JJ I-NP carbonic JJ B-NP anhydrase NN I-NP II CD I-NP ( ( O CAII NN B-NP ) ) O COMMA COMMA O a DT B-NP gene NN I-NP whose WP$ B-NP transcription NN I-NP is VBZ B-VP efficiently RB I-VP suppressed VBN I-VP by IN B-PP v-erbA NN B-NP . . O This DT B-NP erbA-binding JJ I-NP site NN I-NP confers VBZ B-VP thyroid NN B-NP hormone NN I-NP responsiveness NN I-NP to TO B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP in IN B-PP transient JJ B-NP expression NN I-NP experiments NNS I-NP and CC O is VBZ B-VP a DT B-NP target NN I-NP for IN B-PP efficient JJ B-NP down-regulation NN I-NP of IN B-PP CAII NN B-NP transcription NN I-NP by IN B-PP the DT B-NP v-erbA NN I-NP oncoprotein NN I-NP . . O In IN B-PP stably RB B-NP transformed VBN I-NP erythroblasts NNS I-NP coexpressing VBG B-VP the DT B-NP v-erbA NN I-NP oncoprotein NN I-NP and CC O the DT B-NP c-erbA\/T3 NN I-NP receptor NN I-NP at IN B-PP an DT B-NP approximately RB I-NP equimolar JJ I-NP ratio NN I-NP COMMA COMMA O c-erbA NN B-NP activity NN I-NP is VBZ B-VP dominant JJ B-ADJP over IN B-PP v-erbA NN B-NP . . O T3 NN B-NP efficiently RB B-ADVP induced VBD B-VP erythroid JJ B-NP differentiation NN I-NP in IN B-PP these DT B-NP cells NNS I-NP COMMA COMMA O thus RB O overcoming VBG B-VP the DT B-NP v-erbA-mediated JJ I-NP differentiation NN I-NP arrest NN I-NP . . O Likewise RB B-ADVP COMMA COMMA O T3 NN B-NP activated VBD B-VP CAII NN B-NP transcription NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP transient JJ B-NP expression NN I-NP of IN B-PP a DT B-NP T3-responsive JJ I-NP reporter NN I-NP gene NN I-NP containing VBG B-VP the DT B-NP CAII-specific JJ I-NP erbA-binding JJ I-NP site NN I-NP . . O The DT B-NP c-erbA-dependent JJ I-NP activation NN I-NP of IN B-PP this DT B-NP CAII NN I-NP reporter NN I-NP construct NN I-NP could MD B-VP only RB I-VP be VB I-VP suppressed VBN I-VP by IN B-PP very RB B-NP high JJ I-NP amounts NNS I-NP of IN B-PP v-erbA NN B-NP . . O Our PRP$ B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR overexpression NN B-NP of IN B-PP v-erbA NN B-NP is VBZ B-VP required VBN I-VP for IN B-PP its PRP$ B-NP function NN I-NP as IN B-PP an DT B-NP oncoprotein NN I-NP . . O Inhibition NN B-NP of IN B-PP phorbol NN B-NP ester-induced JJ I-NP monocytic JJ I-NP differentiation NN I-NP by IN B-PP dexamethasone NN B-NP is VBZ B-VP associated VBN I-VP with IN B-PP down-regulation NN B-NP of IN B-PP c-fos NN B-NP and CC O c-jun NN B-NP ( ( O AP-1 NN B-NP ) ) O . . O Previous JJ B-NP studies NNS I-NP have VBP B-VP shown VBN I-VP that IN B-SBAR treatment NN B-NP of IN B-PP human JJ B-NP myeloid JJ I-NP leukemia NN I-NP cells NNS I-NP with IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( O TPA NN B-NP ) ) O is VBZ B-VP associated VBN I-VP with IN B-PP induction NN B-NP of IN B-PP monocytic JJ B-NP differentiation NN B-NP and CC O expression NN B-NP of IN B-PP the DT O c-jun NN B-NP and CC O c-fos NN B-NP early JJ B-NP response NN I-NP genes NNS I-NP . . O The DT B-NP present JJ I-NP work NN I-NP demonstrates VBZ B-VP that IN B-SBAR the DT B-NP glucocorticoid NN I-NP dexamethasone NN I-NP inhibits VBZ B-VP TPA-induced JJ B-NP increases NNS I-NP in IN B-PP c-jun NN B-NP and CC O c-fos NN B-NP mRNA NN B-NP levels NNS I-NP in IN B-PP U-937 NN B-NP leukemia NN I-NP cells NNS I-NP . . O These DT B-NP findings NNS I-NP were VBD B-VP associated VBN I-VP with IN B-PP a DT B-NP block NN I-NP in IN B-PP appearance NN B-NP of IN B-PP the DT B-NP monocytic JJ I-NP phenotype NN I-NP COMMA COMMA O including VBG B-PP inhibition NN B-NP of IN B-PP TPA-induced JJ B-NP increases NNS I-NP in IN B-PP lamin NN B-NP A NN I-NP COMMA COMMA O lamin NN B-NP C NN I-NP COMMA COMMA O and CC O vimentin NN B-NP transcripts NNS I-NP . . O Other JJ B-NP studies NNS I-NP have VBP B-VP demonstrated VBN I-VP that IN B-SBAR TPA-induced JJ B-NP monocytic JJ I-NP differentiation NN B-NP and CC O expression NN B-NP of IN B-PP the DT O c-jun NN B-NP and CC O c-fos NN B-NP genes NNS B-NP in IN B-PP myeloid JJ B-NP leukemia NN I-NP cells NNS I-NP are VBP B-VP regulated VBN I-VP by IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O . . O The DT B-NP finding NN I-NP that IN B-SBAR dexamethasone NN B-NP has VBZ B-VP no DT B-NP effect NN I-NP on IN B-PP TPA-induced JJ B-NP activation NN I-NP of IN B-PP PKC NN B-NP suggests VBZ B-VP that IN B-SBAR this DT B-NP glucocorticoid NN I-NP inhibits VBZ B-VP signals NNS B-NP downstream JJ B-ADJP or CC O parallel JJ B-ADJP to TO B-PP this DT B-NP enzyme NN I-NP . . O Nuclear JJ B-NP run-on JJ I-NP assays NNS I-NP demonstrate VBP B-VP that IN B-SBAR : : O ( ( B-LST 1 LS I-LST ) ) O induction NN B-NP of IN B-PP c-jun NN B-NP and CC O c-fos NN B-NP expression NN B-NP by IN B-PP TPA NN B-NP is VBZ B-VP regulated VBN I-VP by IN B-PP transcriptional JJ B-NP mechanisms NNS I-NP COMMA COMMA O ( ( B-LST 2 LS I-LST ) ) O TPA-induced JJ B-NP expression NN I-NP of IN B-PP c-jun NN B-NP and CC O c-fos NN B-NP does VBZ B-VP not RB I-VP require VB I-VP protein NN B-NP synthesis NN I-NP COMMA COMMA O and CC O ( ( B-LST 3 LS I-LST ) ) O TPA-induced JJ B-NP expression NN I-NP of IN B-PP both DT B-NP genes NNS I-NP is VBZ B-VP inhibited VBN I-VP at IN B-PP the DT B-NP transcriptional JJ I-NP level NN I-NP by IN B-PP dexamethasone NN B-NP . . O To TO B-VP further RB I-VP define VB I-VP the DT B-NP effects NNS I-NP of IN B-PP dexamethasone NN B-NP at IN B-PP the DT B-NP molecular JJ I-NP level NN I-NP COMMA COMMA O we PRP B-NP prepared VBD B-VP a DT B-NP series NN I-NP of IN B-PP deleted VBN B-NP c-jun NN I-NP promoter NN I-NP fragments NNS I-NP linked VBN B-VP to TO B-PP the DT O chloramphenicol NN B-NP acetyltransferase NN I-NP ( ( O CAT NN B-NP ) ) O gene NN B-NP . . O Increases NNS B-NP in IN B-PP CAT NN B-NP activity NN I-NP during IN B-PP transient JJ B-NP expression NN I-NP of IN B-PP these DT B-NP constructs NNS I-NP in IN B-PP TPA-treated JJ B-NP U-937 NN I-NP cells NNS I-NP could MD B-VP be VB I-VP assigned VBN I-VP to TO B-PP the DT B-NP region NN I-NP ( ( O -97 CD B-NP to TO O -20 CD B-NP ) ) O of IN B-PP the DT B-NP promoter NN I-NP that WDT B-NP contains VBZ B-VP the DT B-NP AP-1 NN I-NP binding NN I-NP site NN I-NP . . O This DT B-NP induction NN I-NP of IN B-PP CAT NN B-NP activity NN I-NP was VBD B-VP sensitive JJ B-ADJP to TO B-PP dexamethasone NN B-NP . . O These DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR dexamethasone NN B-NP down-regulates VBZ B-VP TPA-induced JJ B-NP transcription NN I-NP of IN B-PP the DT B-NP c-jun NN I-NP gene NN I-NP during IN B-PP monocytic JJ B-NP differentiation NN I-NP by IN B-PP inhibiting VBG B-VP activation NN B-NP of IN B-PP the DT B-NP AP-1 NN I-NP site NN I-NP . . O Charybdotoxin-sensitive JJ B-NP COMMA COMMA I-NP Ca(2+)-dependent JJ I-NP membrane NN I-NP potential JJ I-NP changes NNS I-NP are VBP B-VP not RB I-VP involved VBN I-VP in IN B-PP human JJ B-NP T NN I-NP or CC I-NP B NN I-NP cell NN I-NP activation NN B-NP and CC O proliferation NN B-NP . . O The DT B-NP involvement NN I-NP of IN B-PP ion NN B-NP channels NNS I-NP in IN B-PP B NN B-NP and CC I-NP T NN I-NP lymphocyte NN I-NP activation NN I-NP is VBZ B-VP supported VBN I-VP by IN B-PP many JJ B-NP reports NNS I-NP of IN B-PP changes NNS B-NP in IN B-PP ion NN B-NP fluxes NNS I-NP and CC O membrane NN B-NP potential NN I-NP after IN B-PP mitogen NN B-NP binding NN I-NP . . O Human JJ B-NP T NN I-NP and CC I-NP B NN I-NP lymphocytes NNS I-NP demonstrate VBP B-VP an DT B-NP early JJ I-NP and CC I-NP transient JJ I-NP hyperpolarization NN I-NP after IN B-PP ligand JJ B-NP binding NN I-NP . . O Inasmuch RB B-SBAR as IN I-SBAR the DT B-NP change NN I-NP in IN B-PP membrane NN B-NP potential NN I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP elevation NN B-NP of IN B-PP free JJ B-NP cytosolic JJ I-NP calcium NN I-NP COMMA COMMA O the DT B-NP hyperpolarization NN I-NP is VBZ B-VP presumably RB B-ADVP through IN B-PP opening NN B-NP of IN B-PP Ca(2+)-stimulated JJ B-NP K+ NN I-NP channels NNS I-NP . . O We PRP B-NP have VBP B-VP used VBN I-VP charybdotoxin NN B-NP COMMA COMMA O a DT B-NP known JJ I-NP inhibitor NN I-NP of IN B-PP Ca(2+)-dependent JJ B-NP K+ NN I-NP channels NNS I-NP COMMA COMMA O to TO B-VP study VB I-VP the DT B-NP role NN I-NP of IN B-PP these DT B-NP channels NNS I-NP in IN B-PP lymphocyte NN B-NP activation NN B-NP and CC O mitogenesis NN B-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR charybdotoxin NN B-NP inhibits VBZ B-VP the DT B-NP ligand-induced JJ I-NP transient JJ I-NP membrane NN I-NP hyperpolarization NN I-NP in IN B-PP B NN B-NP and CC O T NN B-NP cells NNS B-NP in IN B-PP a DT B-NP dose-dependent JJ I-NP fashion NN I-NP COMMA COMMA O without IN B-PP affecting VBG B-VP changes NNS B-NP in IN B-PP cytosolic JJ B-NP Ca2+ NN I-NP . . O However RB B-ADVP COMMA COMMA O blockade NN B-NP of IN B-PP the DT B-NP Ca(2+)-activated JJ I-NP K+ NN I-NP channel NN I-NP is VBZ B-VP not RB I-VP associated VBN I-VP with IN B-PP changes NNS B-NP in IN B-PP cell-cycle JJ B-NP gene NN I-NP activation NN I-NP COMMA COMMA O IL-2 NN B-NP production NN I-NP COMMA COMMA O IL-2R NN B-NP expression NN I-NP or CC O B NN B-NP and CC O T NN B-NP cell NN B-NP mitogenesis NN I-NP . . O These DT B-NP results NNS I-NP imply VBP B-VP that IN B-SBAR membrane NN B-NP potential JJ I-NP changes NNS I-NP secondary JJ B-ADJP to TO B-PP the DT B-NP ligand-dependent JJ I-NP opening NN I-NP of IN B-PP Ca(2+)-activated JJ B-NP K+ NN I-NP channels NNS I-NP are VBP B-VP not RB I-VP involved VBN I-VP in IN B-PP B NN B-NP and CC O T NN B-NP lymphocyte NN B-NP activation NN B-NP and CC O mitogenesis NN B-NP . . O Evaluation NN B-NP of IN B-PP the DT B-NP role NN I-NP of IN B-PP ligand NN B-NP and CC O thermal JJ B-NP activation NN I-NP of IN B-PP specific JJ B-NP DNA NN I-NP binding NN I-NP by IN B-PP in FW B-ADVP vitro FW I-ADVP synthesized VBN B-NP human JJ I-NP glucocorticoid NN I-NP receptor NN I-NP . . O We PRP B-NP have VBP B-VP used VBN I-VP a DT B-NP DNA-binding\/immunoprecipitation JJ I-NP assay NN I-NP to TO B-VP analyze VB I-VP the DT B-NP capacity NN I-NP of IN B-PP human JJ B-NP glucocorticoid NN I-NP receptor NN I-NP ( ( O hGR NN B-NP ) ) O COMMA COMMA O generated VBN B-VP in IN B-PP rabbit NN B-NP reticulocyte NN I-NP lysates NNS I-NP COMMA COMMA O to TO B-VP bind VB I-VP DNA NN B-NP . . O In FW B-ADVP vitro FW I-ADVP translated VBN B-NP hGR NN I-NP was VBD B-VP indistinguishable JJ B-ADJP from IN B-PP native JJ B-NP hGR NN I-NP COMMA COMMA O as IN B-SBAR determined VBN B-VP by IN B-PP migration NN B-NP on IN B-PP sodium NN B-NP dodecyl NN I-NP sulfate-polyacrylamide JJ I-NP gels NNS I-NP COMMA COMMA O sedimentation NN B-NP on IN B-PP sucrose NN B-NP density NN I-NP gradients NNS I-NP COMMA COMMA O and CC O reactivity NN B-NP with IN B-PP antipeptide JJ B-NP antibodies NNS I-NP generated VBN B-VP against IN B-PP hGR NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O cell-free JJ B-NP synthesized VBN I-NP hGR NN I-NP was VBD B-VP capable JJ B-ADJP of IN B-PP specific JJ B-NP binding NN I-NP to TO B-PP glucocorticoid NN B-NP response NN I-NP element NN I-NP ( ( I-NP GRE NN I-NP ) ) I-NP -containing JJ I-NP DNA NN I-NP fragments NNS I-NP . . O Using VBG B-VP this DT B-NP assay NN I-NP system NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP evaluated VBN I-VP the DT B-NP contributions NNS I-NP of IN B-PP ligand NN B-NP binding NN I-NP and CC O heat NN B-NP activation NN I-NP to TO B-PP DNA NN B-NP binding NN I-NP by IN B-PP these DT B-NP glucocorticoid NN I-NP receptors NNS I-NP . . O In FW B-ADVP vitro FW I-ADVP translated VBN B-NP hGR NN I-NP was VBD B-VP capable JJ B-ADJP of IN B-PP selective JJ B-NP DNA NN I-NP binding NN I-NP even RB B-PP in IN I-PP the DT I-PP absence NN I-PP of IN I-PP glucocorticoid NN B-NP . . O Treatment NN B-NP with IN B-PP dexamethasone NN B-NP or CC O the DT B-NP antiglucocorticoid JJ I-NP RU486 NN I-NP had VBD B-VP no DT B-NP additional JJ I-NP effect NN I-NP on IN B-PP the DT B-NP DNA-binding JJ I-NP capacity NN I-NP when WRB B-ADVP receptor NN B-NP preparations NNS I-NP were VBD B-VP maintained VBN I-VP at IN B-PP 0 CD B-NP C NN I-NP ( ( O no DT B-NP activation NN I-NP ) ) O . . O In IN B-PP contrast NN B-NP COMMA COMMA O addition NN B-NP of IN B-PP either CC O ligand NN B-NP or CC O antagonist NN B-NP in IN B-PP combination NN B-NP with IN B-PP a DT B-NP heat NN I-NP activation NN I-NP step NN I-NP promoted VBD B-VP DNA NN B-NP binding NN I-NP by IN B-PP approximately RB B-NP 3-fold RB I-NP over IN B-PP that DT B-NP of IN B-PP heat-activated JJ B-NP unliganded JJ I-NP receptors NNS I-NP . . O Agonist NN B-NP ( ( O dexamethasone NN B-NP ) ) O was VBD B-VP slightly RB B-ADJP more JJR I-ADJP effective JJ I-ADJP in IN B-PP supporting VBG B-VP specific JJ B-NP DNA NN I-NP binding NN I-NP than IN B-PP antagonist NN B-NP ( ( O RU486 NN B-NP ) ) O . . O DNA NN B-NP binding NN I-NP by IN B-PP in FW B-ADVP vitro FW I-ADVP synthesized VBN B-NP GR NN I-NP was VBD B-VP blocked VBN I-VP by IN B-PP the DT B-NP addition NN I-NP of IN B-PP sodium NN B-NP molybdate NN I-NP to TO B-PP the DT B-NP receptor NN I-NP preparations NNS I-NP before IN B-PP steroid NN B-NP addition NN I-NP and CC O thermal JJ B-NP activation NN I-NP . . O Addition NN B-NP of IN B-PP KCl NN B-NP resulted VBD B-VP in IN B-PP less RBR B-NP DNA NN I-NP binding NN I-NP either CC B-PP due JJ I-PP to TO I-PP blockage NN B-NP of IN B-PP DNA-receptor JJ B-NP complex NN I-NP formation NN I-NP or CC O disruption NN B-NP of IN B-PP the DT B-NP complexes NNS I-NP . . O The DT B-NP specificity NN I-NP of IN B-PP DNA NN B-NP binding NN I-NP by IN B-PP cell-free JJ B-NP synthesized VBN I-NP hGR NN I-NP was VBD B-VP analyzed VBN I-VP further RB B-ADVP by IN B-PP examining VBG B-VP the DT B-NP abilities NNS I-NP of IN B-PP various JJ B-NP DNAs NNS I-NP to TO B-VP compete VB I-VP for IN B-PP binding VBG B-VP to TO B-PP a DT B-NP naturally RB I-NP occurring VBG I-NP GRE NN I-NP found VBD B-VP in IN B-PP the DT B-NP mouse NN I-NP mammary JJ I-NP tumor NN I-NP virus-long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O Oligonucleotides NNS B-NP containing VBG B-VP the DT B-NP consensus NN I-NP GRE NN I-NP were VBD B-VP the DT B-NP most RBS I-NP efficient JJ I-NP competitors NNS I-NP COMMA COMMA O and CC O fragments NNS B-NP containing VBG B-VP regulatory JJ B-NP sequences NNS I-NP from IN B-PP glucocorticoid-repressible JJ B-NP genes NNS I-NP were VBD B-VP somewhat RB B-ADJP competitive JJ I-ADJP COMMA COMMA O whereas IN O single JJ B-NP stranded JJ I-NP oligonucleotides NNS I-NP were VBD B-VP unable JJ B-ADJP to TO B-VP compete VB I-VP for IN B-PP mouse NN B-NP mammary JJ I-NP tumor NN I-NP virus-long JJ I-NP terminal JJ I-NP repeat NN I-NP DNA NN I-NP binding NN I-NP COMMA COMMA O except IN B-PP when WRB B-ADVP competitor NN B-NP was VBD B-VP present JJ B-ADJP at IN B-PP extremely RB B-NP high JJ I-NP concentrations NNS I-NP . . O Together RB B-ADVP these DT B-NP studies NNS I-NP indicate VBP B-VP that IN B-SBAR hGR NN B-NP synthesized VBN B-VP in IN B-PP rabbit NN B-NP reticulocyte NN I-NP lysates NNS I-NP displays VBZ B-VP many JJ B-NP of IN B-PP the DT B-NP same JJ I-NP properties NNS I-NP COMMA COMMA O including VBG B-PP GRE-specific JJ B-NP DNA NN I-NP binding NN I-NP COMMA COMMA O observed VBN B-VP for IN B-PP glucocorticoid NN B-NP receptor NN I-NP present JJ B-ADJP in IN B-PP cytosolic JJ B-NP extracts NNS I-NP of IN B-PP mammalian JJ B-NP cells NNS B-NP and CC O tissues NNS B-NP . . O Similarities NNS B-NP between IN B-PP the DT B-NP effects NNS I-NP of IN B-PP dexamethasone NN B-NP and CC O RU486 NN B-NP suggest VBP B-VP that IN B-SBAR the DT B-NP antiglucocorticoid JJ I-NP properties NNS I-NP of IN B-PP RU486 NN B-NP do VBP B-VP not RB I-VP occur VB I-VP at IN B-PP the DT B-NP level NN I-NP of IN B-PP specific JJ B-NP DNA NN I-NP binding NN I-NP . . O One CD B-NP base NN I-NP pair NN I-NP change NN I-NP abolishes VBZ B-VP the DT B-NP T NN I-NP cell-restricted JJ I-NP activity NN I-NP of IN B-PP a DT B-NP kB-like JJ I-NP proto-enhancer NN I-NP element NN I-NP from IN B-PP the DT B-NP interleukin NN I-NP 2 CD I-NP promoter NN I-NP . . O The DT B-NP inducible JJ I-NP COMMA COMMA I-NP T NN I-NP cell-specific JJ I-NP enhancers NNS I-NP of IN B-PP murine JJ O and CC O human JJ O Interleukin NN B-NP 2 CD I-NP ( ( O Il-2 NN B-NP ) ) O genes NNS B-NP contain VBP B-VP the DT B-NP kB-like JJ I-NP sequence NN I-NP GGGATTTCACC NN I-NP as IN B-PP an DT B-NP essential JJ I-NP cis-acting JJ I-NP enhancer NN I-NP motif NN I-NP . . O When WRB B-ADVP cloned VBN B-VP in IN B-PP multiple JJ B-NP copies NNS I-NP this DT B-NP so-called JJ I-NP TCEd NN B-NP ( ( O distal JJ B-NP T NN I-NP cell NN I-NP element NN I-NP ) ) O acts VBZ B-VP as IN B-PP an DT B-NP inducible JJ I-NP proto-enhancer NN I-NP element NN I-NP in IN B-PP E14 NN B-NP T NN I-NP lymphoma NN I-NP cells NNS I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP in IN I-PP HeLa NN B-NP cells NNS I-NP . . O In IN B-PP extracts NNS B-NP of IN B-PP induced VBN B-NP COMMA COMMA I-NP Il-2 NN I-NP secreting NN I-NP El4 NN I-NP cells NNS I-NP three CD B-NP individual JJ I-NP protein NN I-NP factors NNS I-NP bind VBP B-VP to TO B-PP TCEd NN B-NP DNA NN I-NP . . O The DT B-NP binding NN I-NP of IN B-PP the DT B-NP most RBS I-NP prominent JJ I-NP factor NN I-NP COMMA COMMA O named VBN B-VP TCF-1 NN B-NP ( ( O T NN B-NP cell NN I-NP factor NN I-NP 1 CD I-NP ) ) O COMMA COMMA O is VBZ B-VP correlated VBN I-VP with IN B-PP the DT B-NP proto-enhancer NN I-NP activity NN I-NP of IN B-PP TCEd NN B-NP . . O TCF-1 NN B-NP consists VBZ B-VP of IN B-PP two CD B-NP polypeptides NNS I-NP of IN B-PP about RB B-ADVP 50 CD B-NP kD NN I-NP and CC O 105 CD B-NP kD NN I-NP ; : O the DT B-NP former JJ I-NP seems VBZ B-VP to TO I-VP be VB I-VP related JJ B-ADJP to TO B-PP the DT B-NP 50 CD B-NP kD NN I-NP polypeptide NN B-NP of IN B-PP NF-kB NN B-NP . . O Purified VBN B-NP NF-kB NN I-NP is VBZ B-VP also RB B-ADJP able JJ I-ADJP to TO B-VP bind VB I-VP to TO B-PP the DT B-NP TCEd NN I-NP COMMA COMMA O but CC O TCF-1 NN B-NP binds VBZ B-VP stronger JJR B-ADVP than IN B-PP NF-kB NN B-NP to TO B-PP TCEd NN B-NP DNA NN I-NP . . O The DT B-NP conversion NN I-NP of IN B-PP the DT B-NP TCEd NN I-NP to TO B-PP a DT B-NP ' `` I-NP perfect JJ I-NP ' '' I-NP NF-kB NN I-NP binding NN I-NP site NN I-NP leads VBZ B-VP to TO B-PP a DT B-NP tighter JJR I-NP binding NN I-NP of IN B-PP NF-kB NN B-NP to TO B-PP TCEd NN B-NP DNA NN I-NP and CC O COMMA COMMA O as IN B-PP a DT B-NP functional JJ I-NP consequence NN I-NP COMMA COMMA O to TO B-PP the DT B-NP activity NN I-NP of IN B-PP the DT B-NP ' `` I-NP converted VBN I-NP ' '' I-NP TCEd NN I-NP motifs NNS I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP substitution NN I-NP of IN B-PP the DT B-NP underlined VBN I-NP A NN I-NP residue NN I-NP to TO B-PP a DT B-NP C NN I-NP within IN B-PP the DT B-NP GGGATTTCACC NN I-NP motif NN I-NP abolishes VBZ B-VP its PRP$ B-NP T NN I-NP cell-restricted JJ I-NP activity NN I-NP and CC O leads VBZ B-VP to TO B-PP its PRP$ B-NP functioning VBG B-VP in IN B-PP both CC O El4 NN B-NP cells NNS I-NP and CC O HeLa NN B-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR lymphocyte-specific JJ B-NP factors NNS I-NP binding VBG B-VP to TO B-PP the DT B-NP TCEd NN I-NP are VBP B-VP involved VBN I-VP in IN B-PP the DT B-NP control NN I-NP of IN B-PP T NN B-NP cell NN I-NP specific-transcription NN I-NP of IN B-PP the DT B-NP Il-2 NN I-NP gene NN I-NP . . O Negative JJ B-NP regulation NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP expression NN I-NP in IN B-PP monocytes NNS B-NP : : O role NN B-NP of IN B-PP the DT B-NP 65-kDa JJ I-NP plus CC I-NP 50-kDa JJ I-NP NF-kappa NN I-NP B NN I-NP dimer NN I-NP . . O Although IN B-SBAR monocytic JJ B-NP cells NNS I-NP can MD B-VP provide VB I-VP a DT B-NP reservoir NN I-NP for IN B-PP viral JJ B-NP production NN I-NP in FW B-ADVP vivo FW I-ADVP COMMA COMMA O their PRP$ B-NP regulation NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O transcription NN B-NP can MD B-VP be VB I-VP either CC O latent JJ B-ADJP COMMA COMMA O restricted JJ B-ADJP COMMA COMMA O or CC O productive JJ B-ADJP . . O These DT B-NP differences NNS I-NP in IN B-PP gene NN B-NP expression NN I-NP have VBP B-VP not RB I-VP been VBN I-VP molecularly RB B-ADJP defined VBN I-ADJP . . O In IN B-PP THP-1 NN B-NP cells NNS I-NP with IN B-PP restricted JJ B-NP HIV NN I-NP expression NN I-NP COMMA COMMA O there EX B-NP is VBZ B-VP an DT B-NP absence NN I-NP of IN B-PP DNA-protein JJ B-NP binding NN I-NP complex NN I-NP formation NN I-NP with IN B-PP the DT B-NP HIV-1 NN I-NP promoter-enhancer NN I-NP associated VBN B-VP with IN B-PP markedly RB B-ADVP less JJR I-ADVP viral JJ B-NP RNA NN I-NP production NN I-NP . . O This DT B-NP absence NN I-NP of IN B-PP binding NN B-NP was VBD B-VP localized JJ B-ADJP to TO B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP region NN I-NP of IN B-PP the DT B-NP HIV-1 NN I-NP enhancer NN I-NP ; : O the DT B-NP 65-kDa JJ I-NP plus CC I-NP 50-kDa JJ I-NP NF-kappa NN I-NP B NN I-NP heterodimer NN I-NP was VBD B-VP preferentially RB B-ADJP lost VBN I-ADJP . . O Adding VBG B-VP purified VBN B-NP NF-kappa NN I-NP B NN I-NP protein NN I-NP to TO B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP cells NNS B-NP with IN B-PP restricted JJ B-NP expression NN I-NP overcomes VBZ B-VP this DT B-NP lack NN I-NP of IN B-PP binding NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O treatment NN B-NP of IN B-PP these DT B-NP nuclear JJ I-NP extracts NNS I-NP with IN B-PP sodium NN B-NP deoxycholate NN I-NP restored VBD B-VP their PRP$ B-NP ability NN I-NP to TO B-VP form VB I-VP the DT B-NP heterodimer NN I-NP COMMA COMMA O suggesting VBG B-VP the DT B-NP presence NN I-NP of IN B-PP an DT B-NP inhibitor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activity NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O treatment NN B-NP of IN B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP these DT B-NP cells NNS I-NP that WDT B-NP had VBD B-VP restricted JJ B-NP expression NN I-NP with IN B-PP lipopolysaccharide NN B-NP increased VBD B-VP viral JJ B-NP production NN I-NP and CC O NF-kappa NN B-NP B NN I-NP activity NN I-NP . . O Antiserum NN B-NP specific JJ B-ADJP for IN B-PP NF-kappa NN B-NP B NN I-NP binding NN I-NP proteins NNS I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP c-rel-specific JJ B-NP antiserum NN I-NP COMMA COMMA O disrupted VBD B-VP heterodimer NN B-NP complex NN I-NP formation NN I-NP . . O Thus RB B-ADVP COMMA COMMA O both DT B-NP NF-kappa NN I-NP B-binding JJ I-NP complexes NNS I-NP are VBP B-VP needed VBN I-VP for IN B-PP optimal JJ B-NP viral JJ I-NP transcription NN I-NP . . O Binding NN B-NP of IN B-PP the DT B-NP 65-kDa JJ I-NP plus CC I-NP 50-kDa JJ I-NP heterodimer NN I-NP to TO B-PP the DT B-NP HIV-1 NN I-NP enhancer NN I-NP can MD B-VP be VB I-VP negatively RB I-VP regulated VBN I-VP in IN B-PP monocytes NNS B-NP COMMA COMMA O providing VBG B-VP one CD B-NP mechanism NN I-NP restricting VBG B-VP HIV-1 NN B-NP gene NN I-NP expression NN I-NP . . O Isolation NN B-NP of IN B-PP a DT B-NP candidate NN I-NP repressor\/activator NN B-NP COMMA COMMA O NF-E1 NN B-NP ( ( O YY-1 NN B-NP COMMA COMMA I-NP delta NN I-NP ) ) O COMMA COMMA O that WDT B-NP binds VBZ B-VP to TO B-PP the DT B-NP immunoglobulin NN I-NP kappa NN I-NP 3' JJ I-NP enhancer NN I-NP and CC O the DT B-NP immunoglobulin NN I-NP heavy-chain NN I-NP mu NN I-NP E1 NN I-NP site NN I-NP . . O We PRP B-NP have VBP B-VP determined VBN I-VP that IN B-SBAR the DT B-NP developmental JJ I-NP control NN I-NP of IN B-PP immunoglobulin NN B-NP kappa NN I-NP 3' JJ I-NP enhancer NN I-NP ( ( I-NP kappa NN I-NP E3' NN I-NP ) ) I-NP activity NN I-NP is VBZ B-VP the DT B-NP result NN I-NP of IN B-PP the DT B-NP combined JJ I-NP influence NN I-NP of IN B-PP positive- JJ B-NP and CC I-NP negative-acting JJ I-NP elements NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR a DT B-NP central JJ I-NP core NN I-NP in IN B-PP the DT B-NP kappa NN I-NP E3' NN I-NP enhancer NN I-NP is VBZ B-VP active JJ B-ADJP at IN B-PP the DT B-NP pre-B-cell JJ I-NP stage NN I-NP but CC O is VBZ B-VP repressed VBN I-VP by IN B-PP flanking VBG B-NP negative-acting JJ I-NP elements NNS I-NP . . O The DT B-NP negative-acting JJ I-NP sequences NNS I-NP repress VBP B-VP enhancer NN B-NP activity NN I-NP in IN B-PP a DT O position- NN B-NP and CC O orientation-independent JJ B-ADJP manner NN B-NP at IN B-PP the DT B-NP pre-B-cell JJ I-NP stage NN I-NP . . O We PRP B-NP have VBP B-VP isolated VBN I-VP a DT B-NP human JJ I-NP cDNA NN I-NP clone NN I-NP encoding VBG B-VP a DT B-NP zinc NN I-NP finger NN I-NP protein NN I-NP ( ( O NF-E1 NN B-NP ) ) O that WDT B-NP binds VBZ B-VP to TO B-PP the DT B-NP negative-acting JJ I-NP segment NN I-NP of IN B-PP the DT B-NP kappa NN I-NP E3' NN I-NP enhancer NN I-NP . . O This DT B-NP protein NN I-NP also RB B-ADVP binds VBZ B-VP to TO B-PP the DT B-NP immunoglobulin NN I-NP heavy-chain NN I-NP enhancer NN I-NP mu NN I-NP E1 NN I-NP site NN I-NP . . O NF-E1 NN B-NP is VBZ B-VP encoded VBN I-VP by IN B-PP the DT B-NP same JJ I-NP gene NN I-NP as IN B-PP the DT B-NP YY-1 NN I-NP protein NN I-NP COMMA COMMA O which WDT B-NP binds VBZ B-VP to TO B-PP the DT B-NP adeno-associated JJ I-NP virus NN I-NP P5 NN I-NP promoter NN I-NP . . O NF-E1 NN B-NP is VBZ B-VP also RB B-ADVP the DT B-NP human JJ I-NP homologue NN I-NP of IN B-PP the DT B-NP mouse NN I-NP delta NN I-NP protein NN I-NP COMMA COMMA O which WDT B-NP binds VBZ B-VP to TO B-PP ribosomal JJ B-NP protein NN I-NP gene NN I-NP promoters NNS I-NP . . O The DT B-NP predicted VBN I-NP amino NN I-NP acid NN I-NP sequence NN I-NP of IN B-PP this DT B-NP protein NN I-NP contains VBZ B-VP features NNS B-NP characteristic JJ B-ADJP of IN B-PP transcriptional JJ B-NP activators NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP transcriptional JJ B-NP repressors NNS I-NP . . O Cotransfection NN B-NP studies NNS I-NP with IN B-PP this DT B-NP cDNA NN I-NP indicate VBP B-VP that IN B-SBAR it PRP B-NP can MD B-VP repress VB I-VP basal JJ B-NP promoter NN I-NP activity NN I-NP . . O The DT B-NP apparent JJ I-NP dual JJ I-NP function NN I-NP of IN B-PP this DT B-NP protein NN I-NP is VBZ B-VP discussed VBN I-VP . . O Clone NN B-NP pAT NN I-NP 133 CD I-NP identifies VBZ B-VP a DT B-NP gene NN I-NP that WDT B-NP encodes VBZ B-VP another DT B-NP human JJ I-NP member NN I-NP of IN B-PP a DT B-NP class NN I-NP of IN B-PP growth NN B-NP factor-induced JJ I-NP genes NNS I-NP with IN B-PP almost RB B-NP identical JJ I-NP zinc-finger NN I-NP domains NNS I-NP . . O We PRP B-NP report VBP B-VP the DT B-NP structure NN B-NP and CC O regulation NN B-NP of IN B-PP a DT B-NP gene NN I-NP represented VBN B-VP by IN B-PP clone NN B-NP pAT NN I-NP 133 CD I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP induced VBN I-VP upon IN B-PP transition NN B-NP from IN B-PP a DT B-NP resting JJ I-NP state NN I-NP ( ( O G0 NN B-NP ) ) O through IN B-PP the DT B-NP early JJ I-NP phase NN I-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP ( ( O G1 NN B-NP ) ) O . . O The DT B-NP pAT NN I-NP 133 CD I-NP gene NN I-NP is VBZ B-VP immediately RB I-VP induced VBN I-VP COMMA COMMA O with IN B-PP FOS-like JJ B-NP kinetics NNS I-NP COMMA COMMA O in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP and CC B-PP in IN B-PP fibroblasts NNS B-NP . . O Primary JJ B-NP structure NN I-NP analysis NN I-NP showed VBD B-VP that IN B-SBAR the DT B-NP encoded VBN I-NP protein NN I-NP contains VBZ B-VP three CD B-NP tandem JJ I-NP zinc-finger NN I-NP sequences NNS I-NP of IN B-PP the DT B-NP type NN I-NP Cys2-Xaa12-His2 NN I-NP . . O This DT B-NP zinc-finger NN I-NP region NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP thought VBN I-VP to TO I-VP bind VB I-VP DNA NN B-NP in IN B-PP a DT B-NP sequence-specific JJ I-NP manner NN I-NP COMMA COMMA O is VBZ B-VP similar JJ B-ADJP ( ( O greater JJR B-NP than IN I-NP 80 CD I-NP % NN I-NP on IN B-PP the DT B-NP amino NN I-NP acid NN I-NP level NN I-NP ) ) O to TO B-PP two CD B-NP previously RB I-NP described VBN I-NP transcription NN I-NP factors NNS I-NP pAT NN B-NP 225\/EGR1 NN I-NP and CC O pAT NN B-NP 591\/EGR2 NN I-NP . . O Except IN B-PP for IN I-PP the DT B-NP conserved VBN I-NP zinc-finger NN I-NP domains NNS I-NP COMMA COMMA O the DT B-NP amino NN I-NP acid NN I-NP sequences NNS I-NP of IN B-PP the DT B-NP three CD I-NP proteins NNS I-NP are VBP B-VP distinct JJ B-ADJP . . O This DT B-NP structural JJ I-NP similarity NN I-NP suggests VBZ B-VP that IN B-SBAR the DT B-NP pAT NN I-NP 133 CD I-NP gene NN I-NP encodes VBZ B-VP a DT B-NP transcription NN I-NP factor NN I-NP with IN B-PP a DT B-NP specific JJ I-NP biological JJ I-NP function NN I-NP . . O Comparing VBG B-VP the DT B-NP regulation NN I-NP of IN B-PP these DT B-NP related JJ I-NP zinc-finger-encoding JJ I-NP genes NNS I-NP showed VBD B-VP coordinate JJ B-NP induction NN I-NP upon IN B-PP mitogenic JJ B-NP stimulation NN I-NP of IN B-PP resting VBG B-NP T NN I-NP lymphocytes NNS I-NP and CC B-PP of IN B-PP resting VBG B-NP fibroblasts NNS I-NP . . O However RB B-ADVP COMMA COMMA O upon IN B-PP transition NN B-NP from IN B-PP a DT B-NP proliferating JJ I-NP ( ( O G1 NN B-NP ) ) O to TO B-PP a DT B-NP resting JJ I-NP state NN B-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP the DT B-NP three CD I-NP genes NNS I-NP were VBD B-VP differently RB I-VP regulated VBN I-VP . . O In IN B-PP human JJ B-NP histiocytic JJ I-NP U937 NN I-NP cells NNS I-NP mRNA NN B-NP of IN B-PP clone NN B-NP pAT NN I-NP 133 CD I-NP was VBD B-VP constitutively RB I-VP expressed VBN I-VP COMMA COMMA O whereas IN O mRNA NN B-NP of IN B-PP pAT NN B-NP 225\/EGR1 NN I-NP was VBD B-VP induced VBN I-VP upon IN B-PP induction NN B-NP of IN B-PP terminal JJ B-NP differentiation NN I-NP . . O In IN B-PP contrast NN B-NP mRNA NN B-NP representing VBG B-VP pAT NN B-NP 591\/EGR2 NN I-NP was VBD B-VP not RB I-VP expressed VBN I-VP in IN B-PP these DT B-NP cells NNS I-NP . . O This DT B-NP difference NN I-NP in IN B-PP gene NN B-NP regulation NN I-NP suggests VBZ B-VP distinct JJ B-NP biological JJ I-NP roles NNS I-NP in IN B-PP the DT B-NP control NN I-NP of IN B-PP cell NN B-NP proliferation NN I-NP for IN B-PP the DT B-NP respective JJ I-NP proteins NNS I-NP . . O cAMP-dependent JJ B-NP regulation NN I-NP of IN B-PP proenkephalin NN B-NP by IN B-PP JunD NN B-NP and CC O JunB NN B-NP : : O positive JJ B-NP and CC I-NP negative JJ I-NP effects NNS I-NP of IN B-PP AP-1 NN B-NP proteins NNS I-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR JunD NN B-NP COMMA COMMA O a DT B-NP component NN I-NP of IN B-PP the DT B-NP AP-1 NN I-NP transcription NN I-NP factor NN I-NP complex NN I-NP COMMA COMMA O activates VBZ B-VP transcription NN B-NP of IN B-PP the DT B-NP human JJ I-NP proenkephalin NN I-NP gene NN I-NP in IN B-PP a DT B-NP fashion NN I-NP that WDT B-NP is VBZ B-VP completely RB B-ADJP dependent JJ I-ADJP upon IN B-PP the DT B-NP cAMP-dependent JJ I-NP protein NN I-NP kinase NN I-NP COMMA COMMA O protein NN B-NP kinase NN I-NP A NN I-NP . . O Activation NN B-NP of IN B-PP proenkephalin NN B-NP transcription NN I-NP by IN B-PP JunD NN B-NP is VBZ B-VP dependent JJ B-ADJP upon IN B-PP a DT O previously RB O characterized VBN O cAMP- NN B-NP COMMA COMMA O phorbol NN B-NP ester- NN I-NP COMMA COMMA O and CC O Ca(2+)-inducible JJ B-ADJP enhancer NN B-NP COMMA COMMA O and CC O JunD NN B-NP is VBZ B-VP shown VBN I-VP to TO I-VP bind VB I-VP the DT B-NP enhancer NN I-NP as IN B-PP a DT B-NP homodimer NN I-NP . . O Another DT B-NP component NN I-NP of IN B-PP the DT B-NP AP-1 NN I-NP transcription NN I-NP complex NN I-NP COMMA COMMA O JunB NN B-NP COMMA COMMA O is VBZ B-VP shown VBN I-VP to TO I-VP inhibit VB I-VP activation NN B-NP mediated VBN B-VP by IN B-PP JunD NN B-NP . . O As IN B-PP a DT B-NP homodimer NN I-NP JunB NN B-NP is VBZ B-VP unable JJ B-ADJP to TO B-VP bind VB I-VP the DT B-NP enhancer NN I-NP ; : O however RB O in IN B-PP the DT I-PP presence NN I-PP of IN I-PP c-Fos NN B-NP COMMA COMMA O high-affinity JJ B-NP binding NN I-NP is VBZ B-VP observed VBN I-VP . . O Furthermore RB B-ADVP COMMA COMMA O JunD NN B-NP is VBZ B-VP shown VBN I-VP to TO I-VP activate VB I-VP transcription NN B-NP of IN B-PP genes NNS B-NP linked VBN B-VP to TO B-PP both CC O cAMP NN B-NP and CC O phorbol NN B-NP ester NN I-NP response NN B-NP elements NNS I-NP in IN B-PP a DT B-NP protein NN I-NP kinase NN I-NP A-dependent JJ I-NP fashion NN I-NP COMMA COMMA O further RB B-ADVP blurring VBG B-VP the DT B-NP distinction NN I-NP between IN B-PP these DT B-NP response NN I-NP elements NNS I-NP . . O These DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP an DT B-NP AP-1-related JJ I-NP protein NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP the DT B-NP cAMP-dependent JJ I-NP second-messenger NN I-NP pathway NN I-NP and CC O suggest VBP B-VP that IN B-SBAR JunD NN B-NP and CC O other JJ B-NP AP-1-related JJ I-NP proteins NNS I-NP may MD B-VP play VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP gene NN B-NP expression NN I-NP by IN B-PP cAMP-dependent JJ B-NP intracellular JJ I-NP signaling NN I-NP pathways NNS I-NP . . O Glucocorticoid NN B-NP resistance NN I-NP in IN B-PP chronic JJ B-NP asthma NN I-NP . . O Glucocorticoid NN B-NP pharmacokinetics NNS I-NP COMMA COMMA O glucocorticoid NN B-NP receptor NN I-NP characteristics NNS I-NP COMMA COMMA O and CC O inhibition NN B-NP of IN B-PP peripheral JJ B-NP blood NN I-NP T NN I-NP cell NN I-NP proliferation NN I-NP by IN B-PP glucocorticoids NNS B-NP in FW B-ADJP vitro FW I-ADJP . . O A DT B-NP total NN I-NP of IN B-PP 37 CD B-NP chronic JJ I-NP COMMA COMMA I-NP severe JJ I-NP COMMA COMMA I-NP nonsmoking JJ I-NP asthmatic JJ I-NP patients NNS I-NP with IN B-PP documented JJ B-NP reversible JJ I-NP airways NNS I-NP obstruction NN I-NP were VBD B-VP classified VBN I-VP as IN B-PP glucocorticoid-sensitive JJ B-ADJP or CC O -resistant JJ B-ADJP on IN B-PP the DT I-PP basis NN I-PP of IN I-PP changes NNS B-NP in IN B-PP FEV1 NN B-NP COMMA COMMA O FVC NN B-NP COMMA COMMA O and CC O peak JJ B-NP expiratory NN I-NP flow NN I-NP ( ( O PEF NN B-NP ) ) O after IN B-PP oral JJ B-NP prednisolone NN I-NP . . O The DT B-NP resistant JJ I-NP patients NNS I-NP showed VBD B-VP no DT B-NP significant JJ I-NP improvements NNS I-NP in IN B-PP airflow NN B-NP limitation NN I-NP . . O Phytohemagglutinin NN B-NP ( ( I-NP PHA NN I-NP ) ) I-NP -induced JJ I-NP proliferation NN I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP T NN I-NP lymphocytes NNS I-NP from IN B-PP the DT B-NP sensitive JJ I-NP but CC B-CONJP not RB I-CONJP the DT B-NP resistant JJ I-NP asthmatic JJ B-NP patients NNS I-NP was VBD O significantly RB O ( ( O p NN B-NP less JJR B-ADJP than IN B-PP 0.01 CD B-NP ) ) O inhibited VBN B-VP by IN B-PP dexamethasone NN B-NP ( ( O 10(-7) CD B-NP mol\/L NN I-NP ) ) O COMMA COMMA O reflecting VBG B-VP a DT B-NP shift NN I-NP of IN B-PP the DT B-NP dose-response JJ I-NP curve NN I-NP . . O When WRB B-ADVP all PDT B-NP the DT I-NP asthmatic JJ I-NP patients NNS I-NP were VBD B-VP analyzed VBN I-VP together RB B-ADVP COMMA COMMA O there EX B-NP was VBD B-VP a DT B-NP significant JJ I-NP correlation NN I-NP between IN B-PP the DT B-NP degree NN I-NP of IN B-PP sensitivity NN B-NP of IN B-PP T NN B-NP cells NNS I-NP to TO B-PP dexamethasone NN B-NP and CC O the DT B-NP clinical JJ I-NP responsiveness NN I-NP to TO B-PP prednisolone JJ B-NP ( ( O p NN B-NP less RBR B-ADJP than IN B-PP 0.01 CD B-NP ) ) O . . O No DT B-NP differences NNS I-NP were VBD B-VP observed VBN I-VP between IN B-PP six CD B-NP of IN B-PP the DT B-NP sensitive JJ I-NP and CC I-NP resistant JJ I-NP patients NNS I-NP in IN B-PP the DT B-NP clearance NN I-NP of IN B-PP plasma NN B-NP prednisolone JJ I-NP derived VBN B-VP from IN B-PP orally RB B-NP administered VBN I-NP prednisone NN I-NP . . O Peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cell NN I-NP glucocorticoid NN I-NP receptors NNS I-NP were VBD B-VP also RB I-VP characterized VBN I-VP in IN B-PP five CD B-NP sensitive JJ I-NP and CC O seven CD B-NP resistant JJ I-NP patients NNS B-NP . . O The DT B-NP numbers NNS B-NP and CC O binding NN B-NP affinities NNS I-NP of IN B-PP these DT B-NP receptors NNS I-NP could MD B-VP not RB I-VP account VB I-VP for IN B-PP the DT B-NP observed VBN I-NP difference NN I-NP in IN B-PP the DT B-NP susceptibility NN I-NP of IN B-PP these DT B-NP cells NNS I-NP to TO B-PP functional JJ B-NP inhibition NN I-NP by IN B-PP dexamethasone NN B-NP in FW B-ADJP vitro FW I-ADJP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR clinical JJ B-NP glucocorticoid NN I-NP resistance NN I-NP in IN B-PP chronic JJ B-NP asthma NN I-NP does VBZ B-VP not RB I-VP reflect VB I-VP abnormal JJ B-NP glucocorticoid NN I-NP clearance NN I-NP but CC O may MD B-VP be VB I-VP due JJ O at IN B-ADVP least JJS I-ADVP partly RB B-ADVP to TO B-PP a DT B-NP relative JJ I-NP insensitivity NN I-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP to TO B-PP glucocorticoids NNS B-NP . . O This DT B-NP lack NN I-NP of IN B-PP sensitivity NN B-NP is VBZ B-VP unexplained JJ B-ADJP but CC O is VBZ B-VP not RB O attributable JJ B-ADJP to TO B-PP abnormalities NNS B-NP of IN B-PP cellular JJ B-NP glucocorticoid NN I-NP receptors NNS I-NP . . O Regulation NN B-NP of IN B-PP interleukin-1 NN B-NP beta NN I-NP production NN I-NP by IN B-PP glucocorticoids NNS B-NP in IN B-PP human JJ B-NP monocytes NNS I-NP : : O the DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP depends VBZ B-VP on IN B-PP the DT B-NP activation NN I-NP signal NN I-NP . . O Glucocorticoids NNS B-NP are VBP B-VP known VBN I-VP to TO I-VP downregulate VB I-VP interleukin-1 NN B-NP beta NN I-NP production NN I-NP in IN B-PP monocytic JJ B-NP cells NNS I-NP by IN B-PP two CD B-NP different JJ I-NP mechanims NNS I-NP : : O direct JJ B-NP inhibition NN I-NP of IN B-PP the DT B-NP gene NN I-NP transcription NN I-NP and CC O destabilization NN B-NP of IN B-PP the DT B-NP preformed JJ I-NP interleukin-1 NN I-NP beta NN I-NP mRNA NN I-NP . . O Now RB B-ADVP we PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP effect NN I-NP of IN B-PP the DT B-NP nature NN I-NP of IN B-PP the DT B-NP monocyte NN I-NP activating NN I-NP signal NN I-NP on IN B-PP these DT B-NP two CD I-NP inhibitory JJ I-NP mechanims NNS I-NP . . O When WRB B-ADVP human JJ B-NP monocytes NNS I-NP were VBD B-VP preincubated VBN I-VP with IN B-PP dexamethasone NN B-NP for IN B-PP 1 CD B-NP hour NN I-NP and CC O then RB O stimulated VBN B-VP either CC B-PP with IN I-PP bacterial JJ B-NP lipopolysaccharide NN I-NP or CC O phorbol NN B-NP myristate NN I-NP COMMA COMMA O it PRP B-NP was VBD B-VP found VBN I-VP that IN B-SBAR dexamethasone NN B-NP inhibited VBD B-VP the DT B-NP lipopolysaccharide-induced JJ I-NP interleukin-1 NN I-NP beta NN I-NP protein NN I-NP production NN I-NP COMMA COMMA O but CC O the DT B-NP phorbol NN I-NP myristate-induced JJ I-NP production NN I-NP was VBD B-VP increased VBN I-VP 3-10 CD B-NP fold RB I-NP . . O This DT B-NP difference NN I-NP was VBD B-VP also RB I-VP seen VBN I-VP at IN B-PP the DT B-NP mRNA NN I-NP level NN I-NP . . O When WRB B-ADVP dexamethasone NN B-NP was VBD B-VP added VBN I-VP to TO B-PP the DT B-NP cultures NNS I-NP 3 CD B-NP hours NNS I-NP after IN B-PP the DT B-NP stimulators NNS I-NP COMMA COMMA O it PRP B-NP clearly RB B-ADVP decreased VBD B-VP the DT B-NP interleukin-1 NN I-NP beta NN I-NP mRNA NN I-NP levels NNS I-NP regardless RB B-ADVP of IN B-PP the DT B-NP stimulator NN I-NP used VBN B-VP ( ( O although IN B-SBAR the DT B-NP effect NN I-NP was VBD B-VP clearly RB B-ADJP weaker JJR I-ADJP on IN B-PP the DT B-NP PMA-induced JJ I-NP mRNA NN I-NP ) ) O . . O Thus RB B-ADVP these DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP phorbol NN I-NP myristate-induced JJ I-NP signal NN I-NP ( ( O prolonged JJ B-NP protein NN I-NP kinase NN I-NP C NN I-NP activation NN I-NP ? . O ) ) O can MD B-VP not RB I-VP be VB I-VP inhibited VBN I-VP by IN B-PP prior JJ B-NP incubation NN I-NP with IN B-PP dexamethasone NN B-NP and CC O it PRP B-NP also RB B-ADVP protects VBZ B-VP the DT B-NP induced VBN I-NP mRNA NN I-NP for IN B-PP the DT B-NP degradative JJ I-NP action NN I-NP of IN B-PP dexamethasone NN B-NP . . O Identification NN B-NP of IN B-PP transcriptional JJ B-NP suppressor NN I-NP proteins NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP negative JJ I-NP regulatory JJ I-NP element NN I-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP . . O Two CD B-NP different JJ I-NP proteins NNS I-NP which WDT B-NP independently RB B-ADVP bound VBD B-VP to TO B-PP neighboring VBG B-NP sequences NNS I-NP within IN B-PP the DT B-NP negative JJ I-NP regulatory JJ I-NP element NN I-NP ( ( O NRE NN B-NP ) ) O of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O were VBD B-VP detected VBN I-VP in IN B-PP the DT B-NP nuclear JJ I-NP extract NN I-NP of IN B-PP a DT B-NP virus-infected JJ I-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP . . O One CD B-NP of IN B-PP the DT B-NP factors NNS I-NP bound VBD B-VP to TO B-PP a DT B-NP novel JJ I-NP dyad NN I-NP symmetrical JJ I-NP sequence NN I-NP . . O This DT B-NP sequence NN I-NP is VBZ B-VP well RB I-VP conserved VBN I-VP in IN B-PP various JJ B-NP HIV-1 NN I-NP isolates NNS I-NP and CC O partial JJ B-NP homology NN I-NP was VBD B-VP found VBN I-VP with IN B-PP the DT B-NP promoter JJ I-NP region NN I-NP of IN B-PP the DT B-NP human JJ I-NP retinoblastoma NN I-NP gene NN I-NP . . O Similar JJ B-NP DNA NN I-NP binding NN I-NP activity NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP a DT B-NP variety NN I-NP of IN B-PP virus-uninfected JJ B-NP human JJ I-NP T NN B-NP cell NN I-NP lines NNS I-NP and CC O HeLa NN B-NP cells NNS I-NP by IN B-PP means NNS I-PP of IN I-PP a DT B-NP gel NN I-NP mobility NN I-NP shift NN I-NP assay NN I-NP . . O The DT B-NP other JJ I-NP factor NN I-NP bound VBN B-VP to TO B-PP a DT B-NP putative JJ I-NP AP-1 NN I-NP recognition NN I-NP sequence NN I-NP predicted VBD B-VP for IN B-PP the DT B-NP HIV-1 NN I-NP NRE NN I-NP . . O However RB B-ADVP COMMA COMMA O this DT B-NP factor NN I-NP did VBD B-VP not RB I-VP bind VB I-VP to TO B-PP a DT B-NP typical JJ I-NP AP-1 NN I-NP site NN I-NP . . O The DT B-NP insertion NN I-NP of IN B-PP multiple JJ B-NP copies NNS I-NP of IN B-PP the DT B-NP binding VBG I-NP site NN I-NP for IN B-PP the DT B-NP former JJ I-NP or CC I-NP latter JJ I-NP factor NN I-NP into IN B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP reduced VBD B-VP the DT B-NP promoter NN I-NP activity NN I-NP to TO B-PP one-tenth CD B-NP or CC O one-third CD B-NP COMMA COMMA O respectively RB B-ADVP . . O Thus RB B-ADVP COMMA COMMA O each DT B-NP factor NN I-NP may MD B-VP function VB I-VP as IN B-PP a DT B-NP novel JJ I-NP negative JJ I-NP regulator NN I-NP of IN B-PP transcription NN B-NP . . O Constitutive JJ B-NP activation NN I-NP of IN B-PP NF-kB NN B-NP in IN B-PP human JJ B-NP thymocytes NNS I-NP . . O NF-kB NN B-NP is VBZ B-VP a DT B-NP eukaryotic JJ I-NP transcription NN I-NP regulatory JJ I-NP factor NN I-NP . . O In IN B-PP T NN B-NP cells NNS I-NP and CC O T NN B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O NF-kB NN B-NP is VBZ B-VP bound VBN I-VP to TO B-PP a DT B-NP cytoplasmic JJ I-NP proteic JJ I-NP inhibitor NN I-NP COMMA COMMA O the DT B-NP IkB NN I-NP . . O Treatment NN B-NP of IN B-PP T NN B-NP cells NNS I-NP with IN B-PP mitogens NNS B-NP ( ( O phorbol NN B-NP esters NNS I-NP ) ) O or CC O cytokines NNS B-NP ( ( O TNF NN B-NP alpha NN I-NP ) ) O induces VBZ B-VP NF-kB NN B-NP nuclear JJ I-NP translocation NN I-NP and CC O the DT B-NP subsequent JJ I-NP expression NN I-NP of IN B-PP NF-kB NN B-NP dependent JJ I-NP T NN I-NP cell NN I-NP genes NNS I-NP . . O Here RB B-ADVP we PRP B-NP examined VBD B-VP the DT B-NP activation NN I-NP of IN B-PP NF-kB NN B-NP in IN B-PP human JJ B-NP T NN I-NP cell NN I-NP thymic JJ I-NP progenitors NNS I-NP . . O We PRP B-NP report VBP B-VP differences NNS B-NP in IN B-PP (Ca2+)i NN B-NP requirement NN I-NP for IN B-NP NF-kB NN B-NP activation NN I-NP in IN B-PP thymocytes NNS B-NP as IN B-SBAR compared VBN B-VP to TO B-PP mature JJ B-NP T NN I-NP cells NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O our PRP$ B-NP results NNS I-NP indicated VBD B-VP that IN B-SBAR thymocytes NNS B-NP have VBP B-VP a DT B-NP constitutively RB I-NP active JJ I-NP form NN I-NP of IN B-PP NF-kB NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR they PRP B-NP are VBP B-VP activated VBN I-VP in FW B-ADVP vivo FW I-ADVP . . O The DT B-NP role NN I-NP of IN B-PP jun NN B-NP and CC I-NP fos NN I-NP gene NN I-NP family NN I-NP members NNS I-NP in IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP induced VBD I-NP hemopoietic JJ I-NP differentiation NN I-NP . . O Terminal JJ B-NP differentiation NN I-NP of IN B-PP the DT B-NP leukemic JJ I-NP cell NN I-NP lines NNS I-NP U-937 NN B-NP and CC O HL-60 NN B-NP by IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP is VBZ B-VP accompanied VBN I-VP by IN B-PP marked JJ B-NP changes NNS I-NP in IN B-PP gene NN B-NP expression NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP expression NN I-NP of IN B-PP jun NN B-NP and CC I-NP fos NN I-NP gene NN I-NP family NN I-NP members NNS I-NP is VBZ B-VP induced VBN I-VP with IN B-PP variable JJ B-NP kinetics NNS I-NP during IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP induced VBD I-NP differentiation NN I-NP COMMA COMMA O with IN B-PP c-jun NN B-NP expression NN I-NP best RB B-ADVP paralleling JJ B-VP differentiation NN B-NP . . O The DT B-NP generation NN I-NP of IN B-PP AP-1 NN B-NP complexes NNS I-NP COMMA COMMA O as IN B-SBAR measured VBN B-VP by IN B-PP DNA NN B-NP binding NN I-NP activity NN I-NP COMMA COMMA O closely RB B-ADVP parallels VBZ B-VP morphological JJ B-NP differentiation NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP ability NN I-NP of IN B-PP these DT B-NP complexes NNS I-NP to TO B-VP regulate VB I-VP gene NN B-NP expression NN I-NP is VBZ B-VP demonstrated VBN I-VP by IN B-PP increased VBN B-NP transcription NN I-NP from IN B-PP an DT B-NP AP-1 NN I-NP driven VBN I-NP reporter NN I-NP construct NN I-NP and CC O marked JJ B-NP increases NNS I-NP in IN B-PP the DT B-NP expression NN I-NP of IN B-PP endogenous JJ B-NP AP-1 NN I-NP regulated JJ I-NP genes NNS I-NP . . O Differentiation NN B-NP assays NNS I-NP using VBG B-VP water NN B-NP soluble JJ I-NP phorbol NN I-NP esters NNS I-NP reveal VBP B-VP that IN B-SBAR differentiation NN B-NP becomes VBZ B-VP irreversible JJ B-ADJP soon RB B-ADVP after IN B-SBAR AP-1 NN B-NP appears VBZ B-VP . . O This DT B-NP tight JJ I-NP correlation NN I-NP between IN B-PP c-jun NN B-NP expression NN I-NP COMMA COMMA O the DT B-NP generation NN I-NP of IN B-PP AP-1 NN B-NP activity NN I-NP COMMA COMMA O and CC O differentiation NN B-NP suggests VBZ B-VP a DT B-NP critical JJ I-NP role NN I-NP for IN B-PP this DT O gene NN B-NP and CC O transcriptional JJ B-ADJP complex NN B-NP during IN B-PP this DT B-NP process NN I-NP . . O TCF-1 NN B-NP COMMA COMMA O a DT B-NP T NN I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP of IN B-PP the DT B-NP HMG NN I-NP box NN I-NP family NN I-NP COMMA COMMA O interacts VBZ B-VP with IN B-PP sequence NN B-NP motifs NNS I-NP in IN B-PP the DT O TCR NN B-NP beta NN I-NP and CC O TCR NN B-NP delta NN I-NP enhancers NNS B-NP . . O We PRP B-NP have VBP B-VP recently RB I-VP identified VBN I-VP and CC O cloned VBN B-VP TCF-1 NN B-NP COMMA COMMA O a DT B-NP T NN I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP with IN B-PP specificity NN B-NP for IN B-PP the DT B-NP AACAAAG NN I-NP motif NN I-NP in IN B-PP the DT B-NP CD3 NN I-NP epsilon NN I-NP enhancer NN I-NP and CC B-PP for IN B-PP the DT B-NP TTCAAAG NN I-NP motif NN I-NP in IN B-PP the DT B-NP TCR NN I-NP alpha NN I-NP enhancer NN I-NP . . O TCF-1 NN B-NP belongs VBZ B-VP to TO B-PP the DT B-NP family NN I-NP of IN B-PP transcription-regulating JJ B-NP proteins NNS I-NP which WDT B-NP share VBP B-VP a DT B-NP region NN I-NP of IN B-PP homology NN B-NP termed VBN B-VP the DT B-NP HMG-box NN I-NP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP show VBP B-VP by IN B-PP gel NN B-NP retardation NN I-NP analysis NN I-NP that IN B-SBAR TCF-1 NN B-NP specifically RB B-ADVP recognizes VBZ B-VP the DT B-NP T NN I-NP beta NN I-NP 5 CD I-NP element NN I-NP of IN B-PP the DT B-NP TCR NN I-NP beta NN I-NP enhancer NN I-NP and CC O the DT B-NP T NN I-NP delta NN I-NP 7 CD I-NP element NN I-NP of IN B-PP the DT B-NP TCR NN I-NP delta NN I-NP enhancer NN I-NP . . O Comparison NN B-NP of IN B-PP the DT B-NP sequences NNS I-NP of IN B-PP all DT B-NP elements NNS I-NP recognized VBN B-VP by IN B-PP TCF-1 NN B-NP defines VBZ B-VP a DT B-NP consensus NN I-NP motif NN I-NP A\/T NN I-NP A\/T NN I-NP C NN I-NP A NN I-NP A\/G NN I-NP A NN I-NP G NN I-NP . . O These DT B-NP observations NNS I-NP imply VBP B-VP that IN B-SBAR TCF-1 NN B-NP is VBZ B-VP involved VBN I-VP in IN B-PP the DT B-NP control NN I-NP of IN B-PP several JJ B-NP T NN I-NP cell-specific JJ I-NP genes NNS I-NP and CC O might MD B-VP thus RB I-VP play VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP establishment NN B-NP and CC O maintenance NN B-NP of IN B-PP the DT B-NP mature JJ I-NP T NN I-NP cell NN I-NP phenotype NN I-NP . . O The DT B-NP cellular JJ I-NP oncogene NN I-NP c-myb NN I-NP can MD B-VP interact VB I-VP synergistically RB B-ADVP with IN B-PP the DT B-NP Epstein-Barr JJ I-NP virus NN I-NP BZLF1 NN I-NP transactivator NN I-NP in IN B-PP lymphoid JJ B-NP cells NNS I-NP . . O Regulation NN B-NP of IN B-PP replicative JJ B-NP functions NNS I-NP in IN B-PP the DT O Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O genome NN B-NP is VBZ B-VP mediated VBN I-VP through IN B-PP activation NN B-NP of IN B-PP a DT B-NP virally RB I-NP encoded VBN I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O Z NN B-NP ( ( O BZLF1 NN B-NP ) ) O . . O We PRP B-NP have VBP B-VP shown VBN I-VP that IN B-SBAR the DT B-NP Z NN I-NP gene NN I-NP product NN I-NP COMMA COMMA O which WDT B-NP binds VBZ B-VP to TO B-PP AP-1 NN B-NP sites NNS I-NP as IN B-PP a DT B-NP homodimer NN I-NP and CC O has VBZ B-VP sequence NN B-NP similarity NN I-NP to TO B-PP c-Fos NN B-NP COMMA COMMA O can MD B-VP efficiently RB I-VP activate VB I-VP the DT B-NP EBV NN I-NP early JJ I-NP promoter NN I-NP COMMA COMMA O BMRF1 NN B-NP COMMA COMMA O in IN B-PP certain JJ B-NP cell NN I-NP types NNS I-NP ( ( O i.e. FW B-NP COMMA COMMA O HeLa NN B-NP cells NNS I-NP ) ) O but CC B-CONJP not RB I-CONJP others NNS B-NP ( ( O i.e. FW B-NP COMMA COMMA O Jurkat NN B-NP cells NNS I-NP ) ) O . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP c-myb NN I-NP proto-oncogene NN I-NP product NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP itself PRP B-NP a DT B-NP DNA-binding JJ I-NP protein NN I-NP and CC O transcriptional JJ B-NP transactivator NN I-NP COMMA COMMA O can MD B-VP interact VB I-VP synergistically RB B-ADVP with IN B-PP Z NN B-NP in IN B-PP activating VBG B-VP the DT B-NP BMRF1 NN I-NP promoter NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP ( ( O a DT B-NP T-cell NN I-NP line NN I-NP ) ) O or CC O Raji NN B-NP cells NNS I-NP ( ( O an DT B-NP EBV-positive JJ I-NP B-cell NN I-NP ) ) O COMMA COMMA O whereas IN O the DT B-NP c-myb NN I-NP gene NN I-NP product NN I-NP by IN B-PP itself PRP B-NP has VBZ B-VP little JJ B-NP effect NN I-NP . . O The DT B-NP simian JJ I-NP virus NN I-NP 40 CD I-NP early JJ I-NP promoter NN I-NP is VBZ B-VP also RB I-VP synergistically RB I-VP activated VBN I-VP by IN B-PP the DT B-NP Z\/c-myb NN I-NP combination NN I-NP . . O Synergistic JJ B-NP transactivation NN I-NP of IN B-PP the DT B-NP BMRF1 NN I-NP promoter NN I-NP by IN B-PP the DT B-NP Z\/c-myb NN I-NP combination NN I-NP appears VBZ B-VP to TO I-VP involve VB I-VP direct JJ B-NP binding NN I-NP by IN B-PP the DT B-NP Z NN I-NP protein NN I-NP but CC B-CONJP not RB I-CONJP the DT B-NP c-myb NN I-NP protein NN I-NP . . O A DT B-NP 30-bp JJ I-NP sequence NN I-NP in IN B-PP the DT B-NP BMRF1 NN I-NP promoter NN I-NP which WDT B-NP contains VBZ B-VP a DT B-NP Z NN I-NP binding NN I-NP site NN I-NP ( ( O a DT B-NP consensus NN I-NP AP-1 NN I-NP site NN I-NP ) ) O is VBZ B-VP sufficient JJ B-ADJP to TO B-VP transfer VB I-VP high-level JJ B-NP lymphoid-specific JJ I-NP responsiveness NN I-NP to TO B-PP the DT B-NP Z\/c-myb NN I-NP combination NN I-NP to TO B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP . . O That IN B-SBAR the DT B-NP c-myb NN I-NP oncogene NN I-NP product NN I-NP can MD B-VP interact VB I-VP synergistically RB B-ADVP with IN B-PP an DT B-NP EBV-encoded JJ I-NP member NN I-NP of IN B-PP the DT B-NP leucine NN I-NP zipper NN I-NP protein NN I-NP family NN I-NP suggests VBZ B-VP c-myb NN B-NP is VBZ B-VP likely JJ B-ADJP to TO B-VP engage VB I-VP in IN B-PP similar JJ B-NP interactions NNS I-NP with IN B-PP cellularly RB B-NP encoded VBN I-NP transcription NN I-NP factors NNS I-NP . . O The DT B-NP 29-kDa JJ I-NP proteins NNS I-NP phosphorylated VBN B-VP in IN B-PP thrombin-activated JJ B-NP human JJ I-NP platelets NNS I-NP are VBP B-VP forms NNS B-NP of IN B-PP the DT B-NP estrogen NN I-NP receptor-related JJ I-NP 27-kDa JJ I-NP heat NN I-NP shock NN I-NP protein NN I-NP . . O Thrombin NN B-NP plays VBZ B-VP a DT B-NP critical JJ I-NP role NN I-NP in IN B-PP platelet NN B-NP activation NN I-NP COMMA COMMA O hemostasis NN B-NP COMMA COMMA O and CC O thrombosis NN B-NP . . O Cellular JJ B-NP activation NN I-NP by IN B-PP thrombin NN B-NP leads VBZ B-VP to TO B-PP the DT B-NP phosphorylation NN I-NP of IN B-PP multiple JJ B-NP proteins NNS I-NP COMMA COMMA O most JJS B-NP of IN B-PP which WDT B-NP are VBP B-VP unidentified JJ B-ADJP . . O We PRP B-NP have VBP B-VP characterized VBN I-VP several JJ B-NP 29-kDa JJ I-NP proteins NNS I-NP that WDT B-NP are VBP B-VP rapidly RB I-VP phosphorylated VBN I-VP following VBG B-PP exposure NN B-NP of IN B-PP intact JJ B-NP human JJ I-NP platelets NNS I-NP to TO B-PP thrombin NN B-NP . . O A DT B-NP murine JJ I-NP monoclonal JJ I-NP antibody NN I-NP raised VBN B-VP to TO B-PP an DT B-NP unidentified JJ I-NP estrogen NN I-NP receptor-related JJ I-NP 29-kDa JJ I-NP protein NN I-NP selectively RB B-ADVP recognized VBD B-VP these DT B-NP proteins NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP a DT B-NP more RBR I-NP basic JJ I-NP COMMA COMMA I-NP unphosphorylated JJ I-NP 27-kDa JJ I-NP protein NN I-NP . . O Cellular JJ B-NP activation NN I-NP by IN B-PP thrombin NN B-NP led VBN B-VP to TO B-PP a DT B-NP marked JJ I-NP shift NN I-NP in IN B-PP the DT B-NP proportion NN I-NP of IN B-PP protein NN B-NP from IN B-PP the DT B-NP 27-kDa JJ I-NP unphosphorylated JJ I-NP form NN I-NP to TO B-PP the DT B-NP 29-kDa JJ I-NP phosphoprotein NN I-NP species NNS I-NP . . O Using VBG B-VP this DT B-NP antibody NN I-NP COMMA COMMA O we PRP B-NP isolated VBD B-VP and CC O sequenced VBD B-VP a DT B-NP human JJ I-NP cDNA NN I-NP clone NN I-NP encoding VBG B-VP a DT B-NP protein NN I-NP that WDT B-NP was VBD B-VP identical JJ B-ADJP to TO B-PP the DT B-NP mammalian JJ I-NP 27-kDa JJ I-NP heat NN I-NP shock NN I-NP protein NN I-NP ( ( O HSP27 NN B-NP ) ) O COMMA COMMA O a DT B-NP protein NN I-NP of IN B-PP uncertain JJ B-NP function NN I-NP that WDT B-NP is VBZ B-VP known VBN I-VP to TO B-VP be VB I-VP phosphorylated VBN I-VP to TO B-PP several JJ B-NP forms NNS I-NP and CC O to TO B-VP be VB I-VP transcriptionally RB I-VP induced VBN I-VP by IN B-PP estrogen NN B-NP . . O The DT B-NP 29-kDa JJ I-NP proteins NNS I-NP were VBD B-VP confirmed VBN I-VP to TO I-VP be VB I-VP phosphorylated VBN B-NP forms NNS I-NP of IN B-PP HSP27 NN B-NP by IN B-PP immunoprecipitation NN B-NP studies NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP " `` I-NP estrogen NN I-NP receptor-related JJ I-NP protein NN I-NP " '' O is VBZ B-VP HSP27 NN B-NP COMMA COMMA O and CC O the DT B-NP three CD I-NP major JJ I-NP 29-kDa JJ I-NP proteins NNS I-NP phosphorylated VBN B-VP in IN B-PP thrombin-activated JJ B-NP platelets NNS I-NP are VBP B-VP forms NNS B-NP of IN B-PP HSP27 NN B-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP a DT B-NP role NN I-NP for IN B-PP HSP27 NN B-NP in IN B-PP the DT B-NP signal NN I-NP transduction NN I-NP events NNS I-NP of IN B-PP platelet NN B-NP activation NN I-NP . . O Characterization NN B-NP of IN B-PP a DT B-NP cofactor NN I-NP that WDT B-NP regulates VBZ B-VP dimerization NN B-NP of IN B-PP a DT B-NP mammalian JJ I-NP homeodomain NN I-NP protein NN I-NP . . O Dimerization NN B-NP among IN B-PP transcription NN B-NP factors NNS I-NP has VBZ B-VP become VBN I-VP a DT B-NP recurrent JJ I-NP theme NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP eukaryotic JJ B-NP gene NN I-NP expression NN I-NP . . O Hepatocyte NN B-NP nuclear JJ I-NP factor-1 NN I-NP alpha NN I-NP ( ( O HNF-1 NN B-NP alpha NN I-NP ) ) O is VBZ B-VP a DT B-NP homeodomain-containing JJ I-NP protein NN I-NP that WDT B-NP functions VBZ B-VP as IN B-PP a DT B-NP dimer NN I-NP . . O A DT B-NP dimerization NN I-NP cofactor NN I-NP of IN B-PP HNF-1 NN B-NP alpha NN I-NP ( ( O DCoH NN B-NP ) ) O was VBD B-VP identified VBN I-VP that WDT B-NP displayed VBD B-VP a DT B-NP restricted JJ I-NP tissue NN I-NP distribution NN I-NP and CC O did VBD B-VP not RB I-VP bind VB I-VP to TO B-PP DNA NN B-NP COMMA COMMA O but CC B-CONJP COMMA COMMA I-CONJP rather RB I-CONJP COMMA COMMA O selectively RB B-VP stabilized VBD I-VP HNF-1 NN B-NP alpha NN I-NP dimers NNS I-NP . . O The DT B-NP formation NN I-NP of IN B-PP a DT B-NP stable JJ I-NP tetrameric JJ I-NP DCoH-HNF-1 NN I-NP alpha NN I-NP complex NN I-NP COMMA COMMA O which WDT B-NP required VBD B-VP the DT B-NP dimerization NN I-NP domain NN I-NP of IN B-PP HNF-1 NN B-NP alpha NN I-NP COMMA COMMA O did VBD B-VP not RB I-VP change VB I-VP the DT B-NP DNA NN I-NP binding NN I-NP characteristics NNS I-NP of IN B-PP HNF-1 NN B-NP alpha NN I-NP COMMA COMMA O but CC O enhanced VBD B-VP its PRP$ B-NP transcriptional JJ I-NP activity NN I-NP . . O However RB B-ADVP COMMA COMMA O DCoH NN B-NP did VBD B-VP not RB I-VP confer VB I-VP transcriptional JJ B-NP activation NN I-NP to TO B-PP the DT B-NP GAL4 NN I-NP DNA NN I-NP binding NN I-NP domain NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR DCoH NN B-NP regulates VBZ B-VP formation NN B-NP of IN B-PP transcriptionally RB B-NP active JJ I-NP tetrameric JJ I-NP complexes NNS I-NP and CC O may MD B-VP contribute VB I-VP to TO B-PP the DT B-NP developmental JJ I-NP specificity NN I-NP of IN B-PP the DT B-NP complex NN I-NP . . O High JJ B-NP affinity NN I-NP aldosterone NN I-NP binding VBG B-VP to TO B-PP plasma NN B-NP membrane NN I-NP rich JJ I-NP fractions NNS I-NP from IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP : : O is VBZ O there EX B-NP a DT B-NP membrane NN I-NP receptor NN I-NP for IN B-PP mineralocorticoids NNS B-NP ? . O In FW B-NP vitro FW I-NP effects NNS I-NP of IN B-PP aldosterone NN B-NP on IN B-PP the DT B-NP intracellular JJ I-NP concentrations NNS I-NP of IN B-PP sodium NN B-NP COMMA COMMA O potassium NN B-NP and CC O calcium NN B-NP COMMA COMMA O cell NN B-NP volume NN I-NP and CC O the DT B-NP sodium-proton-antiport NN I-NP have VBP B-VP been VBN I-VP described VBN I-VP in IN B-PP intact JJ B-NP human JJ B-NP mononuclear JJ I-NP leukocytes NNS I-NP ( ( O HML NN B-NP ) ) O . . O In IN B-PP the DT B-NP present JJ I-NP paper NN I-NP COMMA COMMA O the DT B-NP binding NN I-NP of IN B-PP a DT B-NP {125I}-labeled JJ I-NP aldosterone NN I-NP derivative JJ I-NP to TO B-PP plasma NN B-NP membrane NN I-NP rich JJ B-NP fractions NNS I-NP of IN B-PP HML NN B-NP was VBD B-VP studied VBN I-VP . . O High JJ B-NP affinity NN I-NP binding NN I-NP of IN B-PP the DT B-NP radioligand NN I-NP with IN B-PP an DT B-NP apparent JJ I-NP Kd NN I-NP of IN B-PP approximately RB B-NP 0.1 CD I-NP nM NN I-NP was VBD B-VP found VBN I-VP . . O Aldosterone NN B-NP displaced VBD B-VP the DT B-NP tracer NN I-NP at IN B-PP a DT B-NP similar JJ I-NP Kd NN I-NP . . O Both CC O canrenone NN B-NP and CC O cortisol NN B-NP were VBD B-VP inactive JJ B-ADJP as IN B-PP ligands NNS B-NP up RB B-PP to TO I-PP concentrations NNS B-NP of IN B-PP 0.1 CD B-NP microM NN I-NP . . O The DT B-NP findings NNS I-NP are VBP B-VP the DT B-NP first JJ I-NP to TO B-VP demonstrate VB I-VP membrane NN B-NP binding NN I-NP sites NNS I-NP with IN B-PP a DT B-NP high JJ I-NP affinity NN I-NP for IN B-PP aldosterone NN B-NP COMMA COMMA B-PP but CC I-PP not RB B-PP for IN I-PP cortisol NN B-NP . . O These DT B-NP data NNS I-NP are VBP B-VP perfectly RB B-ADJP compatible JJ I-ADJP with IN B-PP major JJ B-NP properties NNS I-NP of IN B-PP steroidal JJ B-NP effects NNS I-NP on IN B-PP the DT B-NP sodium-proton-antiport NN I-NP in IN B-PP HML NN B-NP and CC O thus RB O very RB B-VP likely RB I-VP represent VBP I-VP membrane NN B-NP receptors NNS I-NP for IN B-PP aldosterone NN B-NP . . O Transcription NN B-NP factor NN I-NP requirements NNS I-NP for IN B-PP U2 NN B-NP snRNA-encoding JJ I-NP gene NN I-NP activation NN I-NP in IN B-PP B NN B-NP lymphoid JJ I-NP cells NNS I-NP . . O Transcription NN B-NP of IN B-PP a DT B-NP human JJ I-NP U2 NN I-NP small JJ I-NP nuclear JJ I-NP RNA NN I-NP ( ( I-NP snRNA NN I-NP ) ) I-NP -encoding JJ I-NP gene NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP requires VBZ B-VP a DT B-NP distal JJ I-NP enhancer NN I-NP element NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP composed VBN I-VP of IN B-PP one CD B-NP octamer NN B-NP motif NN I-NP ( ( O Oct NN B-NP ) ) O and CC O three CD B-NP Sp NN I-NP 1-binding JJ I-NP sites NNS I-NP . . O To TO B-VP study VB I-VP the DT B-NP transcription NN I-NP factor NN I-NP requirement NN I-NP in IN B-PP B-cells NNS B-NP COMMA COMMA O different JJ B-NP U2 NN I-NP enhancer NN I-NP constructions NNS I-NP were VBD B-VP transfected VBN I-VP into IN B-PP the DT B-NP lymphoid JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O BJA-B NN B-NP . . O The DT B-NP results NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP activation NN I-NP of IN B-PP U2 NN B-NP snRNA NN I-NP transcription NN I-NP in IN B-PP B-cells NNS B-NP also RB B-ADVP requires VBZ B-VP an DT B-NP enhancer NN I-NP comprising VBG B-VP both CC O the DT B-NP Oct NN I-NP and CC O at IN B-NP least JJS I-NP one CD I-NP Sp NN I-NP 1-binding JJ I-NP site NN I-NP . . O Deletion NN B-NP of IN B-PP all PDT B-NP the DT I-NP Sp NN I-NP 1-binding JJ I-NP sites NNS I-NP from IN B-PP the DT B-NP enhancer NN I-NP reduces VBZ B-VP transcription NN B-NP by IN B-PP 80-90 CD B-NP % NN I-NP in IN B-PP HeLa NN B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP BJA-B NN B-NP cells NNS B-NP COMMA COMMA O whereas IN O the DT B-NP removal NN I-NP of IN B-PP the DT B-NP octamer-binding JJ I-NP site NN I-NP reduces VBZ B-VP transcription NN B-NP to TO B-PP levels NNS B-NP below IN B-PP detection NN B-NP in IN B-PP both DT B-NP cell NN I-NP types NNS I-NP . . O Enhancers NNS B-NP containing VBG B-VP a DT B-NP single JJ I-NP Oct NN I-NP have VBP B-VP COMMA COMMA O nevertheless RB B-ADVP COMMA COMMA O the DT B-NP capacity NN I-NP to TO B-VP partially RB I-VP activate VB I-VP U2 NN B-NP snRNA NN I-NP transcription NN I-NP in IN B-PP both DT B-NP HeLa NN I-NP cells NNS I-NP COMMA COMMA O in IN B-PP which WDT B-NP only RB B-NP OTF-1 NN I-NP is VBZ B-VP expressed VBN I-VP COMMA COMMA B-PP and CC I-PP in IN B-PP BJA-B NN B-NP cells NNS I-NP in IN B-PP which WDT B-NP OTF-2 NN B-NP is VBZ B-VP the DT B-NP predominantly RB I-NP expressed VBN I-NP octamer-binding JJ I-NP factor NN I-NP . . O The DT B-NP most RBS I-NP likely JJ I-NP interpretation NN I-NP of IN B-PP our PRP$ B-NP results NNS I-NP is VBZ B-VP that IN B-SBAR both CC O the DT B-NP ubiquitous JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O OTF-1 NN B-NP COMMA COMMA O and CC O the DT B-NP B-cell-specific JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O OTF-2 NN B-NP COMMA COMMA O can MD B-VP activate VB I-VP U2 NN B-NP snRNA NN I-NP transcription NN I-NP . . O The DT B-NP results NNS I-NP also RB B-ADVP revealed VBD B-VP a DT B-NP similar JJ I-NP functional JJ I-NP cooperation NN I-NP between IN B-PP the DT B-NP transcription NN I-NP factors NNS I-NP which WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP Oct NN I-NP and CC O the DT B-NP adjacent JJ I-NP Sp NN I-NP 1-binding JJ I-NP site NN B-NP in IN B-PP BJA-B NN B-NP cells NNS I-NP COMMA COMMA O as IN B-SBAR has VBZ B-VP been VBN I-VP observed VBN I-VP in IN B-PP HeLa NN B-NP cells NNS I-NP COMMA COMMA O since IN B-SBAR a DT B-NP template NN I-NP which WDT B-NP contains VBZ B-VP a DT B-NP weak JJ I-NP binding VBG I-NP site NN I-NP for IN B-PP OTFs NNS B-NP expresses VBZ B-VP wild-type JJ B-NP levels NNS I-NP of IN B-PP U2 NN B-NP snRNA NN I-NP in IN B-PP both DT B-NP cell NN I-NP types NNS I-NP when WRB B-ADVP the DT B-NP weak JJ I-NP octamer-binding JJ I-NP site NN I-NP is VBZ B-VP combined VBN I-VP with IN B-PP a DT B-NP Sp NN I-NP 1-binding JJ I-NP site NN I-NP . . O Cortisol NN B-NP receptor NN I-NP resistance NN I-NP : : O the DT B-NP variability NN I-NP of IN B-PP its PRP$ B-NP clinical JJ B-NP presentation NN I-NP and CC O response NN B-NP to TO B-PP treatment NN B-NP . . O Primary JJ B-NP ( ( I-NP partial JJ I-NP ) ) I-NP cortisol NN I-NP receptor NN I-NP resistance NN I-NP was VBD B-VP previously RB I-VP reported VBN I-VP in IN B-PP a DT B-NP total NN I-NP of IN B-PP 7 CD B-NP patients NNS I-NP and CC O 14 CD B-NP asymptomatic JJ I-NP family NN I-NP members NNS I-NP . . O Its PRP$ B-NP occurrence NN I-NP is VBZ B-VP considered VBN I-VP to TO I-VP be VB I-VP extremely RB B-ADJP rare JJ I-ADJP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP we PRP B-NP report VBP B-VP on IN B-PP 6 CD B-NP patients NNS I-NP ( ( O 2 CD B-NP males NNS I-NP and CC O 4 CD B-NP females NNS I-NP ) ) O with IN B-PP the DT B-NP syndrome NN I-NP . . O The DT B-NP first JJ I-NP male JJ I-NP patient NN I-NP presented VBD B-VP with IN B-PP mild JJ B-NP hypertension NN I-NP . . O Hydrochlorothiazide NN B-NP therapy NN I-NP resulted VBD B-VP in IN B-PP life-threatening JJ B-NP hypokalemia NN I-NP . . O The DT B-NP second JJ I-NP male JJ I-NP patient NN I-NP had VBD B-VP slight JJ B-NP hypertension NN I-NP without IN B-PP hypokalemia NN B-NP . . O All DT B-NP four CD I-NP female JJ I-NP patients NNS I-NP presented VBD B-VP between IN B-PP the DT B-NP age NN I-NP of IN B-PP 20-30 CD B-NP yr NN I-NP with IN B-PP acne NN B-NP COMMA COMMA O hirsutism NN B-NP COMMA COMMA O and CC O irregular JJ B-NP menstruations NNS I-NP . . O Low JJ B-NP dose NN I-NP dexamethasone NN I-NP therapy NN I-NP ( ( O 1-1.5 CD B-NP mg\/day NN I-NP ) ) O was VBD B-VP of IN B-PP clinical JJ B-NP benefit NN I-NP in IN B-PP these DT B-NP patients NNS I-NP . . O All DT B-NP patients NNS I-NP showed VBD B-VP insufficient JJ B-NP suppression NN I-NP of IN B-PP serum NN B-NP cortisol NN I-NP concentrations NNS I-NP in IN B-PP the DT B-NP overnight JJ I-NP 1-mg JJ I-NP dexamethasone NN I-NP test NN I-NP . . O The DT B-NP diurnal JJ I-NP rhythm NN I-NP of IN B-PP ACTH NN B-NP and CC O cortisol NN B-NP was VBD B-VP intact JJ B-ADJP COMMA COMMA O albeit IN B-PP at IN B-PP an DT B-NP elevated JJ I-NP level NN I-NP . . O There EX B-NP was VBD B-VP a DT B-NP normal JJ I-NP increase NN I-NP in IN B-PP ACTH NN B-NP COMMA COMMA O cortisol NN B-NP COMMA COMMA O and CC O GH NN B-NP ( ( O except IN B-PP in IN B-PP one CD B-NP obese JJ I-NP patient NN I-NP ) ) O in IN B-PP response NN I-PP to TO I-PP insulin-induced JJ B-NP hypoglycemia NN I-NP COMMA COMMA O while IN B-SBAR cortisol NN B-NP production NN I-NP was VBD B-VP elevated JJ I-VP in IN B-PP three CD B-NP patients NNS I-NP . . O Circulating VBG B-NP adrenal JJ I-NP androgen NN I-NP levels NNS I-NP were VBD B-VP increased VBN I-VP in IN B-PP all DT B-NP patients NNS I-NP . . O Glucocorticoid NN B-NP receptors NNS I-NP were VBD B-VP investigated VBN I-VP in IN B-PP a DT B-NP whole JJ I-NP cell NN I-NP dexamethasone NN I-NP binding NN I-NP assay NN I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP . . O In IN B-PP the DT B-NP first JJ I-NP male JJ I-NP patient NN I-NP COMMA COMMA O the DT B-NP number NN I-NP of IN B-PP receptors NNS B-NP was VBD B-VP very RB B-ADJP low JJ I-ADJP COMMA COMMA O while IN B-SBAR the DT B-NP affinity NN I-NP was VBD B-VP lower JJR B-ADJP than IN B-PP that DT B-NP in IN B-PP controls NNS B-NP . . O A DT B-NP lowered JJ I-NP affinity NN I-NP to TO B-PP dexamethasone NN B-NP was VBD B-VP found VBN I-VP in IN B-PP one CD B-NP female JJ I-NP patient NN I-NP COMMA COMMA O while IN B-SBAR a DT B-NP lowered JJ I-NP number NN I-NP of IN B-PP receptors NNS B-NP was VBD B-VP found VBN I-VP in IN B-PP three CD B-NP patients NNS I-NP . . O In IN B-PP the DT B-NP second JJ I-NP male JJ I-NP patient NN I-NP COMMA COMMA O no DT B-NP abnormalities NNS I-NP were VBD B-VP found VBN I-VP . . O As IN B-PP a DT B-NP bioassay NN I-NP for IN B-PP glucocorticoid NN B-NP action NN I-NP we PRP B-NP also RB B-ADVP measured VBD B-VP dexamethasone NN B-NP suppressibility NN I-NP of IN B-PP mitogen-stimulated JJ B-NP incorporation NN I-NP of IN B-PP {3H}thymidine NN B-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP . . O In IN B-PP the DT B-NP male JJ I-NP patient NN I-NP with IN B-PP normal JJ B-NP receptor NN I-NP status NN I-NP COMMA COMMA O dexamethasone NN B-NP suppressibility NN I-NP of IN B-PP {3H}thymidine NN B-NP incorporation NN I-NP was VBD B-VP significantly RB B-ADJP lower JJR I-ADJP than IN B-PP that DT B-NP in IN B-PP healthy JJ B-NP controls NNS I-NP with IN B-PP respect NN I-PP to TO I-PP both CC O maximal JJ B-NP suppression NN I-NP and CC O IC50 NN B-NP . . O Partial JJ B-NP cortisol NN I-NP receptor NN I-NP resistance NN I-NP might MD B-VP be VB I-VP less RBR B-ADJP rare JJ I-ADJP than IN B-SBAR previously RB B-VP thought VBN I-VP . . O In IN B-PP the DT B-NP six CD I-NP patients NNS I-NP presented VBN B-VP COMMA COMMA O at IN B-NP least JJS I-NP three CD I-NP different JJ I-NP forms NNS I-NP can MD B-VP be VB I-VP recognized VBN I-VP . . O Therapy NN B-NP with IN B-PP dexamethasone NN B-NP was VBD B-VP successful JJ B-ADJP in IN B-PP female JJ B-NP patients NNS I-NP with IN B-PP acne NN B-NP and CC O hirsutism NN B-NP COMMA COMMA O as IN B-SBAR the DT B-NP secondary JJ I-NP increase NN I-NP in IN B-PP the DT B-NP production NN I-NP of IN B-PP adrenal JJ B-NP androgens NNS I-NP was VBD B-VP effectively RB I-VP controlled VBN I-VP . . O Kappa NN B-NP B-specific JJ I-NP DNA NN I-NP binding NN I-NP proteins NNS I-NP are VBP B-VP differentially RB I-VP inhibited VBN I-VP by IN B-PP enhancer NN B-NP mutations NNS I-NP and CC O biological JJ B-NP oxidation NN I-NP . . O Kappa NN B-NP B NN I-NP ( ( O kappa NN B-NP B NN I-NP ) ) O enhancer NN B-NP binding NN I-NP proteins NNS I-NP isolated VBN B-VP from IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP activated VBN B-NP human JJ I-NP T NN I-NP cells NNS I-NP produce VBP B-VP two CD B-NP distinct JJ I-NP nucleoprotein NN I-NP complexes NNS I-NP when WRB B-ADVP incubated VBN B-VP with IN B-PP the DT B-NP kappa NN I-NP B NN I-NP element NN I-NP from IN B-PP the DT O interleukin-2 NN B-NP receptor-alpha NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O gene NN B-NP . . O These DT B-NP two CD I-NP DNA-protein JJ I-NP complexes NNS I-NP are VBP B-VP composed VBN I-VP of IN B-PP at IN B-NP least JJS I-NP four CD I-NP host NN I-NP proteins NNS I-NP ( ( O p50 NN B-NP COMMA COMMA O p55 NN B-NP COMMA COMMA O p75 NN B-NP COMMA COMMA O p85 NN B-NP ) ) O COMMA COMMA O each DT B-NP of IN B-PP which WDT B-NP shares VBZ B-VP structural JJ B-NP similarity NN I-NP with IN B-PP the DT B-NP v-rel NN I-NP oncogene NN I-NP product NN I-NP . . O Nuclear JJ B-NP expression NN I-NP of IN B-PP these DT B-NP proteins NNS I-NP is VBZ B-VP induced VBN I-VP with IN B-PP distinctly RB B-NP biphasic JJ I-NP kinetics NNS I-NP following VBG B-PP phorbol NN B-NP ester NN I-NP activation NN I-NP of IN B-PP T NN B-NP cells NNS I-NP ( ( O p55\/p75 NN B-NP early JJ I-NP and CC O p50\/p85 NN B-NP late JJ I-NP ) ) O . . O DNA-protein JJ B-NP crosslinking NN I-NP studies NNS I-NP have VBP B-VP revealed VBN I-VP that IN B-SBAR the DT O more RBR B-ADVP rapidly RB I-ADVP migrating VBG B-NP B2 NN I-NP complex NN I-NP contains VBZ B-VP both CC O p50 NN B-NP and CC O p55 NN B-NP while IN B-SBAR the DT O more RBR B-ADVP slowly RB I-ADVP migrating VBG B-NP B1 NN I-NP complex NN I-NP is VBZ B-VP composed VBN I-VP of IN B-PP p50 NN B-NP COMMA COMMA O p55 NN B-NP COMMA COMMA O p75 NN B-NP COMMA COMMA O and CC O p85 NN B-NP . . O Site-directed JJ B-NP mutagenesis NN I-NP of IN B-PP the DT B-NP wild-type JJ I-NP IL-2R NN I-NP alpha NN I-NP kappa NN I-NP B NN I-NP enhancer NN I-NP ( ( O GGGGAATCTCCC NN B-NP ) ) O has VBZ B-VP revealed VBN I-VP that IN B-SBAR the DT B-NP binding NN I-NP of IN B-PP p50 NN B-NP and CC O p55 NN B-NP ( ( O B2 NN B-NP complex NN I-NP ) ) O is VBZ B-VP particularly RB B-ADJP sensitive JJ I-ADJP to TO B-PP alteration NN B-NP of IN B-PP the DT B-NP 5' JJ I-NP triplet NN I-NP of IN B-PP deoxyguanosine NN B-NP residues NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O formation NN B-NP of IN B-PP the DT B-NP B1 NN I-NP complex NN I-NP COMMA COMMA O reflecting VBG B-VP the DT B-NP binding NN I-NP of IN B-PP p75 NN B-NP and CC O p85 NN B-NP COMMA COMMA O critically RB B-ADVP depends VBZ B-VP upon IN B-PP the DT B-NP more RBR I-NP 3' JJ I-NP sequences NNS I-NP of IN B-PP this DT B-NP enhancer NN I-NP element NN I-NP . . O DNA NN B-NP binding NN I-NP by IN B-PP all DT B-NP four CD I-NP of IN B-PP these DT B-NP Rel-related JJ I-NP factors NNS I-NP is VBZ B-VP blocked VBN I-VP by IN B-PP selective JJ B-NP chemical JJ I-NP modification NN I-NP of IN B-PP lysine NN B-NP and CC O arginine NN B-NP residues NNS B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR both DT B-NP of IN B-PP these DT B-NP basic JJ I-NP amino NN I-NP acids NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP binding VBG B-VP to TO B-PP the DT B-NP kappa NN I-NP B NN I-NP element NN I-NP . . O Similarly RB B-ADVP COMMA COMMA O covalent JJ B-NP modification NN I-NP of IN B-PP free JJ B-NP sulfhydryl NN I-NP groups NNS I-NP with IN B-PP diamide NN B-NP ( ( O reversible JJ B-ADJP ) ) O or CC O N-ethylmaleimide NN B-NP ( ( O irreversible JJ B-ADJP ) ) O results VBZ B-VP in IN B-PP a DT B-NP complete JJ I-NP loss NN I-NP of IN B-PP DNA NN B-NP binding NN I-NP activity NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O mild JJ B-NP oxidation NN I-NP with IN B-PP glucose NN B-NP oxidase NN I-NP selectively RB B-ADVP inhibits VBZ B-VP p75 NN B-NP and CC O p85 NN B-NP binding NN B-NP while IN B-SBAR not RB B-VP blocking VBG I-VP p50 NN B-NP and CC O p55 NN B-NP interactions NNS B-NP . . O These DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR reduced VBN B-NP cysteine NN I-NP thiols NNS I-NP play VBP B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP DNA NN I-NP binding NN I-NP activity NN I-NP of IN B-PP this DT B-NP family NN I-NP of IN B-PP Rel-related JJ B-NP transcription NN I-NP factors NNS I-NP . . O A DT B-NP novel JJ I-NP mitogen-inducible JJ I-NP gene NN I-NP product NN I-NP related JJ B-ADJP to TO B-PP p50\/p105-NF-kappa NN B-NP B NN I-NP participates VBZ B-VP in IN B-PP transactivation NN B-NP through IN B-PP a DT B-NP kappa NN I-NP B NN I-NP site NN I-NP . . O A DT B-NP Rel-related JJ I-NP COMMA COMMA I-NP mitogen-inducible JJ I-NP COMMA COMMA I-NP kappa NN I-NP B-binding JJ I-NP protein NN I-NP has VBZ B-VP been VBN I-VP cloned VBN I-VP as IN B-PP an DT B-NP immediate-early JJ I-NP activation NN I-NP gene NN I-NP of IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP . . O The DT B-NP cDNA NN I-NP has VBZ B-VP an DT B-NP open JJ I-NP reading NN I-NP frame NN I-NP of IN B-PP 900 CD B-NP amino NN I-NP acids NNS I-NP capable JJ B-ADJP of IN B-PP encoding VBG B-VP a DT B-NP 97-kDa JJ I-NP protein NN I-NP . . O This DT B-NP protein NN I-NP is VBZ B-VP most RBS B-ADJP similar JJ I-ADJP to TO B-PP the DT B-NP 105-kDa JJ I-NP precursor NN I-NP polypeptide NN I-NP of IN B-PP p50-NF-kappa NN B-NP B NN I-NP . . O Like IN B-PP the DT B-NP 105-kDa JJ I-NP precursor NN I-NP COMMA COMMA O it PRP B-NP contains VBZ B-VP an DT B-NP amino-terminal JJ I-NP Rel-related JJ I-NP domain NN I-NP of IN B-PP about IN B-NP 300 CD I-NP amino NN I-NP acids NNS I-NP and CC O a DT B-NP carboxy-terminal JJ I-NP domain NN I-NP containing VBG B-VP six CD O full JJ B-NP cell NN I-NP cycle NN I-NP or CC O ankyrin NN B-NP repeats NNS B-NP . . O In FW B-NP vitro-translated JJ I-NP proteins NNS I-NP COMMA COMMA O truncated VBN B-VP downstream RB B-ADVP of IN B-PP the DT B-NP Rel NN I-NP domain NN I-NP and CC O excluding VBG B-VP the DT B-NP repeats NNS I-NP COMMA COMMA O bind VBP B-VP kappa NN B-NP B NN I-NP sites NNS I-NP . . O We PRP B-NP refer VBP B-VP to TO B-PP the DT B-NP kappa NN I-NP B-binding JJ I-NP COMMA COMMA O truncated VBN B-NP protein NN I-NP as IN B-PP p50B NN B-NP by IN B-PP analogy NN B-NP with IN B-PP p50-NF-kappa NN B-NP B NN I-NP and CC B-PP to TO B-PP the DT B-NP full-length JJ I-NP protein NN I-NP as IN B-PP p97 NN B-NP . . O p50B NN B-NP is VBZ B-VP able JJ B-ADJP to TO B-VP form VB I-VP heteromeric JJ B-NP kappa NN I-NP B-binding JJ I-NP complexes NNS I-NP with IN B-PP RelB NN B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP with IN B-PP p65 NN B-NP and CC O p50 NN B-NP COMMA COMMA O the DT B-NP two CD I-NP subunits NNS I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O Transient-transfection NN B-NP experiments NNS I-NP in IN B-PP embryonal JJ B-NP carcinoma NN I-NP cells NNS I-NP demonstrate VBP B-VP a DT B-NP functional JJ I-NP cooperation NN I-NP between IN B-PP p50B NN B-NP and CC O RelB NN B-NP or CC O p65 NN B-NP in IN B-PP transactivation NN B-NP of IN B-PP a DT B-NP reporter NN I-NP plasmid NN I-NP dependent JJ B-ADJP on IN B-PP a DT B-NP kappa NN I-NP B NN I-NP site NN I-NP . . O The DT B-NP data NNS I-NP imply VBP B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP complex JJ I-NP family NN I-NP of IN B-PP NF-kappa NN B-NP B-like JJ I-NP transcription NN I-NP factors NNS I-NP . . O { ( O Changes NNS B-NP in IN B-PP leucocytic JJ B-NP estrogen NN I-NP receptor NN I-NP levels NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP climacteric JJ B-NP syndrome NN I-NP and CC O therapeutic JJ B-NP effect NN I-NP of IN B-PP liuwei FW B-NP dihuang FW I-NP pills NNS I-NP } ) O The DT B-NP numbers NNS I-NP of IN B-PP estrogen NN B-NP receptor NN I-NP ( ( O ER NN B-NP ) ) O in IN B-PP human JJ B-NP peripheral JJ I-NP leucocytes NNS I-NP in IN B-PP 22 CD B-NP women NNS I-NP with IN B-PP climacteric JJ B-NP syndrome NN I-NP were VBD B-VP measured VBN I-VP by IN B-PP radioligand NN B-NP method NN I-NP . . O The DT B-NP results NNS I-NP were VBD B-VP compared VBN I-VP with IN B-PP those DT B-NP of IN B-PP 12 CD B-NP normal JJ I-NP child-bearing-age JJ I-NP women NNS I-NP . . O It PRP B-NP wat VBD B-VP found VBN I-VP that IN B-SBAR the DT B-NP contents NNS I-NP of IN B-PP leucocytic JJ B-NP ER NN I-NP in IN B-PP climacteric JJ B-NP syndrome NN I-NP patients NNS I-NP were VBD B-VP significantly RB B-ADJP lower JJR I-ADJP than IN B-PP normal JJ B-NP child-bearing-age JJ I-NP women NNS I-NP . . O The DT B-NP authors NNS I-NP used VBD B-VP a DT B-NP Chinese JJ I-NP prescription NN I-NP -- : O Liuwei FW B-NP Dihuang FW I-NP Pills NNS I-NP ( ( O LDP NN B-NP ) ) O to TO B-VP treat VB I-VP the DT B-NP patients NNS I-NP for IN B-PP 2 CD B-NP months NNS I-NP . . O The DT B-NP numbers NNS I-NP of IN B-PP leucocytic JJ B-NP ER NN I-NP were VBD B-VP significantly RB I-VP increased VBN I-VP after IN B-PP treatment NN B-NP . . O The DT B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR decrease NN B-NP of IN B-PP ER NN B-NP levels NNS I-NP in IN B-PP cell NN B-NP may MD B-VP involve VB I-VP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP climacteric JJ B-NP syndrome NN I-NP . . O LDP NN B-NP not RB B-CONJP only RB I-CONJP increases VBZ B-VP plasma NN B-NP estradiol NN I-NP levels NNS I-NP COMMA COMMA O but CC B-CONJP also RB I-CONJP increases VBZ B-VP the DT B-NP leucocytic JJ I-NP ER NN I-NP levels NNS I-NP . . O This DT B-NP may MD B-VP be VB I-VP the DT B-NP basis NN I-NP of IN B-PP the DT B-NP therapeutic JJ I-NP effect NN I-NP on IN B-PP the DT B-NP disease NN I-NP . . O A DT B-NP novel JJ I-NP primer NN I-NP extension NN I-NP method NN I-NP to TO B-VP detect VB I-VP the DT B-NP number NN I-NP of IN B-PP CAG NN B-NP repeats NNS I-NP in IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP in IN B-PP families NNS B-NP with IN B-PP X-linked JJ B-NP spinal JJ I-NP and CC I-NP bulbar JJ I-NP muscular JJ I-NP atrophy NN I-NP . . O X-linked JJ B-NP spinal JJ I-NP and CC I-NP bulbar JJ I-NP muscular JJ I-NP atrophy NN I-NP ( ( O SBMA NN B-NP ) ) O COMMA COMMA O an DT B-NP adult-onset JJ I-NP form NN I-NP of IN B-PP motor NN B-NP neuron NN I-NP disease NN I-NP COMMA COMMA O was VBD B-VP recently RB I-VP reported VBN I-VP to TO I-VP be VB I-VP caused VBN I-VP by IN B-PP amplification NN B-NP of IN B-PP the DT B-NP CAG NN I-NP repeats NNS I-NP in IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP . . O We PRP B-NP report VBP B-VP here RB B-ADVP a DT B-NP simple JJ I-NP and CC I-NP rapid JJ I-NP strategy NN I-NP to TO B-VP detect VB I-VP the DT B-NP precise JJ I-NP number NN I-NP of IN B-PP the DT B-NP CAGs NNS I-NP . . O After IN B-SBAR the DT B-NP DNA NN I-NP fragment NN I-NP containing VBG B-VP the DT B-NP CAG NN I-NP repeats NNS I-NP is VBZ B-VP amplified VBN I-VP by IN B-PP the DT B-NP polymerase NN I-NP chain NN I-NP reaction NN I-NP COMMA COMMA O a DT B-NP primer NN I-NP extension NN I-NP is VBZ B-VP carried VBN I-VP out RP B-PRT ; : O the DT B-NP extension NN I-NP of IN B-PP the DT B-NP end-labelled JJ I-NP reverse JJ I-NP primer NN I-NP adjacent JJ B-ADJP to TO B-PP 3' JJ B-NP end NN I-NP of IN B-PP CAG NN B-NP repeats NNS I-NP stops VBZ B-VP at IN B-PP the DT B-NP first JJ I-NP T NN I-NP after IN B-PP CAG NN B-NP repeats NNS I-NP with IN B-PP the DT B-NP incorporation NN I-NP of IN B-PP dideoxy JJ B-NP ATP NN I-NP in IN B-PP the DT B-NP reaction NN I-NP mixture NN I-NP . . O The DT B-NP resultant JJ I-NP primer NN I-NP products NNS I-NP are VBP B-VP analysed VBN I-VP by IN B-PP denaturing VBG B-VP polyacrylamide NN B-NP gel NN I-NP electrophoresis NN I-NP and CC O autoradiography NN B-NP . . O This DT B-NP method NN I-NP could MD B-VP be VB I-VP quite RB B-ADJP useful JJ I-ADJP to TO B-VP detect VB I-VP not RB B-CONJP only RB I-CONJP CAG NN B-NP repeats NNS I-NP in IN B-PP SBMA NN B-NP but CC B-CONJP also RB I-CONJP other JJ O polymorphic JJ O dinucleotide JJ B-NP and CC O trinucleotide JJ B-NP repeats NNS B-NP . . O Activity NN B-NP of IN B-PP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP of IN B-PP the DT B-NP interleukin-2 NN I-NP receptor NN I-NP alpha NN I-NP chain NN I-NP in IN B-PP somatic JJ B-NP cell NN I-NP hybrids NNS I-NP is VBZ B-VP accompanied VBN I-VP by IN B-PP the DT B-NP nuclear JJ I-NP localization NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O The DT B-NP two CD I-NP nuclear JJ I-NP proteins NNS I-NP NF-kappa NN I-NP B NN I-NP ( ( O consisting VBG B-VP of IN B-PP subunits NNS B-NP p50 NN B-NP and CC O p65 NN B-NP ) ) O and CC O the DT B-NP DNA-binding JJ I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP ( ( O p50 NN B-NP ) ) O by IN B-PP itself PRP B-NP COMMA COMMA O also RB B-VP called VBN I-VP KBF1 NN B-NP COMMA COMMA O are VBP B-VP constitutively RB I-VP expressed VBN I-VP and CC O localized JJ B-VP in IN B-PP the DT B-NP nucleus NN I-NP of IN B-PP the DT B-NP human JJ I-NP T-cell NN I-NP line NN I-NP IARC NN I-NP 301.5 CD I-NP . . O In IN B-SBAR order NN O to TO O define VB B-VP the DT B-NP roles NNS I-NP of IN B-PP these DT B-NP two CD I-NP factors NNS I-NP COMMA COMMA O which WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP same JJ I-NP kappa NN I-NP B NN I-NP enhancers NNS I-NP COMMA COMMA O in IN B-PP transcription NN B-NP activation NN I-NP we PRP B-NP have VBP B-VP prepared VBN I-VP somatic JJ B-NP cell NN I-NP hybrids NNS I-NP between IN B-PP IARC NN B-NP 301.5 CD I-NP and CC O a DT B-NP murine JJ I-NP myeloma NN I-NP . . O Most JJS B-NP hybrids NNS I-NP express VBP B-VP both CC O KBF1 NN B-NP and CC O NF-kappa NN B-NP B NN I-NP in IN B-PP their PRP$ B-NP nuclei NNS I-NP COMMA COMMA O but CC O one CD B-NP hybrid NN I-NP expresses VBZ B-VP only RB B-NP KBF1 NN I-NP . . O The DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP of IN B-PP the DT B-NP gene NN I-NP encoding VBG B-VP the DT O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O receptor NN B-NP alpha NN I-NP chain NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O is VBZ B-VP functional JJ B-ADJP only RB B-PP in IN I-PP the DT B-NP hybrids NNS I-NP expressing VBG B-VP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP . . O These DT B-NP findings NNS I-NP show VBP B-VP that IN B-SBAR nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP is VBZ B-VP necessary JJ B-ADJP to TO B-VP activate VB I-VP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP COMMA COMMA O while IN B-SBAR KBF1 NN B-NP by IN B-PP itself PRP B-NP is VBZ B-VP not RB O sufficient JJ B-ADJP . . O We PRP B-NP propose VBP B-VP that IN B-SBAR KBF1 NN B-NP is VBZ B-VP a DT B-NP competitive JJ I-NP inhibitor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O discuss VB B-VP how WRB B-ADVP these DT B-NP factors NNS I-NP may MD B-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP transient JJ I-NP expression NN I-NP of IN B-PP IL-2 NN B-NP and CC O IL-2 NN B-NP alpha NN I-NP genes NNS B-NP during IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O Influence NN B-NP of IN B-PP estradiol NN B-NP and CC O tamoxifen NN B-NP on IN B-PP susceptibility NN B-NP of IN B-PP human JJ B-NP breast NN I-NP cancer NN I-NP cell NN I-NP lines NNS I-NP to TO B-PP lysis NN B-NP by IN B-PP lymphokine-activated JJ B-NP killer NN I-NP cells NNS I-NP . . O The DT B-NP design NN I-NP of IN B-PP combination NN B-NP hormonal JJ I-NP and CC I-NP immunotherapeutic JJ I-NP protocols NNS I-NP for IN B-PP breast NN B-NP cancer NN I-NP patients NNS I-NP may MD B-VP be VB I-VP facilitated VBN I-VP by IN B-PP analysis NN B-NP of IN B-PP preclinical JJ B-NP in FW I-NP vitro FW I-NP model JJ I-NP systems NNS I-NP . . O Estrogen NN O receptor NN O positive JJ O ( ( O ER+ JJ B-ADJP : : O MCF-7 NN B-NP ) ) O and CC O negative JJ O ( ( O ER- JJ B-ADJP : : O MDA-MB-231 NN B-NP ) ) O human JJ B-NP breast NN I-NP cancer NN I-NP cell NN I-NP lines NNS I-NP were VBD B-VP utilized VBN I-VP to TO B-VP evaluate VB I-VP the DT B-NP effects NNS I-NP of IN B-PP tamoxifen NN B-NP ( ( O TAM NN B-NP ) ) O and CC O estradiol NN B-NP ( ( O E2 NN B-NP ) ) O on IN B-PP modulation NN B-NP of IN B-PP breast NN B-NP cancer NN I-NP target NN I-NP susceptibility NN I-NP to TO B-PP lysis NN B-NP by IN B-PP lymphokine-activated JJ B-NP killer NN I-NP ( ( O LAK NN B-NP ) ) O cells NNS B-NP . . O E2-stimulated JJ B-NP ER+ JJ I-NP cells NNS I-NP were VBD B-VP more RBR B-ADJP susceptible JJ I-ADJP to TO B-PP lysis NN B-NP by IN B-PP LAK NN B-NP cells NNS I-NP than IN B-PP corresponding VBG O TAM-treated JJ O or CC O control NN B-NP cells NNS B-NP COMMA COMMA O while IN B-SBAR treatment NN B-NP of IN B-PP ER- JJ B-NP cells NNS I-NP with IN B-PP either CC O E2 NN B-NP or CC O TAM NN B-NP alone RB B-ADVP did VBD B-VP not RB I-VP alter VB I-VP from IN B-PP control NN B-NP their PRP$ B-NP susceptibility NN I-NP to TO B-PP this DT B-NP immune-mediated JJ I-NP lysis NN I-NP . . O All DT B-NP ER+ JJ I-NP and CC I-NP ER- JJ I-NP cells NNS I-NP tested VBN B-VP remained VBD B-VP sensitive JJ B-ADJP after IN B-PP treatment NN B-NP with IN B-PP TAM NN B-NP to TO B-PP lysis NN B-NP by IN B-PP LAK NN B-NP cells NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O an DT O adenocarcinoma NN B-NP reactive JJ O human-mouse JJ B-ADJP chimeric JJ I-ADJP monoclonal JJ B-NP antibody NN I-NP ( ( O ING-1 NN B-NP ) ) O was VBD B-VP able JJ B-ADJP to TO B-VP significantly RB I-VP boost VB I-VP in FW B-ADVP vivo FW I-ADVP generated VBN B-NP LAK NN I-NP cell-mediated JJ I-NP lysis NN I-NP of IN B-PP control NN B-NP COMMA COMMA O E2-treated JJ B-ADJP COMMA COMMA O and CC O TAM-treated JJ B-ADJP ER+ JJ B-ADJP and CC O ER- JJ B-ADJP cells NNS B-NP . . O These DT B-NP in FW I-NP vitro FW I-NP results NNS I-NP provide VBP B-VP a DT B-NP preclinical JJ I-NP rationale NN I-NP for IN B-PP in FW B-NP vivo FW I-NP testing NN I-NP of IN B-PP TAM NN B-NP COMMA COMMA O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O COMMA COMMA O and CC O breast NN B-NP cancer NN I-NP reactive JJ I-NP antibody-dependent JJ I-NP cellular JJ I-NP cytotoxicity NN I-NP facilitating VBG B-VP antibody NN B-NP in IN B-PP patients NNS B-NP with IN B-PP refractory JJ O or CC O high JJ B-NP risk NN I-NP breast NN B-NP cancer NN I-NP . . O Glucocorticoid NN B-NP receptor NN I-NP and CC O inhibition NN B-NP of IN B-PP 3-O-methyl-D-glucose NN B-NP uptake NN I-NP by IN B-PP glucocorticoids NNS B-NP in IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP from IN B-PP normal JJ B-NP humans NNS I-NP : : O correlation NN B-NP between IN B-PP receptor NN B-NP level NN I-NP and CC O hormone NN B-NP effect NN I-NP in FW B-ADVP vitro FW I-ADVP . . O We PRP B-NP have VBP B-VP measured VBN I-VP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP concentration NN I-NP in IN B-PP mononuclear JJ B-NP and CC I-NP polymorphonuclear JJ I-NP leukocytes NNS I-NP COMMA COMMA O both DT B-NP of IN B-PP which WDT B-NP were VBD B-VP isolated VBN I-VP from IN B-PP peripheral JJ B-NP blood NN I-NP from IN B-PP ten CD B-NP healthy JJ I-NP male JJ I-NP volunteers NNS I-NP . . O In IN B-PP parallel NN B-NP COMMA COMMA O the DT B-NP inhibitory JJ I-NP effect NN I-NP of IN B-PP dexamethasone NN B-NP on IN B-PP 3-O-methyl-D-glucose NN B-NP uptake NN I-NP was VBD B-VP assayed VBN I-VP in IN B-PP the DT B-NP corresponding JJ I-NP mononuclear JJ I-NP leukocytes NNS I-NP . . O The DT B-NP glucocorticoid NN I-NP receptor NN I-NP levels NNS I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP correlated VBD B-VP with IN B-PP those DT B-NP in IN B-PP polymorphonuclear JJ B-NP leukocytes NNS I-NP COMMA COMMA O and CC O there EX B-NP was VBD B-VP a DT B-NP linear JJ I-NP relationship NN I-NP between IN B-PP the DT B-NP cellular JJ I-NP glucocorticoid NN I-NP receptor NN I-NP levels NNS I-NP and CC O glucocorticoid-mediated JJ B-NP inhibition NN I-NP of IN B-PP the DT B-NP uptake NN I-NP of IN B-PP 3-O-methyl-D-glucose NN B-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP . . O When WRB B-ADVP mononuclear JJ B-NP leukocytes NNS I-NP were VBD B-VP incubated VBN I-VP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP 8-bromo-cAMP NN B-NP COMMA COMMA O cellular JJ B-NP glucocorticoid NN I-NP receptor NN I-NP levels NNS I-NP increased VBD B-VP and CC O a DT B-NP more RBR I-NP pronounced JJ I-NP inhibitory JJ I-NP effect NN I-NP of IN B-PP dexamethasone NN B-NP was VBD B-VP observed VBN I-VP on IN B-PP the DT B-NP transport NN I-NP of IN B-PP 3-O-methyl-D-glucose NN B-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR the DT B-NP cellular JJ I-NP glucocorticoid NN I-NP receptor NN I-NP levels NNS I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP reflect VBP B-VP in FW B-NP vitro FW I-NP responsiveness NN I-NP to TO B-PP glucocorticoids NNS B-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP from IN B-PP healthy JJ B-NP males NNS I-NP COMMA COMMA O and CC O that IN B-SBAR the DT B-NP individual JJ I-NP responsiveness NN I-NP may MD B-VP alter VB I-VP upon IN B-PP changes NNS B-NP in IN B-PP the DT B-NP cellular JJ I-NP levels NNS I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP . . O Stimulation NN B-NP of IN B-PP interferon NN B-NP beta NN I-NP gene NN I-NP transcription NN I-NP in FW B-ADVP vitro FW I-ADVP by IN B-PP purified VBN B-NP NF-kappa NN I-NP B NN I-NP and CC O a DT B-NP novel JJ I-NP TH NN I-NP protein NN I-NP . . O The DT O human JJ O interferon NN B-NP beta NN I-NP ( ( O IFN-beta NN B-NP ) ) O regulatory JJ B-NP element NN I-NP consists VBZ B-VP of IN B-PP multiple JJ B-NP enhanson NN I-NP domains NNS I-NP which WDT B-NP are VBP B-VP targets NNS B-NP for IN B-PP transcription NN B-NP factors NNS I-NP involved VBN B-VP in IN B-PP inducible JJ B-NP expression NN I-NP of IN B-PP the DT B-NP promoter NN I-NP . . O To TO B-VP further RB I-VP characterize VB I-VP the DT B-NP protein-DNA JJ I-NP interactions NNS I-NP mediating VBG B-VP IFN-beta NN B-NP induction NN I-NP COMMA COMMA O positive JJ B-NP regulatory JJ I-NP domain NN I-NP ( ( O PRD NN B-NP ) ) O II CD B-NP binding NN I-NP proteins NNS I-NP were VBD B-VP purified VBN I-VP from IN B-PP phorbol NN B-NP ester NN I-NP induced JJ B-NP Jurkat NN I-NP T-cells NNS I-NP and CC B-PP from IN B-PP IFN NN B-NP primed VBN B-ADJP COMMA COMMA O cycloheximide\/polyinosinic-polycytidylic JJ B-NP acid NN I-NP treated VBN B-ADJP HeLa NN O S3 NN O cells NNS O . . O From IN B-PP HeLa NN B-NP cells NNS I-NP COMMA COMMA O two CD B-NP major JJ I-NP proteins NNS I-NP of IN B-PP 52 CD B-NP and CC O 45 CD B-NP kilodaltons NNS B-NP ( ( O kD NN B-NP ) ) O copurified VBD B-VP with IN B-PP DNA NN B-NP binding NN I-NP activity NN I-NP COMMA COMMA O whereas IN O from IN B-PP T-cells NNS B-NP COMMA COMMA O four CD B-NP proteins NNS I-NP -- : O a DT B-NP major JJ I-NP protein NN I-NP of IN B-PP 52 CD B-NP kD NN I-NP and CC O three CD B-NP minor JJ I-NP proteins NNS I-NP of IN B-PP 82 CD B-NP COMMA COMMA I-NP 67 CD I-NP COMMA COMMA I-NP and CC I-NP 43-47 CD I-NP kD NN I-NP -- : O were VBD B-VP purified VBN I-VP . . O Also RB B-ADVP COMMA COMMA O an DT O induction NN B-NP specific JJ B-NP DNA NN I-NP binding NN I-NP protein NN I-NP was VBD B-VP purified VBN I-VP from IN B-PP HeLa NN B-NP cells NNS I-NP that WDT B-NP interacted VBD B-VP with IN B-PP the DT B-NP ( ( I-NP AAGTGA NN I-NP ) ) I-NP 4 CD I-NP tetrahexamer NN I-NP sequence NN I-NP and CC O the DT B-NP PRDI NN I-NP domain NN I-NP . . O This DT B-NP protein NN I-NP is VBZ B-VP immunologically RB B-ADJP distinct JJ I-ADJP from IN B-PP IRF-1\/ISGF2 NN B-NP . . O Uninduced JJ O or CC O Sendai NN B-NP virus NN I-NP induced JJ B-NP HeLa NN I-NP extracts NNS I-NP were VBD B-VP used VBN I-VP to TO B-VP examine VB I-VP transcription NN B-NP in FW B-ADVP vitro FW I-ADVP using VBG B-VP a DT B-NP series NN I-NP of IN B-PP IFN NN B-NP beta NN I-NP promoter NN I-NP deletions NNS I-NP . . O Deletions NNS B-NP upstream JJ B-ADJP of IN B-PP the DT B-NP PRDII NN I-NP element NN I-NP increased VBD B-VP transcription NN B-NP in IN B-PP the DT B-NP uninduced JJ I-NP extract NN I-NP COMMA COMMA O indicating VBG B-VP predominantly RB B-NP negative JJ I-NP regulation NN I-NP of IN B-PP the DT B-NP promoter NN I-NP . . O A DT B-NP 2-4-fold JJ I-NP increase NN I-NP in IN B-PP IFN-beta NN B-NP promoter NN I-NP transcription NN I-NP was VBD B-VP observed VBN I-VP in IN B-PP Sendai NN B-NP virus NN I-NP induced JJ B-NP extracts NNS I-NP COMMA COMMA O and CC O deletion NN B-NP of IN B-PP PRDI NN B-NP and CC O PRDII NN B-NP elements NNS B-NP decreased VBD B-VP this DT B-NP induced VBN I-NP level NN I-NP of IN B-PP transcription NN B-NP . . O When WRB B-ADVP purified VBN B-NP PRDII NN I-NP and CC O tetrahexamer NN B-NP binding NN I-NP proteins NNS I-NP were VBD B-VP added VBN I-VP to TO B-PP the DT B-NP induced VBN I-NP extract NN I-NP COMMA COMMA O a DT B-NP 4-fold JJ I-NP increase NN I-NP in IN B-PP transcription NN B-NP was VBD B-VP observed VBN I-VP . . O These DT B-NP experiments NNS I-NP demonstrate VBP B-VP that IN B-SBAR it PRP B-NP is VBZ B-VP possible JJ B-ADJP to TO B-VP modulate VB I-VP IFN-beta NN B-NP transcription NN I-NP in FW B-ADVP vitro FW I-ADVP but CC O indicate VBP B-VP that IN B-SBAR additional JJ B-NP proteins NNS I-NP may MD B-VP be VB I-VP required VBN I-VP to TO I-VP fully RB I-VP activate VB I-VP IFN-beta NN B-NP transcription NN I-NP . . O Structure NN B-NP function NN I-NP analysis NN I-NP of IN B-PP vitamin NN B-NP D NN I-NP analogs NNS I-NP with IN B-PP C-ring NN B-NP modifications NNS I-NP . . O Analogs NNS B-NP of IN B-PP 1 CD B-NP alphaCOMMA25-dihydroxyvitamin NN I-NP D3 NN I-NP ( ( O 1 CD B-NP alphaCOMMA25-(OH) NN I-NP 2D3 NN I-NP ) ) O with IN B-PP substitutions NNS B-NP on IN B-PP C-11 NN B-NP were VBD B-VP synthesized VBN I-VP . . O Small JJ B-NP apolar JJ I-NP substitutions NNS I-NP ( ( O 11 CD B-NP alpha-methyl NN I-NP COMMA COMMA O 11 CD B-NP alpha-fluoromethyl NN I-NP ) ) O did VBD B-VP not RB I-VP markedly RB I-VP decrease VB I-VP the DT B-NP affinity NN I-NP for IN B-PP the DT B-NP vitamin NN I-NP D NN I-NP receptor NN I-NP COMMA COMMA O but CC O larger JJR O ( ( O 11 CD B-NP alpha-chloromethyl NN I-NP or CC O 11 CD B-NP alpha- NN I-NP or CC B-NP 11 CD I-NP beta-phenyl NN I-NP ) ) O or CC B-NP more RBR I-NP polar JJ I-NP substitutions NNS I-NP ( ( O 11 CD B-NP alpha-hydroxymethyl NN I-NP COMMA COMMA O 11 CD B-NP alpha-(2-hydroxyethyl NN I-NP } ) O decreased VBD B-VP the DT B-NP affinity NN I-NP to TO B-PP less JJR B-NP than IN I-NP 5 CD I-NP % NN I-NP of IN B-PP that DT B-NP of IN B-PP 1 CD B-NP alphaCOMMA25-OH)2D3 NN I-NP . . O Their PRP$ B-NP affinity NN I-NP for IN B-PP the DT B-NP vitamin NN I-NP D-binding JJ I-NP protein NN I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O increased VBD B-VP up RB B-ADVP to TO I-ADVP 4-fold RB I-ADVP . . O The DT B-NP biological JJ I-NP activity NN I-NP of IN B-PP 11 CD B-NP alpha-methyl-1 NN I-NP alphaCOMMA25-(OH)2D3 NN I-NP closely RB B-ADVP resembled VBD B-VP that DT B-NP of IN B-PP the DT B-NP natural JJ I-NP hormone NN I-NP on IN B-PP normal JJ B-NP and CC I-NP leukemic JJ I-NP cell NN B-NP proliferation NN I-NP and CC O bone NN B-NP resorption NN I-NP COMMA COMMA O whereas IN O its PRP$ B-NP in FW I-NP vivo FW I-NP effect NN I-NP on IN B-PP calcium NN B-NP metabolism NN I-NP of IN B-PP the DT B-NP rachitic JJ I-NP chick NN I-NP was VBD B-VP about IN B-NP 50 CD I-NP % NN I-NP of IN B-PP that DT B-NP of IN B-PP 1 CD B-NP alphaCOMMA25-(OH)2D3 NN I-NP . . O The DT B-NP 11 CD I-NP beta-methyl NN I-NP analog NN I-NP had VBD B-VP a DT O greater JJR B-ADVP than IN I-ADVP 10-fold RB I-ADVP lower JJR B-NP activity NN I-NP . . O The DT B-NP differentiating JJ I-NP effects NNS I-NP of IN B-PP the DT B-NP other JJ I-NP C-11 NN I-NP analogs NNS I-NP on IN B-PP human JJ B-NP promyeloid JJ I-NP leukemia NN I-NP cells NNS I-NP ( ( O HL-60 NN B-NP ) ) O agreed VBD B-VP well RB B-ADVP with IN B-PP their PRP$ B-NP bone-resorbing JJ B-NP activity NN I-NP and CC O receptor NN B-NP affinity NN I-NP COMMA COMMA O but CC O they PRP B-NP demonstrated VBD B-VP lower JJR B-NP calcemic JJ I-NP effects NNS I-NP in FW B-ADVP vivo FW I-ADVP . . O Large JJ B-NP or CC I-NP polar JJ I-NP substitutions NNS I-NP on IN B-PP C-11 NN B-NP of IN B-PP 1 CD B-NP alphaCOMMA25-(OH)2D3 NN I-NP thus RB B-ADVP impair VBP B-VP the DT B-NP binding NN I-NP of IN B-PP the DT B-NP vitamin NN I-NP D NN I-NP receptor NN I-NP but CC O increase VBP B-VP the DT B-NP affinity NN I-NP to TO B-PP vitamin NN B-NP D-binding JJ I-NP protein NN I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP many JJ B-NP C-11-substituted JJ I-NP 1 CD I-NP alphaCOMMA25-(OH)2D3 NN I-NP analogs NNS I-NP on IN B-PP HL-60 NN B-NP cell NN I-NP differentiation NN I-NP exceeded VBD B-VP their PRP$ B-NP activity NN I-NP on IN B-PP calcium NN B-NP metabolism NN I-NP . . O Transcriptional JJ B-NP regulation NN I-NP during IN B-PP T-cell NN B-NP development NN I-NP : : O the DT B-NP alpha NN I-NP TCR NN I-NP gene NN I-NP as IN B-PP a DT B-NP molecular JJ I-NP model NN I-NP . . O The DT B-NP regulation NN I-NP of IN B-PP gene NN B-NP expression NN I-NP during IN B-PP lymphocyte NN B-NP differentiation NN I-NP is VBZ B-VP a DT B-NP complex JJ I-NP process NN I-NP involving VBG B-VP interactions NNS B-NP between IN B-PP multiple JJ B-NP positive JJ I-NP and CC I-NP negative JJ I-NP transcriptional JJ I-NP regulatory JJ I-NP elements NNS I-NP . . O In IN B-PP this DT B-NP article NN I-NP COMMA COMMA O transcriptional JJ B-NP regulation NN I-NP of IN B-PP the DT B-NP archetypal JJ I-NP T-cell-specific JJ I-NP gene NN I-NP COMMA COMMA O alpha NN B-NP TCR NN I-NP COMMA COMMA O is VBZ B-VP discussed VBN I-VP . . O Major JJ B-NP recent JJ I-NP developments NNS I-NP COMMA COMMA O including VBG B-PP the DT B-NP identification NN I-NP of IN B-PP novel JJ B-NP families NNS I-NP of IN B-PP transcription NN B-NP factors NNS I-NP that WDT B-NP regulate VBP B-VP multiple JJ B-NP T-cell NN I-NP genes NNS I-NP during IN B-PP thymocyte NN B-NP ontogeny NN I-NP and CC O T-cell NN B-NP activation NN I-NP COMMA COMMA O are VBP B-VP described VBN I-VP . . O Cortisol NN B-NP resistance NN I-NP in IN B-PP acquired VBN B-NP immunodeficiency NN I-NP syndrome NN I-NP . . O This DT B-NP study NN I-NP concerns VBZ B-VP 9 CD B-NP iv NN I-NP drug NN I-NP abusers NNS I-NP with IN B-PP acquired VBN B-NP immunodeficiency NN I-NP syndrome NN I-NP ( ( O AIDS NN B-NP ) ) O who WP B-NP developed VBD B-VP hypercortisolism NN B-NP without IN B-PP the DT B-NP clinical JJ B-NP signs NNS I-NP or CC O metabolic JJ B-NP consequences NNS I-NP of IN B-PP hypercortisolism NN B-NP . . O All DT B-NP patients NNS I-NP were VBD B-VP characterized VBN I-VP by IN B-PP an DT B-NP Addisonian JJ I-NP picture NN I-NP ( ( O weakness NN B-NP COMMA COMMA O weight NN B-NP loss NN I-NP COMMA COMMA O hypotension NN B-NP COMMA COMMA O hyponatremia NN B-NP COMMA COMMA O and CC O intense JJ B-NP mucocutaneous JJ I-NP melanosis NN I-NP ) ) O . . O An DT B-NP acquired JJ I-NP form NN I-NP of IN B-PP peripheral JJ B-NP resistance NN I-NP to TO B-PP glucocorticoids NNS B-NP was VBD B-VP suspected VBN I-VP . . O We PRP B-NP COMMA COMMA O therefore RB B-ADVP COMMA COMMA O examined VBD B-VP glucocorticoid NN B-NP receptor NN I-NP characteristics NNS I-NP on IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP by IN B-PP measuring VBG B-VP {3H}dexamethasone NN B-NP binding NN I-NP and CC O the DT B-NP effect NN I-NP of IN B-PP dexamethasone NN B-NP on IN B-PP {3H}thymidine NN B-NP incorporation NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP one CD B-NP of IN B-PP the DT B-NP effects NNS I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP activation NN I-NP . . O Glucocorticoid NN B-NP receptor NN I-NP density NN I-NP was VBD B-VP increased VBN I-VP in IN B-PP AIDS NN B-NP patients NNS I-NP with IN B-PP an DT B-NP Addisonian JJ I-NP picture NN I-NP ( ( O group NN B-NP 1 CD I-NP ; : O 16.2 CD B-NP +\/- CC I-NP 9.4 CD I-NP fmol\/million NN I-NP cells NNS I-NP ) ) O compared VBN B-VP to TO B-PP values NNS B-NP in IN B-PP 12 CD B-NP AIDS NN I-NP patients NNS I-NP without IN B-PP an DT B-NP Addisonian JJ I-NP picture NN I-NP ( ( O group NN B-NP 2 CD I-NP ; : O 6.05 CD B-NP +\/- CC I-NP 2.6 CD I-NP fmol\/million NN I-NP cells NNS I-NP ; : O P NN B-NP less JJR B-NP than IN I-NP 0.01 CD I-NP ) ) O and CC O sex- NN B-NP and CC O age-matched JJ B-ADJP controls NNS B-NP ( ( O 3.15 CD B-NP +\/- CC I-NP 2.3 CD I-NP fmol\/million NN I-NP cells NNS I-NP ; : O P NN B-NP less JJR B-NP than IN I-NP 0.01 CD I-NP ) ) O . . O The DT B-NP affinity NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP ( ( O Kd NN B-NP ) ) O was VBD B-VP strikingly RB I-VP decreased VBN I-VP ( ( O 9.36 CD B-NP +\/- CC I-NP 3.44 CD I-NP nM NN I-NP in IN B-PP group NN B-NP 1 CD I-NP ; : O 3.2 CD B-NP +\/- CC I-NP 1.5 CD I-NP nM NN I-NP in IN B-PP group NN B-NP 2 CD I-NP ; : O 2.0 CD B-NP +\/- CC I-NP 0.8 CD I-NP nM NN I-NP in IN B-PP controls NNS B-NP ; : O P NN B-NP less JJR B-NP than IN I-NP 0.01 CD I-NP ) ) O . . O {3H}Thymidine NN B-NP incorporation NN I-NP was VBD B-VP decreased VBN I-VP dose-dependently RB B-ADVP by IN B-PP dexamethasone NN B-NP in IN B-PP controls NNS B-NP and CC O patients NNS B-NP ; : O the DT B-NP effect NN I-NP was VBD B-VP significantly RB I-VP blunted VBN I-VP ( ( O P NN B-NP less JJR B-NP than IN I-NP 0.05 CD I-NP ) ) O in IN B-PP group NN B-NP 1 CD I-NP patients NNS I-NP COMMA COMMA O which WDT B-NP suggests VBZ B-VP that IN B-SBAR activation NN B-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP is VBZ B-VP impaired JJ B-ADJP as IN B-PP a DT B-NP result NN I-NP of IN B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP abnormality NN I-NP . . O In IN B-PP conclusion NN B-NP COMMA COMMA O AIDS NN B-NP patients NNS I-NP with IN B-PP hypercortisolism NN B-NP and CC O clinical JJ B-NP features NNS I-NP of IN B-PP peripheral JJ B-NP resistance NN I-NP to TO B-PP glucocorticoids NNS B-NP are VBP B-VP characterized VBN I-VP by IN B-PP abnormal JJ B-NP glucocorticoid NN I-NP receptors NNS I-NP on IN B-PP lymphocytes NNS B-NP . . O Resistance NN B-NP to TO B-PP glucocorticoids NNS B-NP implies VBZ B-VP a DT B-NP complex JJ I-NP change NN I-NP in IN B-PP immune-endocrine JJ B-NP function NN I-NP COMMA COMMA O which WDT B-NP may MD B-VP be VB I-VP important JJ B-ADJP in IN B-PP the DT B-NP course NN I-NP of IN B-PP immunodeficiency NN B-NP syndrome NN I-NP . . O Induction NN B-NP of IN B-PP monocytic JJ B-NP differentiation NN I-NP and CC O NF-kappa NN B-NP B-like JJ I-NP activities NNS I-NP by IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP 1 CD I-NP infection NN I-NP of IN B-PP myelomonoblastic JJ B-NP cells NNS I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O infection NN B-NP on IN B-PP cellular JJ B-NP differentiation NN I-NP and CC O NF-kappa NN B-NP B NN I-NP DNA NN I-NP binding NN I-NP activity NN I-NP have VBP B-VP been VBN I-VP investigated VBN I-VP in IN B-PP a DT B-NP new JJ I-NP model NN I-NP of IN B-PP myeloid JJ B-NP differentiation NN I-NP . . O PLB-985 NN B-NP cells NNS I-NP represent VBP B-VP a DT B-NP bipotential JJ I-NP myelomonoblastic JJ I-NP cell NN I-NP population NN I-NP capable JJ B-ADJP of IN B-PP either CC B-NP granulocytic JJ I-NP or CC I-NP monocytic JJ I-NP differentiation NN I-NP after IN B-PP induction NN B-NP with IN B-PP appropriate JJ B-NP inducers NNS I-NP . . O By IN B-PP virtue NN I-PP of IN I-PP the DT B-NP presence NN I-NP of IN B-PP CD4 NN B-NP on IN B-PP the DT B-NP cell NN I-NP surface NN I-NP COMMA COMMA O PLB-985 NN B-NP cells NNS I-NP were VBD B-VP chronically RB I-VP infected VBN I-VP with IN B-PP HIV-1 NN B-NP strain NN I-NP IIIB NN I-NP . . O PLB-IIIB NN B-NP cells NNS I-NP clearly RB B-ADVP possessed VBD B-VP a DT B-NP more RBR I-NP monocytic JJ I-NP phenotype NN I-NP than IN B-PP the DT B-NP parental JJ I-NP myeloblasts NNS I-NP COMMA COMMA O as IN B-SBAR determined VBN B-VP by IN B-PP differential JJ B-NP staining NN I-NP COMMA COMMA O increased VBN B-NP expression NN I-NP of IN B-PP the DT B-NP myeloid-specific JJ I-NP surface NN I-NP markers NNS I-NP COMMA COMMA O and CC O transcription NN B-NP of IN B-PP the DT B-NP c-fms NN I-NP proto-oncogene NN I-NP . . O NF-kappa NN B-NP B NN I-NP binding NN I-NP activity NN I-NP was VBD B-VP inducible JJ B-ADJP by IN B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP and CC O phorbol NN B-NP myristate NN I-NP acetate NN I-NP in IN B-PP PLB-985 NN B-NP . . O However RB B-ADVP COMMA COMMA O in IN B-PP PLB-IIIB NN B-NP cells NNS I-NP COMMA COMMA O constitutive JJ B-NP expression NN I-NP of IN B-PP a DT B-NP novel JJ I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP was VBD B-VP detected VBN I-VP COMMA COMMA O composed VBN B-VP of IN B-PP proteins NNS B-NP ranging VBG B-VP between IN B-PP 70 CD B-NP and CC I-NP 110 CD I-NP kD NN I-NP . . O These DT B-NP proteins NNS I-NP interacted VBD B-VP specifically RB B-PP with IN I-PP the DT B-NP symmetric JJ I-NP NF-kappa NN I-NP B NN I-NP site NN I-NP from IN B-PP the DT O interferon NN B-NP beta NN I-NP ( ( O IFN-beta NN B-NP ) ) O promoter NN B-NP . . O Mutations NNS B-NP affecting VBG B-VP the DT B-NP 5' JJ I-NP guanine JJ I-NP residues NNS I-NP of IN B-PP the DT B-NP kappa NN I-NP B NN I-NP site NN I-NP were VBD B-VP unable JJ B-ADJP to TO B-VP compete VB I-VP for IN B-PP these DT B-NP NF-kappa NN I-NP B-related JJ I-NP proteins NNS I-NP . . O Inducibility NN B-NP of IN B-PP endogenous JJ O IFN-beta NN B-NP and CC O IFN-alpha NN B-NP RNA NN B-NP was VBD B-VP also RB I-VP increased VBN I-VP in IN B-PP PLB-IIIB NN B-NP cells NNS I-NP . . O These DT B-NP studies NNS I-NP indicate VBP B-VP that IN B-SBAR HIV-1 NN B-NP infection NN I-NP of IN B-PP myelomonoblastic JJ B-NP cells NNS I-NP may MD B-VP select VB I-VP for IN B-PP a DT B-NP more RBR I-NP mature JJ I-NP monocytic JJ I-NP phenotype NN I-NP and CC O that IN B-SBAR unique JJ B-NP subunit NN I-NP associations NNS I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP DNA NN I-NP binding NN I-NP proteins NNS I-NP may MD B-VP contribute VB I-VP to TO B-PP differential JJ B-NP NF-kappa NN I-NP B-mediated JJ I-NP gene NN I-NP expression NN I-NP . . O The DT B-NP AP-1 NN I-NP site NN I-NP at IN B-PP -150 CD B-NP bp NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP the DT B-NP NF-kappa NN I-NP B NN I-NP site NN I-NP COMMA COMMA O is VBZ B-VP likely JJ B-ADJP to TO B-VP represent VB I-VP the DT B-NP major JJ I-NP target NN I-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP in IN B-PP the DT B-NP interleukin NN I-NP 2 CD I-NP promoter NN I-NP . . O Stimulation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP with IN B-PP antigen NN B-NP results VBZ B-VP in IN B-PP activation NN B-NP of IN B-PP several JJ B-NP kinases NNS I-NP COMMA COMMA O including VBG B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O COMMA COMMA O that WDT B-NP may MD B-VP mediate VB I-VP the DT B-NP later JJ I-NP induction NN I-NP of IN B-PP activation-related JJ B-NP genes NNS I-NP . . O We PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP potential JJ I-NP role NN I-NP of IN B-PP PKC NN B-NP in IN B-PP induction NN B-NP of IN B-PP the DT O interleukin NN B-NP 2 CD I-NP ( ( O IL-2 NN B-NP ) ) O gene NN B-NP in IN B-PP T NN B-NP cells NNS I-NP stimulated VBN B-VP through IN B-PP the DT B-NP T NN I-NP cell NN I-NP receptor\/CD3 NN I-NP complex NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR prolonged JJ B-NP treatment NN I-NP of IN B-PP the DT B-NP untransformed JJ I-NP T NN I-NP cell NN I-NP clone NN I-NP Ar-5 NN I-NP with IN B-PP phorbol NN B-NP esters NNS I-NP results VBZ B-VP in IN B-PP downmodulation NN B-NP of IN B-PP the DT O alpha NN B-NP and CC O beta NN B-NP isozymes NNS B-NP of IN B-PP PKC NN B-NP COMMA COMMA O and CC O abrogates VBZ B-VP induction NN B-NP of IN B-PP IL-2 NN B-NP mRNA NN I-NP and CC O protein NN B-NP . . O Here RB B-ADVP we PRP B-NP show VBP B-VP that IN B-SBAR phorbol NN B-NP ester NN I-NP treatment NN I-NP also RB B-ADVP abolishes VBZ B-VP induction NN B-NP of IN B-PP chloramphenicol JJ B-NP acetyltransferase NN I-NP activity NN I-NP in IN B-PP Ar-5 NN B-NP cells NNS I-NP transfected VBN B-VP with IN B-PP a DT B-NP plasmid NN I-NP containing VBG B-VP the DT B-NP IL-2 NN I-NP promoter NN I-NP linked VBN B-VP to TO B-PP this DT B-NP reporter NN I-NP gene NN I-NP . . O The DT B-NP IL-2 NN I-NP promoter NN I-NP contains VBZ B-VP binding VBG B-NP sites NNS I-NP for IN B-PP nuclear JJ B-NP factors NNS I-NP including VBG B-PP NFAT-1 NN B-NP COMMA COMMA O Oct NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP COMMA COMMA O and CC O AP-1 NN B-NP COMMA COMMA O which WDT B-NP are VBP B-VP all DT B-ADJP potentially RB I-ADJP sensitive JJ I-ADJP to TO B-PP activation NN B-NP of IN B-PP PKC NN B-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR induction NN B-NP of IN B-PP a DT B-NP trimer NN I-NP of IN B-PP the DT O NFAT NN B-NP and CC O Oct NN B-NP sites NNS B-NP is VBZ B-VP not RB O sensitive JJ B-ADJP to TO B-PP phorbol NN B-NP ester NN I-NP treatment NN I-NP COMMA COMMA O and CC O that IN B-SBAR mutations NNS B-NP in IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP site NN I-NP have VBP B-VP no DT B-NP effect NN I-NP on IN B-PP inducibility NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O mutations NNS B-NP in IN B-PP the DT B-NP AP-1 NN I-NP site NN I-NP located JJ B-ADJP at IN B-PP -150 CD B-NP bp NN I-NP almost RB B-ADVP completely RB I-ADVP abrogate VBP B-VP induction NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP COMMA COMMA O and CC O appearance NN B-NP of IN B-PP an DT B-NP inducible JJ I-NP nuclear JJ I-NP factor NN I-NP binding VBG B-VP to TO B-PP this DT B-NP site NN I-NP is VBZ B-VP sensitive JJ B-ADJP to TO B-PP PKC NN B-NP depletion NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O cotransfections NNS B-NP with IN B-PP c-fos NN B-NP and CC O c-jun NN B-NP expression NN B-NP plasmids NNS I-NP markedly RB B-ADVP enhance VBP B-VP induction NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP in IN B-PP minimally RB B-NP stimulated VBN I-NP T NN I-NP cells NNS I-NP . . O Our PRP$ B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP AP-1 NN I-NP site NN I-NP at IN B-PP -150 CD B-NP bp NN I-NP represents VBZ B-VP a DT B-NP major JJ I-NP COMMA COMMA O if IN B-SBAR not RB O the DT B-NP only JJ I-NP COMMA COMMA O site NN B-NP of IN B-PP PKC NN B-NP responsiveness NN I-NP in IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP . . O Interleukin NN B-NP 6-induced JJ I-NP differentiation NN I-NP of IN B-PP a DT B-NP human JJ I-NP B NN I-NP cell NN I-NP line NN I-NP into IN B-PP IgM-secreting JJ B-NP plasma NN I-NP cells NNS I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP c-fos NN B-NP . . O The DT B-NP role NN I-NP of IN B-PP the DT B-NP protooncogene NN I-NP c-fos NN I-NP in IN B-PP interleukin NN B-NP ( ( I-NP IL NN I-NP ) ) I-NP 6-induced JJ I-NP B NN I-NP cell NN I-NP differentiation NN I-NP was VBD B-VP assessed VBN I-VP . . O Treatment NN B-NP of IN B-PP SKW NN B-NP 6.4 CD I-NP cells NNS I-NP with IN B-PP IL NN B-NP 6 CD I-NP induced VBD B-VP a DT B-NP transient JJ I-NP and CC I-NP early JJ I-NP stimulation NN I-NP of IN B-PP c-fos NN B-NP sense NN I-NP mRNA NN I-NP expression NN I-NP . . O The DT B-NP effect NN I-NP appeared VBD B-VP within IN B-PP 30 CD B-NP min NN I-NP and CC O returned VBD B-VP to TO B-PP basal JJ B-NP levels NNS I-NP after IN B-PP 2 CD B-NP h NN I-NP . . O The DT B-NP addition NN I-NP of IN B-PP antisense JJ B-NP oligonucleotides NNS I-NP to TO B-PP c-fos NN B-NP significantly RB B-ADVP inhibited VBD B-VP IL NN B-NP 6-induced JJ I-NP IgM NN I-NP production NN I-NP by IN B-PP SKW NN B-NP 6.4 CD I-NP cells NNS I-NP ( ( O p NN B-NP less JJR B-NP than IN I-NP 0.001 CD I-NP ) ) O COMMA COMMA O whereas IN O control NN B-NP oligonucleotides NNS I-NP had VBD B-VP no DT B-NP inhibitory JJ I-NP effect NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR activation NN B-NP of IN B-PP c-fos NN B-NP is VBZ B-VP involved VBN I-VP in IN B-PP IL NN B-NP 6-induced JJ I-NP differentiation NN I-NP of IN B-PP SKW NN B-NP 6.4 CD I-NP cells NNS I-NP into IN B-PP IgM-secreting JJ B-NP cells NNS I-NP . . O Binding NN B-NP of IN B-PP erythroid JJ B-NP and CC I-NP non-erythroid JJ I-NP nuclear JJ I-NP proteins NNS I-NP to TO B-PP the DT B-NP silencer NN I-NP of IN B-PP the DT B-NP human JJ I-NP epsilon-globin-encoding JJ I-NP gene NN I-NP . . O To TO B-VP clarify VB I-VP the DT B-NP molecular JJ I-NP mechanisms NNS I-NP involved VBN B-VP in IN B-PP the DT B-NP developmental JJ I-NP control NN I-NP of IN B-PP hemoglobin-encoding JJ B-NP genes NNS I-NP we PRP B-NP have VBP B-VP been VBN I-VP studying VBG I-VP the DT B-NP expression NN I-NP of IN B-PP these DT B-NP genes NNS I-NP in IN B-PP human JJ B-NP cells NNS I-NP in IN B-PP continuous JJ B-NP culture NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP reported VBN I-VP the DT B-NP presence NN I-NP of IN B-PP a DT B-NP transcriptional JJ I-NP control NN I-NP element NN I-NP with IN B-PP the DT B-NP properties NNS I-NP of IN B-PP a DT B-NP silencer NN I-NP extending VBG B-VP from IN B-PP -392 CD B-NP to TO B-PP -177 CD B-NP bp NN B-NP relative JJ B-PP to TO I-PP the DT B-NP cap NN I-NP site NN I-NP of IN B-PP the DT B-NP human JJ I-NP epsilon-globin-encoding JJ I-NP gene NN I-NP { ( O Cao NNP B-NP et FW B-NP al. FW B-NP COMMA COMMA O Proc.Natl.Acad.Sci.USA NNP B-NP 86 CD I-NP ( ( I-NP 1989 CD I-NP ) ) I-NP 5306-5309 CD I-NP } ) O . . O We PRP B-NP also RB B-ADVP showed VBD B-VP that IN B-SBAR this DT B-NP silencer NN I-NP has VBZ B-VP stronger JJR B-NP inhibitory JJ I-NP activity NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP COMMA COMMA O as IN B-SBAR compared VBN B-VP to TO B-PP K562 NN B-NP human JJ I-NP erythroleukemia NN I-NP cells NNS I-NP . . O Using VBG B-VP deletion NN B-NP mutants NNS I-NP and CC O cis-cloned JJ B-NP synthetic JJ I-NP oligodeoxyribonucleotides NNS I-NP in IN B-PP transient JJ B-NP expression NN I-NP assays NNS I-NP COMMA COMMA O nucleotide NN B-NP sequences NNS I-NP responsible JJ B-ADJP for IN B-PP this DT B-NP effect NN I-NP have VBP B-VP now RB I-VP been VBN I-VP further RBR I-VP delimited VBN I-VP to TO B-PP 44 CD B-NP bp NN I-NP located JJ B-ADJP from IN B-PP -294 CD B-NP to TO B-PP -251 CD B-NP bp NN B-NP . . O Gel NN B-NP electrophoresis NN I-NP mobility NN I-NP shift NN I-NP assays NNS I-NP and CC O DNaseI NN B-NP footprinting NN I-NP assays NNS I-NP demonstrate VBP B-VP that IN B-SBAR these DT B-NP negative JJ I-NP regulatory JJ I-NP sequences NNS I-NP are VBP B-VP recognized VBN I-VP differently RB B-ADVP by IN B-PP proteins NNS B-NP present JJ B-ADJP in IN B-PP nuclear JJ B-NP extracts NNS I-NP obtained VBN B-VP from IN B-PP HeLa NN B-NP and CC O K562 NN B-NP cells NNS B-NP . . O Two CD B-NP binding VBG I-NP proteins NNS I-NP are VBP B-VP detected VBN I-VP in IN B-PP K562 NN B-NP nuclear JJ I-NP extracts NNS I-NP COMMA COMMA O while IN B-SBAR only RB B-NP one CD I-NP is VBZ B-VP found VBN I-VP in IN B-PP extracts NNS B-NP from IN B-PP HeLa NN B-NP cells NNS I-NP . . O Possible JJ B-NP mechanisms NNS I-NP by IN B-PP which WDT B-NP these DT B-NP proteins NNS I-NP may MD B-VP regulate VB I-VP transcription NN B-NP of IN B-PP the DT B-NP epsilon-globin-encoding JJ I-NP gene NN I-NP in IN B-PP erythroid JJ B-NP and CC I-NP non-erythroid JJ I-NP cells NNS I-NP are VBP B-VP discussed VBN I-VP . . O Gangliosides NN B-NP suppress VBP B-VP tumor NN B-NP necrosis NN I-NP factor NN I-NP production NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP . . O Both CC B-NP normal JJ I-NP and CC I-NP malignant JJ I-NP cells NNS I-NP contain VBP B-VP gangliosides NNS B-NP as IN B-PP important JJ B-NP cell NN I-NP membrane NN I-NP constituents NNS I-NP that WDT B-NP COMMA COMMA O after IN B-PP being VBG B-VP shed VBN I-VP COMMA COMMA O may MD B-VP influence VB I-VP cells NNS B-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O We PRP B-NP have VBP B-VP studied VBN I-VP the DT B-NP impact NN I-NP of IN B-PP gangliosides NNS B-NP on IN B-PP the DT B-NP expression NN I-NP of IN B-PP TNF NN B-NP in IN B-PP blood NN B-NP monocytes NNS I-NP and CC B-PP in IN B-PP the DT B-NP monocytic JJ I-NP cell NN I-NP line NN I-NP Mono NN I-NP Mac NN I-NP 6 CD I-NP . . O Although IN B-SBAR under IN B-PP standard JJ B-NP culture NN I-NP conditions NNS I-NP COMMA COMMA O bovine JJ B-NP brain NN I-NP gangliosides NNS I-NP ( ( O 100 CD B-NP micrograms\/ml NNS I-NP ) ) O suppressed VBD B-VP LPS-stimulated JJ B-NP TNF NN I-NP production NN I-NP 5-fold RB B-ADVP in IN B-PP PBMC NN B-NP and CC O 10-fold RB B-ADVP in IN B-PP Mono NN B-NP Mac NN I-NP 6 CD I-NP cells NNS I-NP COMMA COMMA O suppression NN B-NP was VBD B-VP more RBR B-ADJP efficient JJ I-ADJP under IN B-PP serum-free JJ B-NP conditions NNS I-NP . . O Looking VBG B-VP at IN B-PP highly RB B-NP purified VBN I-NP gangliosides NNS I-NP COMMA COMMA O GD3 NN B-NP COMMA COMMA O GD1a NN B-NP COMMA COMMA O GM3 NN B-NP COMMA COMMA O GM2 NN B-NP COMMA COMMA O and CC O GM1 NN B-NP were VBD B-VP all DT B-ADJP effective JJ I-ADJP in IN B-PP reducing VBG B-VP TNF NN B-NP production NN I-NP in IN B-PP PBMC NN B-NP COMMA COMMA B-PP and CC I-PP in IN B-PP Mono NN B-NP Mac NN I-NP 6 CD I-NP by IN B-PP factor NN B-NP 10 CD B-NP to TO O 50 CD B-NP . . O The DT B-NP suppressive JJ I-NP activity NN I-NP was VBD B-VP lost VBN I-VP in IN B-PP molecules NNS B-NP COMMA COMMA O lacking VBG B-VP the DT B-NP sugar NN I-NP moiety NN I-NP or CC O the DT B-NP lipid NN I-NP moiety NN I-NP . . O Gangliosides NNS B-NP appear VBP B-VP to TO I-VP act VB I-VP at IN B-PP an DT B-NP early JJ I-NP step NN I-NP of IN B-PP activation NN B-NP in IN B-PP that IN B-NP TNF NN B-NP transcripts NNS I-NP were VBD B-VP reduced VBN I-VP and CC O the DT B-NP mobilization NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP factor NN I-NP kappa NN I-NP B NN I-NP was VBD B-VP blocked VBN I-VP . . O Furthermore RB B-ADVP COMMA COMMA O in IN B-PP time NN B-NP kinetics NNS I-NP COMMA COMMA O gangliosides NNS B-NP were VBD B-VP effective JJ B-ADJP for IN B-PP up RB B-NP to TO I-NP 30 CD I-NP min NN I-NP after IN B-PP addition NN B-NP of IN B-PP LPS NN B-NP COMMA COMMA O but CC O not RB B-ADVP thereafter RB I-ADVP . . O However RB B-ADVP COMMA COMMA O the DT B-NP expression NN I-NP of IN B-PP the DT B-NP CD14 NN I-NP Ag NN I-NP COMMA COMMA O a DT B-NP receptor NN I-NP molecule NN I-NP for IN B-PP LPS-LPS NN B-NP binding NN I-NP protein NN I-NP complexes NNS I-NP COMMA COMMA O was VBD B-VP unaffected JJ I-VP by IN B-PP gangliosides NNS B-NP . . O Finally RB B-ADVP COMMA COMMA O when WRB B-ADVP using VBG B-VP Staphylococcus FW B-NP aureus FW I-NP or CC O platelet NN B-NP activating NN I-NP factor NN I-NP as IN B-PP a DT B-NP stimulus NN I-NP COMMA COMMA O gangliosides NNS B-NP were VBD B-VP able JJ B-ADJP to TO B-VP suppress VB I-VP TNF NN B-NP production NN I-NP in IN B-PP Mono NN B-NP Mac NN I-NP 6 CD I-NP cells NNS I-NP by IN B-PP factor NN B-NP 5 CD B-NP to TO O 10 CD B-NP COMMA COMMA O as RB B-PP well RB B-ADVP . . O On IN B-PP the DT B-NP other JJ I-NP hand NN I-NP COMMA COMMA O phorbol NN B-NP ester-induced JJ I-NP production NN I-NP of IN B-PP O2- NN B-NP was VBD B-VP similar JJ B-ADJP in IN B-PP cells NNS B-NP treated VBN B-VP with IN B-PP and CC B-PP without IN B-PP gangliosides NNS B-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O our PRP$ B-NP data NNS I-NP demonstrate VBP B-VP that IN B-SBAR TNF NN B-NP gene NN I-NP expression NN I-NP in IN B-PP monocytes NNS B-NP induced VBN B-VP by IN B-PP different JJ B-NP types NNS I-NP of IN B-PP stimuli NNS B-NP can MD B-VP be VB I-VP blocked VBN I-VP by IN B-PP gangliosides NNS B-NP at IN B-PP an DT B-NP early JJ I-NP step NN I-NP of IN B-PP signal JJ B-NP transduction NN I-NP . . O T NN B-NP cell-specific JJ I-NP negative JJ I-NP regulation NN I-NP of IN B-PP transcription NN B-NP of IN B-PP the DT B-NP human JJ I-NP cytokine NN I-NP IL-4 NN I-NP . . O IL-4 NN B-NP secreted VBN B-VP by IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP is VBZ B-VP a DT B-NP pleiotropic JJ I-NP cytokine NN I-NP affecting VBG B-VP growth NN B-NP and CC O differentiation NN B-NP of IN B-PP diverse JJ B-NP cell NN I-NP types NNS I-NP such JJ B-PP as IN I-PP T NN B-NP cells NNS I-NP COMMA COMMA O B NN B-NP cells NNS I-NP COMMA COMMA O and CC O mast NN B-NP cells NNS I-NP . . O We PRP B-NP investigated VBD B-VP the DT B-NP upstream JJ I-NP regulatory JJ I-NP elements NNS I-NP of IN B-PP the DT B-NP human JJ I-NP IL-4 NN I-NP promoter NN I-NP . . O A DT B-NP novel JJ I-NP T NN I-NP cell-specific JJ I-NP negative JJ I-NP regulatory JJ I-NP element NN I-NP ( ( O NRE NN B-NP ) ) O composed VBN B-VP of IN B-PP two CD B-NP protein-binding JJ I-NP sites NNS I-NP were VBD B-VP mapped VBN I-VP in IN B-PP the DT B-NP 5' JJ I-NP flanking JJ I-NP region NN I-NP of IN B-PP the DT B-NP IL-4 NN I-NP gene NN I-NP : : O -311CTCCCTTCT-303 NN B-NP ( ( O NRE-I NN B-NP ) ) O and CC O -288CTTTTTGCTT-TGC-300 NN B-NP ( ( O NRE-II NN B-NP ) ) O . . O A DT B-NP T NN I-NP cell-specific JJ I-NP protein NN I-NP Neg-1 NN I-NP and CC O a DT B-NP ubiquitous JJ I-NP protein NN I-NP Neg-2 NN I-NP binding VBG B-VP to TO B-PP NRE-I NN B-NP and CC O NRE-II NN B-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O were VBD B-VP identified VBN I-VP . . O Furthermore RB B-ADVP COMMA COMMA O a DT B-NP positive JJ I-NP regulatory JJ I-NP element NN I-NP was VBD B-VP found VBN I-VP 45 CD B-NP bp NN I-NP downstream RB B-ADVP of IN B-PP the DT B-NP NRE NN I-NP . . O The DT B-NP enhancer NN I-NP activity NN I-NP of IN B-PP the DT B-NP PRE NN I-NP was VBD B-VP completely RB I-VP suppressed VBN I-VP when WRB B-ADVP the DT B-NP NRE NN I-NP was VBD B-VP present JJ B-ADJP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR IL-4 NN B-NP promoter NN I-NP activity NN I-NP is VBZ B-VP normally RB I-VP down-regulated VBN I-VP by IN B-PP an DT B-NP NRE NN I-NP via IN B-PP repression NN B-NP of IN B-PP the DT B-NP enhancer NN I-NP positive JJ I-NP regulatory JJ I-NP element NN I-NP . . O These DT B-NP data NNS I-NP may MD B-VP have VB I-VP implications NNS B-NP for IN B-PP the DT B-NP stringent JJ I-NP control NN I-NP of IN B-PP IL-4 NN B-NP expression NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O { ( O Regulatory JJ B-NP effect NN I-NP of IN B-PP insulin NN B-NP on IN B-PP glucocorticoid NN B-NP receptor NN I-NP in IN B-PP human JJ B-NP peripheral JJ I-NP leukocytes NNS I-NP } ) O The DT B-NP regulatory JJ I-NP effect NN I-NP of IN B-PP insulin NN B-NP on IN B-PP the DT B-NP specific JJ I-NP binding VBG I-NP power NN I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O of IN B-PP human JJ B-NP leukocytes NNS I-NP was VBD B-VP assessed VBN I-VP by IN B-PP the DT B-NP unoccupied JJ I-NP receptor NN I-NP sites NNS I-NP capable JJ B-ADJP of IN B-PP combining VBG B-VP with IN B-PP {3H} NN B-NP labelled JJ I-NP dexamethasone NN I-NP measured VBN B-VP at IN B-PP 3 CD B-NP and CC I-NP 24 CD I-NP h NN I-NP after IN B-PP incubation NN B-NP with IN B-PP various JJ B-NP concentrations NNS I-NP of IN B-PP insulin NN B-NP added VBN B-VP to TO B-PP the DT B-NP medium NN I-NP . . O After IN B-PP 3 CD B-NP h NN I-NP incubation NN I-NP the DT B-NP specific JJ I-NP binding VBG I-NP power NN I-NP with IN B-PP {3H} NN B-NP Dex NN I-NP was VBD B-VP decreased VBN I-VP by IN B-PP 23.3 CD B-NP +\/- CC I-NP 10.0 CD I-NP COMMA COMMA O 32.2 CD B-NP +\/- CC I-NP 13.2 CD I-NP and CC O 54.3 CD B-NP +\/- CC I-NP 9.2 CD I-NP % NN B-NP ( ( O P NN B-NP greater JJR B-ADJP than IN B-PP 0.05 CD B-NP COMMA COMMA O P NN B-NP greater JJR B-ADJP than IN B-PP 0.05 CD B-NP and CC O P NN B-NP less JJR B-ADJP than IN B-PP 0.01 CD B-NP as IN B-SBAR compared VBN B-VP with IN B-PP the DT B-NP control NN I-NP value NN I-NP of IN B-PP 100 CD B-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP insulin NN B-NP ) ) O respectively RB B-ADVP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP 20 CD B-NP mU\/L NN I-NP ( ( O physiological JJ B-NP testing NN I-NP concentration NN I-NP ) ) O COMMA COMMA O 200 CD B-NP mU\/L NN I-NP ( ( O physiological JJ B-NP upper JJ I-NP limit NN I-NP ) ) O and CC O 2COMMA000 CD B-NP mU\/L NN I-NP ( ( O pharmacological JJ B-NP concentration NN I-NP ) ) O insulin NN B-NP in IN B-PP the DT B-NP incubation NN I-NP medium NN I-NP . . O After IN B-PP 24 CD B-NP h NN I-NP incubation NN I-NP the DT B-NP decrease NN I-NP of IN B-PP these DT B-NP values NNS I-NP increased VBD B-VP respectively RB B-ADVP to TO B-PP 43.5 CD B-NP +\/- CC I-NP 19.0 CD I-NP COMMA COMMA O 56.1 CD B-NP +\/- CC I-NP 20.7 CD I-NP and CC O 80.2 CD B-NP +\/- CC I-NP 15.5 CD I-NP ( ( O P NN B-NP less JJR B-ADJP than IN B-PP 0.05 CD B-NP COMMA COMMA O P NN B-NP less JJR B-ADJP than IN B-PP 0.01 CD B-NP and CC O P NN B-NP less JJR B-ADJP than IN B-PP 0.01 CD B-NP compared VBN B-VP with IN B-PP control NN B-NP ) ) O . . O Thus RB B-ADVP the DT B-NP inhibitory JJ I-NP effect NN I-NP of IN B-PP insulin NN B-NP on IN B-PP the DT B-NP GR NN I-NP binding NN I-NP power NN I-NP is VBZ B-VP both CC O dose- NN B-NP and CC O time-dependent JJ B-ADJP COMMA COMMA O which WDT B-NP strongly RB B-ADVP suggests VBZ B-VP that IN B-SBAR GR NN B-NP is VBZ B-VP tonically RB I-VP controlled VBN I-VP by IN B-PP insulin NN B-NP concentration NN I-NP change NN I-NP under IN B-PP physiological JJ B-NP conditions NNS I-NP . . O Human JJ B-NP T NN I-NP cell NN I-NP activation NN I-NP through IN B-PP the DT B-NP activation-inducer JJ I-NP molecule\/CD69 NN I-NP enhances VBZ B-VP the DT B-NP activity NN I-NP of IN B-PP transcription NN B-NP factor NN I-NP AP-1 NN I-NP . . O The DT B-NP induction NN I-NP of IN B-PP the DT B-NP AP-1 NN I-NP transcription NN I-NP factor NN I-NP has VBZ B-VP been VBN I-VP ascribed VBN I-VP to TO B-PP the DT B-NP early JJ I-NP events NNS I-NP leading VBG B-VP to TO B-PP T NN B-NP cell NN I-NP differentiation NN B-NP and CC O activation NN B-NP . . O We PRP B-NP have VBP B-VP studied VBN I-VP the DT B-NP regulation NN I-NP of IN B-PP AP-1 NN B-NP activity NN I-NP in IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP lymphocytes NNS I-NP stimulated VBN B-VP through IN B-PP the DT B-NP activation NN I-NP inducer NN I-NP molecule NN I-NP ( ( I-NP AIM NN I-NP ) ) I-NP \/CD69 NN I-NP activation NN I-NP pathway NN I-NP . . O Phorbol NN B-NP esters NNS I-NP are VBP B-VP required VBN I-VP to TO B-VP induce VB I-VP AIM\/CD69 NN B-NP cell-surface JJ I-NP expression NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP for IN B-PP triggering VBG B-VP the DT B-NP proliferation NN I-NP of IN B-PP T NN B-NP cells NNS I-NP in IN B-PP conjunction NN I-PP with IN I-PP anti-AIM JJ B-NP mAb NN I-NP . . O Mobility NN B-NP shift NN I-NP assays NNS I-NP showed VBD B-VP that IN B-SBAR addition NN B-NP of IN B-PP anti-AIM JJ B-NP mAb NN I-NP to TO B-PP PMA-treated JJ B-NP T NN I-NP lymphocytes NNS I-NP markedly RB B-ADVP enhanced VBD B-VP the DT B-NP binding NN I-NP activity NN I-NP of IN B-PP AP-1 NN B-NP to TO B-PP its PRP$ B-NP cognate JJ I-NP sequence NN I-NP COMMA COMMA O the DT B-NP phorbol NN I-NP ester NN I-NP response NN I-NP element NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O anti-AIM NN B-NP mAb NN I-NP did VBD B-VP not RB I-VP induce VB I-VP any DT B-NP change NN I-NP in IN B-PP the DT B-NP binding NN I-NP activity NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O a DT B-NP transcription NN I-NP factor NN I-NP whose WP$ B-NP activity NN I-NP is VBZ B-VP also RB I-VP regulated VBN I-VP by IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP . . O The DT B-NP increase NN I-NP in IN B-PP AP-1-binding JJ B-NP activity NN I-NP was VBD B-VP accompanied VBN I-VP by IN B-PP the DT B-NP marked JJ I-NP stimulation NN I-NP of IN B-PP the DT B-NP transcription NN I-NP of IN B-PP c-fos NN B-NP but CC B-CONJP not RB I-CONJP that DT B-NP of IN B-PP c-jun NN B-NP . . O Blockade NN B-NP of IN B-PP the DT B-NP DNA-binding JJ I-NP complexes NNS I-NP with IN B-PP an DT B-NP anti-Fos JJ I-NP mAb NN I-NP demonstrated VBD B-VP a DT B-NP direct JJ I-NP participation NN I-NP of IN B-PP c-Fos NN B-NP in IN B-PP the DT B-NP AP-1 NN I-NP complexes NNS I-NP induced VBN B-VP by IN B-PP anti-AIM NN B-NP mAb NN I-NP . . O Most JJS B-NP of IN B-PP the DT B-NP AP-1 NN I-NP activity NN I-NP could MD B-VP be VB I-VP eliminated VBN I-VP when WRB B-ADVP the DT B-NP anti-AIM NN I-NP mAb NN I-NP was VBD B-VP added VBN I-VP to TO B-PP the DT B-NP culture NN I-NP medium NN I-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP cycloheximide NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR de FW B-NP novo FW I-NP protein NN I-NP synthesis NN I-NP is VBZ B-VP crucial JJ B-ADJP for IN B-PP the DT B-NP induction NN I-NP of IN B-PP AP-1-binding JJ B-NP activity NN I-NP . . O These DT B-NP data NNS I-NP provide VBP B-VP the DT B-NP evidence NN I-NP that IN B-SBAR activation NN B-NP of IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP through IN B-PP the DT B-NP AIM NN I-NP activation NN I-NP pathway NN I-NP regulate VBP B-VP the DT B-NP activity NN I-NP of IN B-PP AP-1 NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O this DT B-NP pathway NN I-NP appears VBZ B-VP as IN B-PP a DT B-NP crucial JJ I-NP step NN I-NP in IN B-PP the DT B-NP initiation NN I-NP of IN B-PP early JJ B-NP T NN I-NP cell NN I-NP activation NN I-NP events NNS I-NP . . O cis-acting JJ B-NP sequences NNS I-NP required VBN B-VP for IN B-PP inducible JJ B-NP interleukin-2 NN I-NP enhancer NN I-NP function NN I-NP bind VBP B-VP a DT B-NP novel JJ I-NP Ets-related JJ I-NP protein NN I-NP COMMA COMMA O Elf-1 NN B-NP . . O The DT B-NP recent JJ I-NP definition NN I-NP of IN B-PP a DT B-NP consensus NN I-NP DNA NN I-NP binding NN I-NP sequence NN I-NP for IN B-PP the DT B-NP Ets NN I-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP has VBZ B-VP allowed VBN I-VP the DT B-NP identification NN I-NP of IN B-PP potential JJ B-NP Ets NN I-NP binding NN I-NP sites NNS I-NP in IN B-PP the DT B-NP promoters NNS B-NP and CC O enhancers NNS B-NP of IN B-PP many JJ B-NP inducible JJ I-NP T-cell NN I-NP genes NNS I-NP . . O In IN B-PP the DT B-NP studies NNS I-NP described VBN B-VP in IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP identified VBN I-VP two CD B-NP potential JJ I-NP Ets NNS I-NP binding NN I-NP sites NNS I-NP COMMA COMMA O EBS1 NN B-NP and CC O EBS2 NN B-NP COMMA COMMA O which WDT B-NP are VBP B-VP conserved VBN I-VP in IN B-PP both CC B-NP the DT I-NP human JJ I-NP and CC I-NP murine JJ I-NP interleukin-2 NN I-NP enhancers NNS I-NP . . O Within IN B-PP the DT B-NP human JJ I-NP enhancer NN I-NP COMMA COMMA O these DT B-NP two CD I-NP sites NNS I-NP are VBP B-VP located JJ O within IN B-PP the DT B-NP previously RB I-NP defined VBN I-NP DNase NN I-NP I CD I-NP footprints NNS I-NP COMMA COMMA O NFAT-1 NN B-NP and CC O NFIL-2B NN B-NP COMMA COMMA O respectively RB B-ADJP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP and CC O methylation NN B-NP interference NN I-NP analyses NNS B-NP demonstrated VBD B-VP that IN B-SBAR EBS1 NN B-NP and CC O EBS2 NN B-NP are VBP B-VP essential JJ B-ADJP for IN B-PP the DT B-NP formation NN I-NP of IN B-PP the DT O NFAT-1 NN B-NP and CC O NFIL-2B NN B-NP nuclear JJ B-NP protein NN I-NP complexes NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O in FW B-NP vitro FW I-NP mutagenesis NN I-NP experiments NNS I-NP demonstrated VBD B-VP that IN B-SBAR inducible JJ B-NP interleukin-2 NN I-NP enhancer NN I-NP function NN I-NP requires VBZ B-VP the DT B-NP presence NN I-NP of IN B-PP either CC O EBS1 NN B-NP or CC O EBS2 NN B-NP . . O Two CD B-NP well-characterized JJ I-NP Ets NN I-NP family NN I-NP members NNS I-NP COMMA COMMA O Ets-1 NN B-NP and CC O Ets-2 NN B-NP COMMA COMMA O are VBP B-VP reciprocally RB I-VP expressed VBN I-VP during IN B-PP T-cell NN B-NP activation NN I-NP . . O Surprisingly RB B-ADVP COMMA COMMA O however RB B-ADVP COMMA COMMA O neither DT B-NP of IN B-PP these DT B-NP proteins NNS I-NP bound VBD B-VP in FW B-ADVP vitro FW I-ADVP to TO B-PP EBS1 NN B-NP or CC O EBS2 NN B-NP . . O We PRP B-NP therefore RB B-ADVP screened VBD B-VP a DT B-NP T-cell NN I-NP cDNA NN I-NP library NN I-NP under IN B-PP low-stringency NN B-NP conditions NNS I-NP with IN B-PP a DT B-NP probe NN I-NP from IN B-PP the DT B-NP DNA NN I-NP binding NN I-NP domain NN I-NP of IN B-PP Ets-1 NN B-NP and CC O isolated VBD B-VP a DT B-NP novel JJ I-NP Ets NN I-NP family NN I-NP member NN I-NP COMMA COMMA O Elf-1 NN B-NP . . O Elf-1 NN B-NP contains VBZ B-VP a DT B-NP DNA NN I-NP binding NN I-NP domain NN I-NP that WDT B-NP is VBZ B-VP nearly RB B-ADJP identical JJ I-ADJP to TO B-PP that DT B-NP of IN B-PP E74 NN B-NP COMMA COMMA O the DT B-NP ecdysone-inducible JJ I-NP Drosophila NN I-NP transcription NN I-NP factor NN I-NP required VBN B-VP for IN B-PP metamorphosis NN B-NP ( ( O hence RB B-ADVP the DT B-NP name NN I-NP Elf-1 NN I-NP COMMA COMMA O for IN B-PP E74-like JJ B-NP factor NN I-NP 1 CD I-NP ) ) O . . O Elf-1 NN B-NP bound VBD B-VP specifically RB B-PP to TO I-PP both CC O EBS1 NN B-NP and CC O EBS2 NN B-NP in IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP . . O It PRP B-NP also RB B-ADVP bound VBD B-VP to TO B-PP the DT B-NP purine-rich JJ I-NP CD3R NN I-NP element NN I-NP from IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 2 CD I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP required VBN I-VP for IN B-PP inducible JJ B-NP virus NN I-NP expression NN I-NP in IN B-PP response NN I-PP to TO I-PP signalling NN B-NP through IN B-PP the DT B-NP T-cell NN I-NP receptor NN I-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR multiple JJ B-NP Ets NN I-NP family NN I-NP members NNS I-NP with IN B-PP apparently RB B-NP distinct JJ I-NP DNA NN I-NP binding NN I-NP specificities NNS I-NP regulate VBP B-VP differential JJ B-NP gene NN I-NP expression NN I-NP in IN B-PP resting VBG B-NP and CC I-NP activated VBN I-NP T NN I-NP cells NNS I-NP . . O Mineralocorticoids NNPS B-NP and CC O mineralocorticoid NN B-NP receptors NNS I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP pregnancy-induced JJ B-NP hypertension NN I-NP . . O To TO B-VP examine VB I-VP the DT B-NP role NN I-NP of IN B-PP mineralocorticoids NNS B-NP in IN B-PP the DT B-NP pathophysiology NN I-NP of IN B-PP pregnancy-induced JJ B-NP hypertension NN I-NP ( ( O PIH NN B-NP ) ) O COMMA COMMA O we PRP B-NP studied VBD B-VP plasma NN B-NP aldosterone NN I-NP and CC O 18-hydroxycorticosterone NN B-NP levels NNS B-NP in IN B-PP 25 CD B-NP women NNS I-NP with IN B-PP PIH NN B-NP and CC O 25 CD B-NP normal JJ I-NP pregnant JJ I-NP women NNS I-NP COMMA COMMA O as IN B-PP controls NNS B-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP evaluated VBD B-VP the DT O mineralocorticoid NN B-NP receptor NN I-NP ( ( O MR NN B-NP ) ) O status NN B-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP in IN B-PP the DT B-NP 2 CD I-NP groups NNS I-NP . . O MR NN B-NP count NN I-NP was VBD B-VP significantly RB B-ADVP ( ( O P NN B-NP less JJR B-NP than IN I-NP 0.0005 CD I-NP ) ) O decreased VBN B-VP in IN B-PP the DT B-NP PIH NN I-NP group NN I-NP ( ( O 148 CD B-NP +\/- CC I-NP 9 CD I-NP binding VBG I-NP sites\/cell NNS I-NP ) ) O compared VBN B-PP with IN B-PP the DT B-NP control NN I-NP group NN I-NP ( ( O 300 CD B-NP +\/- CC I-NP 17 CD I-NP binding VBG I-NP sites\/cell NNS I-NP ; : O mean NN B-NP +\/- CC I-NP SEM NN I-NP ) ) O . . O Plasma NN B-NP aldosterone NN I-NP in IN B-PP women NNS B-NP with IN B-PP PIH NN B-NP was VBD B-VP 281 CD B-NP +\/- CC I-NP 61 CD I-NP pmol\/L NN I-NP ; : O in IN B-PP normal JJ B-NP pregnant JJ I-NP women NNS I-NP it PRP B-NP was VBD B-VP 697 CD B-NP +\/- CC I-NP 172 CD I-NP pmol\/L NN I-NP ( ( O P NN B-NP less JJR B-NP than IN I-NP 0.025 CD I-NP ) ) O . . O Plasma NN B-NP 18-hydroxycorticosterone NN I-NP was VBD B-VP also RB B-ADVP significantly RB O ( ( O P NN B-NP less JJR B-NP than IN I-NP 0.025 CD I-NP ) ) O lower JJR B-ADJP ( ( O PIH NN B-NP COMMA COMMA O 1071 CD B-NP +\/- CC I-NP 149 CD I-NP pmol\/L NN I-NP ; : O controls NNS B-NP COMMA COMMA O 1907 CD B-NP +\/- CC I-NP 318 CD I-NP pmol\/L NN I-NP ) ) O . . O These DT B-NP values NNS I-NP were VBD B-VP determined VBN I-VP at IN B-PP the DT B-NP onset NN I-NP of IN B-PP clinical JJ B-NP symptoms NNS I-NP of IN B-PP PIH NN B-NP . . O These DT B-NP results NNS I-NP can MD B-VP not RB I-VP be VB I-VP explained VBN I-VP by IN B-PP receptor NN B-NP down-regulation NN I-NP due JJ B-PP to TO I-PP higher JJR B-NP levels NNS I-NP of IN B-PP mineralocorticoids NNS B-NP in IN B-PP PIH NN B-NP ; : O a DT B-NP hitherto RB I-NP unknown JJ I-NP mineralocorticoid NN I-NP may MD B-VP COMMA COMMA O thus RB B-ADVP COMMA COMMA O be VB B-VP responsible JJ B-ADJP for IN B-PP the DT O hypertension NN B-NP and CC O altered JJ B-NP MR NN I-NP status NN B-NP . . O Mineralocorticoid NN B-NP effector NN I-NP mechanism NN I-NP in IN B-PP preeclampsia NN B-NP . . O Mineralocorticoid NN B-NP effector NN I-NP mechanisms NNS I-NP were VBD B-VP evaluated VBN I-VP in IN B-PP 29 CD B-NP patients NNS I-NP with IN B-PP preeclampsia NN B-NP and CC B-PP in IN B-PP 25 CD B-NP uncomplicated JJ I-NP pregnancies NNS I-NP by IN B-PP measurement NN B-NP of IN B-PP plasma NN B-NP aldosterone NN I-NP COMMA COMMA O levels NNS B-NP of IN B-PP mineralocorticoid NN B-NP receptor NN I-NP ( ( O MR NN B-NP ) ) O in IN B-PP mononuclear JJ B-NP leucocytes NNS I-NP COMMA COMMA O and CC O subtraction NN B-NP potential NN I-NP difference NN I-NP ( ( O SPD NN B-NP ; : O rectal JJ B-NP minus CC I-NP oral JJ I-NP values NNS I-NP ) ) O . . O Mean NN B-NP values NNS I-NP for IN B-PP plasma NN B-NP aldosterone NN I-NP were VBD B-VP not RB O different JJ B-ADJP between IN B-PP the DT B-NP two CD I-NP groups NNS I-NP COMMA COMMA O but CC O significant JJ B-NP differences NNS I-NP were VBD B-VP observed VBN I-VP for IN B-PP MR NN B-NP ( ( O preeclampsia NN B-NP COMMA COMMA O 81 CD B-NP +\/- CC I-NP 44 CD I-NP receptors\/cell NNS I-NP ; : O controls NNS B-NP COMMA COMMA O 306 CD B-NP +\/- CC I-NP 168 CD I-NP ) ) O and CC O SPD NN B-NP ( ( O preeclampsia NN B-NP COMMA COMMA O 65 CD B-NP +\/- CC I-NP 7 CD I-NP mV NN I-NP ; : O controls NNS B-NP COMMA COMMA O 12 CD B-NP +\/- CC I-NP 5 CD I-NP mV NN I-NP ) ) O . . O In IN B-PP six CD B-NP cases NNS I-NP we PRP B-NP determined VBD B-VP MR NN B-NP COMMA COMMA O plasma NN B-NP aldosterone NN I-NP COMMA COMMA O and CC O SPD NN B-NP in IN B-PP patients NNS B-NP with IN B-PP preeclampsia NN B-NP before IN B-PP and CC B-PP 3 CD B-NP months NNS I-NP after IN B-PP delivery NN B-NP . . O MR NNS B-NP were VBD B-VP reduced VBN I-VP before IN B-PP delivery NN B-NP ( ( O 96 CD B-NP +\/- CC I-NP 27 CD I-NP receptors\/cell NNS I-NP ) ) O COMMA COMMA O and CC O SPD NN B-NP increased VBD B-VP ( ( O 64 CD B-NP +\/- CC I-NP 8 CD I-NP mV NN I-NP ) ) O COMMA COMMA O with IN B-PP both DT B-NP parameters NNS I-NP normalizing VBG B-VP after IN B-PP delivery NN B-NP ( ( O MR NN B-NP COMMA COMMA O 242 CD B-NP +\/- CC I-NP 79 CD I-NP ; : O SPD NN B-NP COMMA COMMA O 14.0 CD B-NP +\/- CC I-NP 4 CD I-NP mV NN I-NP ) ) O . . O Aldosterone NN B-NP levels NNS I-NP returned VBD B-VP to TO B-PP normal JJ B-NP nonpregnant JJ I-NP values NNS I-NP after IN B-PP delivery NN B-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP an DT B-NP important JJ I-NP role NN I-NP for IN B-PP abnormalities NNS B-NP in IN B-PP mineralocorticoid NN B-NP effector NN I-NP mechanisms NNS I-NP in IN B-PP the DT B-NP etiology NN I-NP of IN B-PP preeclampsia NN B-NP and CC O could MD B-VP be VB I-VP an DT B-NP useful JJ I-NP marker NN I-NP for IN B-PP diagnosis NN B-NP . . O A DT B-NP lymphoid JJ I-NP cell-specific JJ I-NP nuclear JJ I-NP factor NN I-NP containing VBG B-VP c-Rel-like JJ B-NP proteins NNS I-NP preferentially RB B-ADVP interacts VBZ B-VP with IN B-PP interleukin-6 NN B-NP kappa NN I-NP B-related JJ I-NP motifs NNS I-NP whose WP$ B-NP activities NNS I-NP are VBP B-VP repressed VBN I-VP in IN B-PP lymphoid JJ B-NP cells NNS I-NP . . O The DT B-NP proto-oncoprotein NN I-NP c-Rel NN I-NP is VBZ B-VP a DT B-NP member NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP factor NN I-NP kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP family NN I-NP COMMA COMMA O which WDT B-NP includes VBZ B-VP the DT O p50 NN B-NP and CC O p65 NN B-NP subunits NNS B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP . . O We PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR c-Rel NN B-NP binds VBZ B-VP to TO B-PP kappa NN B-NP B NN I-NP sites NNS I-NP as IN B-PP homodimers NNS B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP heterodimers NNS B-NP with IN B-PP p50 NN B-NP . . O These DT B-NP homodimers NNS B-NP and CC O heterodimers NNS B-NP show VBP B-VP distinct JJ B-NP DNA-binding JJ I-NP specificities NNS I-NP and CC O affinities NNS B-NP for IN B-PP various JJ B-NP kappa NN I-NP B NN I-NP motifs NNS I-NP . . O In IN B-PP particular JJ B-NP COMMA COMMA O the DT B-NP c-Rel NN I-NP homodimer NN I-NP has VBZ B-VP a DT B-NP high JJ I-NP affinity NN I-NP for IN B-PP interleukin-6 NN B-NP ( ( O IL-6 NN B-NP ) ) O and CC O beta NN B-NP interferon NN I-NP kappa NN I-NP B NN I-NP sites NNS B-NP . . O In IN B-PP spite NN I-PP of IN I-PP its PRP$ B-NP association NN I-NP with IN B-PP p50 NN B-NP in FW B-ADVP vitro FW I-ADVP COMMA COMMA O however RB B-ADVP COMMA COMMA O we PRP B-NP found VBD B-VP a DT B-NP lymphoid JJ I-NP cell-specific JJ I-NP nuclear JJ I-NP factor NN I-NP in FW B-ADVP vivo FW I-ADVP that WDT B-NP contains VBZ B-VP c-Rel NN B-NP but CC B-CONJP not RB I-CONJP p50 NN B-NP epitopes NNS B-NP ; : O this DT B-NP factor NN I-NP COMMA COMMA O termed VBN B-VP IL-6 NN B-NP kappa NN I-NP B NN I-NP binding NN I-NP factor NN I-NP II CD I-NP COMMA COMMA O appears VBZ B-VP to TO I-VP contain VB I-VP the DT B-NP c-Rel NN I-NP homodimer NN I-NP and CC O preferentially RB B-VP recognizes VBZ I-VP several JJ B-NP IL-6 NN I-NP kappa NN I-NP B-related JJ I-NP kappa NN I-NP B NN I-NP motifs NNS I-NP . . O Although IN B-SBAR it PRP B-NP has VBZ B-VP been VBN I-VP previously RB I-VP shown VBN I-VP that IN B-SBAR the DT B-NP IL-6 NN I-NP kappa NN I-NP B NN I-NP motif NN I-NP functions VBZ B-VP as IN B-PP a DT B-NP potent JJ I-NP IL-1\/tumor NN I-NP necrosis NN I-NP factor-responsive JJ I-NP element NN I-NP in IN B-PP nonlymphoid JJ B-NP cells NNS I-NP COMMA COMMA O its PRP$ B-NP activity NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP repressed VBN I-VP in IN B-PP lymphoid JJ B-NP cells NNS I-NP such JJ B-PP as IN I-PP a DT B-NP Jurkat NN I-NP T-cell NN I-NP line NN I-NP . . O We PRP B-NP also RB B-ADVP present VBP B-VP evidence NN B-NP that IN B-SBAR IL-6 NN B-NP kappa NN I-NP B NN I-NP binding NN I-NP factor NN I-NP II CD I-NP functions VBZ B-VP as IN B-PP a DT B-NP repressor NN I-NP specific JJ B-ADJP for IN B-PP IL-6 NN B-NP kappa NN I-NP B-related JJ I-NP kappa NN I-NP B NN I-NP motifs NNS I-NP in IN B-PP lymphoid JJ B-NP cells NNS I-NP . . O Modulation NN B-NP of IN B-PP normal JJ B-NP erythroid JJ I-NP differentiation NN I-NP by IN B-PP the DT O endogenous JJ B-NP thyroid NN I-NP hormone NN I-NP and CC O retinoic JJ B-NP acid NN I-NP receptors NNS B-NP : : O a DT B-NP possible JJ I-NP target NN I-NP for IN B-PP v-erbA NN B-NP oncogene NN I-NP action NN I-NP . . O The DT B-NP v-erbA NN I-NP oncogene NN I-NP COMMA COMMA O a DT B-NP mutated VBN I-NP version NN I-NP of IN B-PP the DT B-NP thyroid NN I-NP hormone NN I-NP receptor NN I-NP alpha NN I-NP ( ( O c-erbA\/TR-alpha NN B-NP ) ) O COMMA COMMA O inhibits VBZ B-VP erythroid JJ B-NP differentiation NN I-NP and CC O constitutively RB B-VP represses VBZ I-VP transcription NN B-NP of IN B-PP certain JJ B-NP erythrocyte NN I-NP genes NNS I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP normal JJ I-NP function NN I-NP of IN B-PP the DT B-NP proto-oncogene NN I-NP c-erbA NN I-NP in IN B-PP erythropoiesis NN B-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP endogenous JJ I-NP thyroid NN I-NP hormone NN I-NP receptor NN I-NP alpha NN I-NP ( ( O c-erbA\/TR-alpha NN B-NP ) ) O and CC O the DT B-NP closely RB I-NP related JJ I-NP retinoic JJ B-NP acid NN I-NP receptor NN I-NP alpha NN I-NP ( ( O RAR-alpha NN B-NP ) ) O play VBP B-VP a DT B-NP role NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP normal JJ B-NP erythroid JJ I-NP differentiation NN I-NP . . O Retinoic JJ B-NP acid NN I-NP ( ( O RA NN B-NP ) ) O distinctly RB B-ADVP modulated VBD B-VP the DT B-NP erythroid JJ I-NP differentiation NN I-NP program NN I-NP of IN B-PP normal JJ B-NP erythroid JJ I-NP progenitors NNS I-NP and CC O erythroblasts NNS B-NP reversibly RB B-VP transformed VBN I-VP by IN B-PP a DT B-NP conditional JJ I-NP tyrosine NN I-NP kinase NN I-NP oncogene NN I-NP . . O When WRB B-ADVP added VBN B-VP pulsewise RB B-ADVP to TO B-PP immature JJ B-NP cells NNS I-NP COMMA COMMA O differentiation NN B-NP was VBD B-VP accelerated VBN I-VP while IN B-SBAR more RBR B-NP mature JJ I-NP cells NNS I-NP underwent VBD B-VP premature JJ B-NP cell NN I-NP death NN I-NP . . O Thyroid NN B-NP hormone NN I-NP ( ( O T3 NN B-NP ) ) O alone RB B-ADVP caused VBD B-VP similar JJ B-NP but CC I-NP weaker JJR I-NP effects NNS I-NP . . O Interestingly RB B-ADVP COMMA COMMA O T3 NN B-NP strongly RB B-ADVP enhanced VBD B-VP the DT B-NP action NN I-NP of IN B-PP RA NN B-NP COMMA COMMA O suggesting VBG B-VP cooperative JJ B-NP action NN I-NP of IN B-PP the DT B-NP two CD I-NP receptors NNS I-NP in IN B-PP modulating VBG B-VP erythroid JJ B-NP differentiation NN I-NP . . O Expression NN B-NP of IN B-PP the DT B-NP human JJ I-NP RAR-alpha NN I-NP in IN B-PP receptor-negative JJ B-NP erythroblasts NNS I-NP conferred VBD B-VP RA-induced JJ B-NP regulation NN I-NP of IN B-PP differentiation NN B-NP to TO B-PP the DT B-NP otherwise RB I-NP unresponsive JJ I-NP cells NNS I-NP COMMA COMMA O thus RB O showing VBG B-VP that IN B-SBAR the DT B-NP RAR-alpha NN I-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP the DT B-NP RA NN I-NP effect NN I-NP . . O Likewise RB B-ADVP COMMA COMMA O enhanced VBN B-NP expression NN I-NP of IN B-PP exogenous JJ B-NP c-erbA\/TR-alpha NN I-NP in IN B-PP erythroblasts NNS B-NP rendered VBD B-VP them PRP B-NP susceptible JJ B-ADJP to TO B-PP modulation NN B-NP of IN B-PP differentiation NN B-NP by IN B-PP T3 NN B-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP similar JJ I-NP function NN I-NP of IN B-PP both DT B-NP receptors NNS I-NP . . O Leukotriene NN B-NP B4 NN I-NP stimulates VBZ B-VP c-fos NN B-NP and CC O c-jun NN B-NP gene NN B-NP transcription NN I-NP and CC O AP-1 NN B-NP binding NN I-NP activity NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP . . O We PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP effect NN I-NP of IN B-PP leukotriene NN B-NP B4 NN I-NP ( ( O LTB4 NN B-NP ) ) O COMMA COMMA O a DT B-NP potent JJ I-NP lipid NN I-NP proinflammatory JJ I-NP mediator NN I-NP COMMA COMMA O on IN B-PP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP proto-oncogenes NNS I-NP c-jun NN B-NP and CC O c-fos NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O we PRP B-NP looked VBD B-VP at IN B-PP the DT B-NP modulation NN I-NP of IN B-PP nuclear JJ B-NP factors NNS I-NP binding VBG B-VP specifically RB B-PP to TO I-PP the DT B-NP AP-1 NN I-NP element NN I-NP after IN B-PP LTB4 NN B-NP stimulation NN I-NP . . O LTB4 NN B-NP increased VBD B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP c-fos NN I-NP gene NN I-NP in IN B-PP a DT O time- NN B-NP and CC O concentration-dependent JJ B-ADJP manner NN B-NP . . O The DT B-NP c-jun NN I-NP mRNA NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP constitutively RB I-VP expressed VBN I-VP in IN B-PP human JJ B-NP peripheral-blood NN I-NP monocytes NNS I-NP at IN B-PP relatively RB B-NP high JJ I-NP levels NNS I-NP COMMA COMMA O was VBD B-VP also RB I-VP slightly RB I-VP augmented JJ I-VP by IN B-PP LTB4 NN B-NP COMMA COMMA O although IN B-SBAR to TO B-PP a DT B-NP much RB I-NP lower JJR I-NP extent NN I-NP than IN B-PP c-fos NN B-NP . . O The DT B-NP kinetics NNS I-NP of IN B-PP expression NN B-NP of IN B-PP the DT B-NP two CD I-NP genes NNS I-NP were VBD B-VP also RB B-ADJP slightly RB I-ADJP different JJ I-ADJP COMMA COMMA O with IN B-PP c-fos NN B-NP mRNA NN I-NP reaching VBG B-VP a DT B-NP peak NN I-NP at IN B-PP 15 CD B-NP min NN I-NP after IN B-PP stimulation NN B-NP and CC O c-jun NN B-NP at IN B-PP 30 CD B-NP min NN I-NP . . O Both DT B-NP messages NNS I-NP rapidly RB B-ADVP declined VBD B-VP thereafter RB B-ADVP . . O Stability NN B-NP of IN B-PP the DT O c-fos NN B-NP and CC O c-jun NN B-NP mRNA NN B-NP was VBD B-VP not RB I-VP affected VBN I-VP by IN B-PP LTB4 NN B-NP COMMA COMMA O as IN B-SBAR assessed VBN B-VP after IN B-PP actinomycin NN B-NP D NN I-NP treatment NN I-NP . . O Nuclear JJ B-NP transcription NN I-NP studies NNS I-NP in FW B-ADVP vitro FW I-ADVP showed VBD B-VP that IN B-SBAR LTB4 NN B-NP increased VBD B-VP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP c-fos NN I-NP gene NN I-NP 7-fold RB B-ADVP and CC O the DT B-NP c-jun NN I-NP gene NN I-NP 1.4-fold RB B-ADVP . . O Resting VBG B-NP monocytes NNS I-NP contained VBD B-VP nuclear JJ B-NP factors NNS I-NP binding VBG B-VP to TO B-PP the DT B-NP AP-1 NN I-NP element NN I-NP COMMA COMMA O but CC O stimulation NN B-NP of IN B-PP monocytes NNS B-NP with IN B-PP LTB4 NN B-NP induced VBD B-VP greater JJR B-NP AP-1-binding JJ I-NP activity NN I-NP of IN B-PP nuclear JJ B-NP proteins NNS I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR LTB4 NN B-NP may MD B-VP regulate VB I-VP the DT B-NP production NN I-NP of IN B-PP different JJ B-NP cytokines NNS I-NP by IN B-PP modulating VBG B-VP the DT B-NP yield NN I-NP and\/or CC O the DT B-NP function NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP such JJ B-PP as IN I-PP AP-1-binding JJ B-NP proto-oncogene NN I-NP products NNS I-NP . . O An DT B-NP 11-base-pair JJ I-NP DNA NN I-NP sequence NN I-NP motif NN I-NP apparently RB B-ADJP unique JJ I-ADJP to TO B-PP the DT B-NP human JJ I-NP interleukin NN I-NP 4 CD I-NP gene NN I-NP confers VBZ B-VP responsiveness NN B-NP to TO B-PP T-cell NN B-NP activation NN I-NP signals NNS I-NP . . O We PRP B-NP have VBP B-VP identified VBN I-VP a DT B-NP DNA NN I-NP segment NN I-NP that WDT B-NP confers VBZ B-VP responsiveness NN B-NP to TO B-PP antigen NN B-NP stimulation NN I-NP signals NNS I-NP on IN B-PP the DT O human JJ O interleukin NN B-NP ( ( O IL NN B-NP ) ) O 4 CD B-NP gene NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O The DT B-NP human JJ I-NP IL-4 NN I-NP gene NN I-NP COMMA COMMA O of IN B-PP 10 CD B-NP kilobases NNS I-NP COMMA COMMA O is VBZ B-VP composed VBN I-VP of IN B-PP four CD B-NP exons NNS I-NP and CC O three CD B-NP introns NNS I-NP . . O A DT B-NP cis-acting JJ I-NP element NN I-NP ( ( O P NN B-NP sequence NN I-NP ) ) O resides VBZ B-VP in IN B-PP the DT O 5' JJ B-NP upstream JJ B-NP region NN I-NP ; : O no DT B-NP additional JJ I-NP DNA NN I-NP segments NNS I-NP with IN B-PP enhancer NN B-NP activity NN I-NP were VBD B-VP identified VBN I-VP in IN B-PP the DT B-NP human JJ I-NP IL-4 NN I-NP gene NN I-NP . . O For IN B-PP further JJ B-NP mapping NN I-NP purposes NNS I-NP COMMA COMMA O a DT B-NP fusion NN I-NP promoter NN I-NP was VBD B-VP constructed VBN I-VP with IN B-PP the DT B-NP granulocyte\/macrophage JJ I-NP colony-stimulating JJ I-NP factor NN I-NP basic JJ I-NP promoter NN I-NP containing VBG B-VP 60 CD B-NP base NN I-NP pairs NNS I-NP of IN B-PP sequence NN B-NP upstream JJ B-ADJP from IN B-PP the DT B-NP cap NN I-NP site NN I-NP of IN B-PP the DT B-NP mouse NN I-NP granulocyte\/macrophage JJ I-NP colony-stimulating JJ I-NP factor NN I-NP gene NN I-NP and CC O various JJ B-NP lengths NNS I-NP of IN B-PP the DT O 5' JJ B-NP upstream JJ B-NP sequence NN I-NP of IN B-PP the DT B-NP IL-4 NN I-NP gene NN I-NP . . O The DT B-NP P NN I-NP sequence NN I-NP was VBD B-VP located JJ B-ADJP between IN B-PP positions NNS B-NP -79 CD B-NP and CC O -69 CD B-NP relative JJ B-PP to TO I-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP of IN B-PP the DT B-NP human JJ I-NP IL-4 NN I-NP gene NN I-NP COMMA COMMA O and CC O this DT B-NP location NN I-NP was VBD B-VP confirmed VBN I-VP by IN B-PP base-substitution NN B-NP mutations NNS I-NP . . O The DT B-NP plasmids NNS I-NP carrying VBG B-VP multiple JJ B-NP copies NNS I-NP of IN B-PP the DT B-NP P NN I-NP sequence NN I-NP showed VBD B-VP higher JJR B-NP responsiveness NN I-NP to TO B-PP the DT B-NP stimulation NN I-NP . . O The DT B-NP binding VBG I-NP protein NN I-NP ( ( I-NP s NNS I-NP ) ) O that WDT B-NP recognize VBP B-VP the DT B-NP P NN I-NP sequence NN I-NP of IN B-PP the DT B-NP IL-4 NN I-NP gene NN I-NP were VBD B-VP identified VBN I-VP by IN B-PP DNA-mobility-shift JJ B-NP assays NNS I-NP . . O The DT B-NP binding NN I-NP of IN B-PP NF(P) NN B-NP ( ( O a DT B-NP DNA NN I-NP binding NN I-NP protein NN I-NP that WDT B-NP specifically RB B-ADVP recognizes VBZ B-VP the DT B-NP P NN I-NP sequence NN I-NP ) ) O to TO B-PP the DT B-NP P NN I-NP sequence NN I-NP was VBD B-VP abolished VBN I-VP when WRB B-ADVP oligonucleotides NNS B-NP carrying VBG B-VP base NN B-NP substitutions NNS I-NP were VBD B-VP used VBN I-VP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP NF(P) NN I-NP interaction NN I-NP is VBZ B-VP sequence-specific JJ B-ADJP and CC O that IN B-SBAR binding NN B-NP specificity NN I-NP of IN B-PP the DT B-NP protein NN I-NP paralleled VBD B-VP the DT B-NP sequence NN I-NP requirements NNS I-NP for IN B-PP IL-4 NN B-NP expression NN I-NP in FW B-ADVP vivo FW I-ADVP . . O The DT B-NP P NN I-NP sequence NN I-NP does VBZ B-VP not RB I-VP share VB I-VP homology NN B-NP with IN B-PP the DT O 5' JJ B-NP upstream JJ B-NP sequence NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP COMMA COMMA O even RB B-SBAR though IN I-SBAR surrounding VBG B-NP sequences NNS I-NP of IN B-PP the DT B-NP IL-4 NN I-NP gene NN I-NP share NN B-VP high JJ B-NP homology NN I-NP with IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR a DT B-NP different JJ I-NP set NN I-NP of IN B-PP proteins NNS B-NP recognize VBP B-VP IL-2 NN B-NP and CC O IL-4 NN B-NP genes NNS B-NP . . O Glucocorticoid NN B-NP receptor NN I-NP binding NN I-NP in IN B-PP three CD B-NP different JJ I-NP cell NN I-NP types NNS I-NP in IN B-PP major JJ B-NP depressive JJ I-NP disorder NN I-NP : : O lack NN B-NP of IN B-PP evidence NN B-NP of IN B-PP receptor NN B-NP binding NN I-NP defect NN I-NP . . O 1 LS B-LST . . O In IN B-SBAR order NN O to TO O further RB B-ADVP understand VB B-VP the DT B-NP apparent JJ I-NP glucocorticoid NN I-NP resistance NN I-NP in IN B-PP major JJ B-NP depressive JJ I-NP disorder NN I-NP COMMA COMMA O circadian JJ B-NP variation NN I-NP in IN B-PP cortisol NN B-NP concentration NN I-NP COMMA COMMA O dexamethasone NN B-NP suppression NN I-NP and CC O glucocorticoid NN B-NP receptor NN I-NP binding NN I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP COMMA COMMA O polymorphonuclear JJ B-NP leukocytes NNS I-NP and CC O cultured VBN B-NP skin NN I-NP fibroblasts NNS I-NP were VBD B-VP measured VBN I-VP in IN B-PP rigidly RB B-NP defined VBN I-NP major JJ I-NP depressive JJ I-NP disorder NN I-NP patients NNS I-NP and CC O non-depressed JJ B-NP psychiatric JJ I-NP controls NNS I-NP . . O 2 LS B-LST . . O Mononuclear JJ B-NP leukocytes NNS I-NP binding VBG B-VP to TO B-PP glucocorticoid NN B-NP correlated VBD B-VP significantly RB B-ADVP with IN B-PP polymorphonuclear JJ B-NP leukocytes NNS I-NP binding VBG B-VP to TO B-PP glucocorticoid NN B-NP COMMA COMMA O but CC O both DT B-NP determinations NNS I-NP failed VBD B-VP to TO I-VP differentiate VB I-VP major JJ B-NP depressive JJ I-NP disorder NN I-NP and CC O control NN B-NP subjects NNS I-NP . . O 3 LS B-LST . . O Initial JJ B-NP and CC I-NP post-dexamethasone JJ I-NP in FW I-NP vitro FW I-NP fibroblast NN I-NP binding VBG B-VP to TO B-PP glucocorticoid NN B-NP was VBD B-VP not RB O different JJ B-ADJP between IN B-PP major JJ B-NP depressive JJ I-NP disorder NN I-NP and CC O non-depressed JJ B-NP control NN I-NP subjects NNS I-NP . . O 4 LS B-LST . . O The DT B-NP phenomenon NN I-NP of IN B-PP glucocorticoid NN B-NP resistance NN I-NP in IN B-PP major JJ B-NP depressive JJ I-NP disorder NN I-NP remains VBZ B-VP unexplained JJ B-ADJP . . O Kinetics NNS B-NP of IN B-PP nuclear JJ B-NP translocation NN I-NP and CC O turnover NN B-NP of IN B-PP the DT B-NP vitamin NN I-NP D NN I-NP receptor NN I-NP in IN B-PP human JJ B-NP HL60 NN I-NP leukemia NN I-NP cells NNS I-NP and CC O peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP -- : O coincident JJ B-NP rise NN I-NP of IN B-PP DNA-relaxing JJ B-NP activity NN I-NP in IN B-PP nuclear JJ B-NP extracts NNS I-NP . . O High JJ B-NP affinity NN I-NP receptors NNS I-NP ( ( O VDR NN B-NP ) ) O for IN B-PP 1COMMA25-dihydroxycholecalciferol NN B-NP ( ( O calcitriol NN B-NP ) ) O are VBP B-VP expressed VBN I-VP in IN B-PP HL60 NN B-NP human JJ I-NP leukemia NN I-NP cells NNS I-NP and CC B-PP in IN B-PP low JJ B-NP numbers NNS I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP ( ( O PBL NN B-NP ) ) O . . O HL60 NN B-NP cells NNS I-NP COMMA COMMA O expressing VBG B-VP some DT B-NP characteristics NNS I-NP of IN B-PP promyelocytes NNS B-NP COMMA COMMA O can MD B-VP be VB I-VP induced VBN I-VP to TO B-PP monocytoid NN B-NP differentiation NN I-NP by IN B-PP calcitriol NN B-NP . . O Specific JJ B-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP {3H}calcitriol\/VDR NN B-NP was VBD B-VP examined VBN I-VP after IN B-PP exposure NN B-NP of IN B-PP whole JJ B-NP cells NNS I-NP to TO B-PP 10(-9) CD B-NP M\/l NN I-NP calcitriol NN I-NP in IN B-PP the DT B-NP presence NN B-NP and CC O absence NN B-NP of IN B-PP a DT B-NP 500-fold JJ I-NP excess NN I-NP of IN B-PP unlabeled JJ B-NP ligand NN I-NP and CC O subsequent JJ B-NP isolation NN I-NP of IN B-PP nuclei NNS B-NP . . O Specific JJ B-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP {3H}calcitriol\/VDR NN B-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP time NN B-ADJP dependent JJ I-ADJP reaching VBG B-VP a DT B-NP maximum NN I-NP of IN B-PP approximately RB B-NP 2100 CD I-NP binding VBG I-NP sites\/nucleus NNS I-NP after IN B-PP 3 CD B-NP h NN I-NP of IN B-PP incubation NN B-NP in IN B-PP HL60 NN B-NP cells NNS I-NP COMMA COMMA O whereas IN O a DT B-NP maximum NN I-NP of IN B-PP approximately RB B-NP 310 CD I-NP binding VBG I-NP sites\/nucleus NNS I-NP was VBD B-VP found VBN I-VP after IN B-PP 3 CD B-NP h NN I-NP in IN B-PP PBL NN B-NP . . O Pulse NN B-NP exposure NN I-NP of IN B-PP HL60 NN B-NP to TO B-PP radiolabeled VBN B-NP hormone NN I-NP for IN B-PP 3 CD B-NP h NN I-NP followed VBN B-VP by IN B-PP culture NN B-NP in IN B-PP medium NN B-NP without IN B-PP serum NN B-NP and CC O calcitriol NN B-NP lead VBD B-VP to TO B-PP nuclear JJ B-NP retention NN I-NP of IN B-PP approximately RB B-NP 1600 CD I-NP radiolabeled VBN I-NP VDR NN I-NP by IN B-PP 8 CD B-NP h NN I-NP and CC O approximately RB B-NP 1000 CD I-NP VDR NN I-NP by IN B-PP 24 CD B-NP h NN I-NP . . O Radiolabeled VBN B-NP VDR NN I-NP disappeared VBD B-VP from IN B-PP the DT B-NP nuclear JJ I-NP compartment NN I-NP with IN B-PP a DT B-NP halflife NN I-NP of IN B-PP approximately RB B-NP 30 CD I-NP min NN I-NP if IN B-SBAR cells NNS B-NP were VBD B-VP cultured VBN I-VP with IN B-PP identical JJ B-NP concentrations NNS I-NP of IN B-PP unlabeled JJ B-NP hormone NN I-NP after IN B-PP the DT B-NP pulse NN I-NP ( ( O pulse\/chase-experiments NNS B-NP ) ) O . . O No DT B-NP difference NN I-NP of IN B-PP VDR NN B-NP retention NN I-NP in IN B-PP pulse NN B-NP and CC O pulse\/chase-experiments NNS B-NP was VBD B-VP seen VBN I-VP in IN B-PP PBL NN B-NP COMMA COMMA O where WRB B-ADVP VDR NN B-NP halflife NN I-NP was VBD B-VP approximately RB B-NP 30 CD I-NP min NN I-NP . . O No DT B-NP specific JJ I-NP translocation NN I-NP into IN B-PP the DT B-NP nuclear JJ I-NP compartment NN I-NP was VBD B-VP seen VBN I-VP when WRB B-ADVP isolated VBN B-NP nuclei NNS I-NP were VBD B-VP incubated VBN I-VP in IN B-PP {3H}calcitriol NN B-NP . . O Radiolabeled VBN B-NP hormone\/receptor NN I-NP complexes NNS I-NP of IN B-PP nuclei NNS B-NP isolated VBN B-VP from IN B-PP cells NNS B-NP exposed VBN B-VP for IN B-PP 3 CD B-NP h NN I-NP to TO B-PP radiolabeled VBN B-NP hormone NN I-NP -- : O in IN B-PP contrast NN I-PP to TO I-PP identical JJ B-NP experiments NNS I-NP with IN B-PP intact JJ B-NP cells NNS I-NP -- : O did VBD B-VP not RB I-VP disappear VB I-VP from IN B-PP the DT B-NP nuclear JJ I-NP compartment NN I-NP upon IN B-PP incubation NN B-NP of IN B-PP nuclei NNS B-NP with IN B-PP identical JJ B-NP concentrations NNS I-NP of IN B-PP the DT B-NP unlabeled JJ I-NP compound NN I-NP . . O The DT B-NP activity NN I-NP of IN B-PP DNA NN B-NP relaxing NN I-NP enzymes NNS I-NP ( ( O e.g. FW B-ADVP topoisomerases NNS B-NP I CD B-NP and CC O II CD B-NP ) ) O in IN B-PP nuclear JJ B-NP extracts NNS I-NP was VBD B-VP measured VBN I-VP using VBG B-VP a DT B-NP PBR NN I-NP 322-relaxation-assay NN I-NP . . O Enhanced VBN B-NP overall JJ I-NP enzyme NN I-NP activity NN I-NP was VBD B-VP found VBN I-VP in IN B-PP nuclear JJ B-NP extracts NNS I-NP by IN B-PP 1 CD B-NP h NN I-NP after IN B-PP incubation NN B-NP with IN B-PP calcitriol NN B-NP ( ( O final JJ B-NP ethanol NN I-NP concentration NN I-NP 0.0001 CD B-NP % NN I-NP v\/v NN I-NP ) ) O in IN B-PP HL60 NN B-NP and CC O PBL NN B-NP . . O The DT B-NP enhanced VBN I-NP activity NN I-NP disappeared VBD B-VP after IN B-PP 2 CD B-NP h NN I-NP in IN B-PP PBL NN B-NP COMMA COMMA O whereas IN O it PRP B-NP was VBD B-VP still RB I-VP enhanced VBN I-VP by IN B-PP 4 CD B-NP h NN I-NP in IN B-PP HL60 NN B-NP . . O No DT B-NP effect NN I-NP was VBD B-VP seen VBN I-VP in IN B-PP ethanol NN B-NP treated JJ I-NP controls NNS I-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR a DT B-NP specific JJ I-NP nuclear JJ I-NP translocation NN I-NP mechanism NN I-NP exists VBZ B-VP for IN B-PP calcitriol NN B-NP in IN B-PP both DT B-NP cell NN I-NP types NNS I-NP examined VBN B-VP COMMA COMMA O most RBS B-ADVP likely RB I-ADVP due IN B-PP to TO I-PP translocation NN B-NP of IN B-PP receptor NN B-NP proteins NNS I-NP after IN B-PP hormone NN B-NP binding NN I-NP . . O Translocated VBN B-NP hormone\/receptor NN I-NP complexes NNS I-NP compete VBP B-VP for IN B-PP a DT B-NP limited JJ I-NP number NN I-NP of IN B-PP specific JJ B-NP nuclear JJ I-NP binding VBG I-NP sites NNS I-NP . . O Enhanced VBN B-NP activity NN I-NP of IN B-PP topoisomerases NNS B-NP in IN B-PP nuclear JJ B-NP extracts NNS I-NP upon IN B-PP translocation NN B-NP of IN B-PP VDR NN B-NP might MD B-VP reflect VB I-VP interaction NN B-NP of IN B-PP both DT B-NP within IN B-PP the DT B-NP nuclear JJ I-NP compartment NN I-NP COMMA COMMA O thus RB B-ADVP initiating VBG B-VP DNA-unwinding NN B-NP COMMA COMMA O a DT B-NP prerequisite NN I-NP of IN B-PP transcription NN B-NP initiation NN I-NP . . O The DT B-NP B NN I-NP cell-specific JJ I-NP nuclear JJ I-NP factor NN I-NP OTF-2 NN I-NP positively RB B-ADVP regulates VBZ B-VP transcription NN B-NP of IN B-PP the DT B-NP human JJ I-NP class NN I-NP II CD I-NP transplantation NN I-NP gene NN I-NP COMMA COMMA O DRA NN B-NP . . O The DT B-NP promoter NN I-NP of IN B-PP the DT B-NP major JJ I-NP histocompatibility NN I-NP class NN I-NP II CD I-NP gene NN I-NP DRA NN I-NP contains VBZ B-VP an DT B-NP octamer NN I-NP element NN I-NP ( ( O ATTTGCAT NN B-NP ) ) O that WDT B-NP is VBZ B-VP required VBN I-VP for IN B-PP efficient JJ B-NP DRA NN I-NP expression NN I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Several JJ B-NP DNA-binding JJ I-NP proteins NNS I-NP are VBP B-VP known VBN I-VP to TO I-VP bind VB I-VP this DT B-NP sequence NN I-NP . . O The DT B-ADJP best RBS I-ADJP characterized VBN I-ADJP are VBP B-VP the DT B-NP B NN I-NP cell-specific JJ I-NP OTF-2 NN I-NP and CC O the DT B-NP ubiquitous JJ I-NP OTF-1 NN I-NP . . O This DT B-NP report NN I-NP directly RB B-ADVP demonstrates VBZ B-VP that IN B-SBAR OTF-2 NN B-NP but CC B-CONJP not RB I-CONJP OTF-1 NN B-NP regulates VBZ B-VP the DT B-NP DRA NN I-NP gene NN I-NP . . O In FW B-NP vitro FW I-NP transcription NN I-NP analysis NN I-NP using VBG B-VP protein NN B-NP fractions NNS I-NP enriched VBN B-ADJP for IN B-PP the DT B-NP octamer-binding JJ I-NP protein NN I-NP OTF-2 NN I-NP demonstrate VBP B-VP a DT B-NP positive JJ I-NP functional JJ I-NP role NN I-NP for IN B-PP OTF-2 NN B-NP in IN B-PP DRA NN B-NP gene NN I-NP transcription NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O OTF-1-enriched JJ B-NP protein NN I-NP fractions NNS I-NP did VBD B-VP not RB I-VP affect VB I-VP DRA NN B-NP gene NN I-NP transcription NN I-NP although IN B-SBAR it PRP B-NP functionally RB B-ADVP enhanced VBD B-VP the DT B-NP transcription NN I-NP of IN B-PP another DT B-NP gene NN I-NP . . O Recombinant JJ B-NP OTF-2 NN I-NP protein NN I-NP produced VBN B-VP by IN B-PP in FW B-NP vitro FW I-NP transcription\/translation NN I-NP could MD B-VP also RB I-VP enhance VB I-VP DRA NN B-NP gene NN I-NP transcription NN I-NP in FW B-ADVP vitro FW I-ADVP . . O In FW B-NP vivo FW I-NP transient JJ I-NP transfection NN I-NP studies NNS I-NP utilizing VBG B-VP an DT B-NP OTF-2 NN I-NP expression NN I-NP vector NN I-NP resulted VBD B-VP in IN B-PP similar JJ B-NP findings NNS I-NP : : O that IN B-SBAR OTF-2 NN B-NP protein NN I-NP enhanced VBD B-VP DRA NN B-NP gene NN I-NP transcription NN I-NP COMMA COMMA O and CC O that IN B-SBAR this DT B-NP effect NN I-NP requires VBZ B-VP an DT B-NP intact JJ I-NP octamer NN I-NP element NN I-NP . . O Together RB B-ADVP these DT B-NP results NNS I-NP constitute VBP B-VP the DT B-NP first JJ I-NP direct JJ I-NP evidence NN I-NP of IN B-PP a DT B-NP positive JJ I-NP role NN I-NP for IN B-PP the DT B-NP lymphoid-specific JJ I-NP octamer-binding JJ I-NP factor NN I-NP in IN B-PP DRA NN B-NP gene NN I-NP transcription NN I-NP . . O { ( O Regulation NN B-NP of IN B-PP intracellular JJ B-NP cholesterol NN I-NP synthesis NN I-NP in IN B-PP hypercholesterolemia NN B-NP by IN B-PP glucocorticoids NNS B-NP } ) O The DT B-NP rate NN I-NP of IN B-PP endogenous JJ B-NP cholesterol NN I-NP synthesis NN I-NP in IN B-PP blood NN B-NP lymphocytes NNS I-NP and CC O skin NN B-NP fibroblasts NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP type NN B-NP IIa NN I-NP hyperlipidemia NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP increased VBN I-VP in IN B-PP comparison NN I-PP with IN I-PP healthy JJ B-NP donors NNS I-NP . . O The DT B-NP cells NNS I-NP of IN B-PP hyperlipidemic JJ B-NP patients NNS I-NP had VBD B-VP lowered JJ B-NP levels NNS I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP concomitantly RB B-PP with IN I-PP a DT B-NP partial JJ I-NP loss NN I-NP of IN B-PP their PRP$ B-NP sensitivity NN I-NP to TO B-PP glucocorticoids NNS B-NP . . O In IN B-PP fibroblasts NNS B-NP from IN B-PP patients NNS B-NP with IN B-PP hereditary JJ B-NP hypercholesteremia NN I-NP of IN B-PP homozygous JJ B-NP type NN I-NP the DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP did VBD B-VP not RB I-VP exceed VB I-VP 10 CD B-NP % NN I-NP of IN B-PP their PRP$ B-NP content NN I-NP in IN B-PP normal JJ B-NP cells NNS I-NP . . O The DT B-NP decrease NN I-NP of IN B-PP the DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP type NN B-NP IIa NN I-NP hyperlipidemia NN I-NP seems VBZ B-VP to TO I-VP be VB I-VP a DT B-NP compensatory JJ I-NP response NN I-NP of IN B-PP cells NNS B-NP culminating VBG B-VP in IN B-PP activation NN B-NP of IN B-PP endogenous JJ B-NP cholesterol NN I-NP synthesis NN I-NP . . O Transcription NN B-NP factor NN I-NP activation NN I-NP and CC O functional JJ B-NP stimulation NN I-NP of IN B-PP human JJ B-NP monocytes NNS I-NP . . O Activation NN B-NP of IN B-PP expression NN B-NP of IN B-PP genes NNS B-NP encoding VBG B-VP transcription NN B-NP factors NNS I-NP : : O c-fos NN B-NP and CC O c-jun NN B-NP and CC O formation NN B-NP of IN B-PP AP1 NN B-NP transcriptional JJ I-NP complex NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP was VBD B-VP investigated VBN I-VP . . O It PRP B-NP was VBD B-VP found VBN I-VP that IN B-SBAR lipopolysaccharide NN B-NP induced VBD B-VP strongly RB B-ADVP both CC O c-fos NN B-NP and CC O c-jun NN B-NP expression NN B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP AP1 NN B-NP formation NN I-NP . . O Interferon NN B-NP gamma NN I-NP activated VBD B-VP strongly RB B-ADVP c-fos NN B-NP and CC O weakly RB B-ADVP c-jun NN B-NP and CC O AP1 NN B-NP . . O Tumor NN B-NP necrosis NN I-NP factor NN I-NP induced VBD B-VP slightly RB B-ADVP c-fos NN B-NP and CC O had VBD B-VP almost RB B-NP no DT I-NP effect NN I-NP on IN B-PP c-jun NN B-NP and CC O AP1 NN B-NP . . O The DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR differences NNS B-NP in IN B-PP functional JJ B-NP responses NNS I-NP elicited VBN B-VP in IN B-PP monocytes NNS B-NP by IN B-PP all DT B-NP three CD I-NP factors NNS I-NP may MD B-VP be VB I-VP dependent JJ B-ADJP on IN B-PP different JJ B-NP routes NNS I-NP on IN B-PP nuclear JJ B-NP signalling NN I-NP employed VBN B-VP by IN B-PP the DT B-NP factors NNS I-NP . . O Corticosteroid NN B-NP receptors NNS I-NP and CC O lymphocyte NN B-NP subsets NNS I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP in IN B-PP aging NN B-NP . . O Plasma NN B-NP cortisol NN I-NP and CC O aldosterone NN B-NP levels NNS B-NP and CC O number NN B-NP of IN B-PP related JJ B-NP receptors NNS I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP were VBD B-VP measured VBN I-VP in IN B-PP 49 CD B-NP healthy JJ I-NP aged JJ I-NP subjects NNS I-NP ( ( O 62-97 CD B-NP yr NN I-NP ) ) O and CC B-PP in IN B-PP 21 CD B-NP adult JJ I-NP controls NNS I-NP ( ( O 21-50 CD B-NP yr NN I-NP ) ) O . . O In IN B-PP all DT B-NP subjects NNS I-NP COMMA COMMA O in IN B-PP addition NN B-NP COMMA COMMA O lymphocyte NN B-NP subsets NNS I-NP were VBD B-VP determined VBN I-VP as IN B-PP an DT B-NP index NN I-NP of IN B-PP corticosteroid NN B-NP action NN I-NP . . O The DT B-NP mean NN I-NP number NN I-NP of IN B-PP type NN B-NP I CD I-NP and CC O type NN B-NP II CD I-NP receptors NNS B-NP was VBD B-VP significantly RB B-ADJP lower JJR I-ADJP in IN B-PP aged JJ B-NP subjects NNS I-NP than IN B-PP in IN B-PP controls NNS B-NP ( ( O respectively RB B-ADVP COMMA COMMA O 198 CD B-NP +\/- CC I-NP 96 CD I-NP and CC I-NP 272 CD I-NP +\/- CC I-NP 97 CD I-NP receptors\/cell NNS I-NP for IN B-PP type NN B-NP I CD I-NP COMMA COMMA O and CC O 1COMMA794 CD B-NP +\/- CC I-NP 803 CD I-NP and CC I-NP 3COMMA339 CD I-NP +\/- CC I-NP 918 CD I-NP for IN B-PP type NN B-NP II CD I-NP receptors NNS B-NP ) ) O . . O Plasma NN B-NP aldosterone NN B-NP and CC O cortisol NN B-NP and CC O lymphocyte NN B-NP subsets NNS I-NP were VBD B-VP not RB O different JJ B-ADJP in IN B-PP the DT B-NP two CD I-NP groups NNS I-NP . . O All DT B-NP of IN B-PP the DT B-NP parameters NNS I-NP were VBD B-VP also RB I-VP tested VBN I-VP for IN B-PP correlation NN B-NP COMMA COMMA O and CC O a DT B-NP significant JJ I-NP inverse JJ I-NP correlation NN I-NP was VBD B-VP found VBN I-VP between IN B-PP age NN B-NP and CC O type NN B-NP I CD I-NP and CC O type NN B-NP II CD I-NP receptors NNS B-NP when WRB B-ADVP all DT B-NP subjects NNS I-NP were VBD B-VP plotted VBN I-VP and CC O between IN B-PP aged JJ B-NP and CC I-NP CD4 NN I-NP and CC I-NP age NN I-NP and CC I-NP CD4\/CD8 NN I-NP in IN B-PP the DT B-NP aged JJ I-NP group NN I-NP . . O These DT B-NP data NNS I-NP show VBP B-VP that IN B-SBAR aged JJ B-NP subjects NNS I-NP have VBP B-VP reductions NNS B-NP of IN B-PP corticosteroid NN B-NP receptors NNS I-NP that WDT B-NP are VBP B-VP not RB I-VP associated VBN I-VP with IN B-PP increase NN B-NP of IN B-PP related JJ B-NP steroids NNS I-NP and CC O that IN B-SBAR this DT B-NP situation NN I-NP probably RB B-ADVP represents VBZ B-VP a DT B-NP concomitant NN I-NP of IN B-PP the DT B-NP normal JJ I-NP aging NN I-NP process NN I-NP . . O Stable JJ B-NP expression NN I-NP of IN B-PP HB24 NN B-NP COMMA COMMA O a DT B-NP diverged JJ I-NP human JJ I-NP homeobox NN I-NP gene NN I-NP COMMA COMMA O in IN B-PP T NN B-NP lymphocytes NNS I-NP induces VBZ B-VP genes NNS B-NP involved VBN B-VP in IN B-PP T NN B-NP cell NN I-NP activation NN B-NP and CC O growth NN B-NP . . O A DT B-NP diverged JJ I-NP homeobox NN I-NP gene NN I-NP COMMA COMMA O HB24 NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP known VBN I-VP to TO I-VP be VB I-VP induced VBN I-VP following VBG B-PP lymphocyte NN B-NP activation NN I-NP COMMA COMMA O was VBD B-VP introduced VBN I-VP into IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP under IN B-PP the DT B-NP control NN I-NP of IN B-PP a DT B-NP constitutive JJ I-NP promoter NN I-NP . . O Stable JJ B-NP transfectants NNS I-NP of IN B-PP HB24 NN B-NP were VBD B-VP established VBN I-VP that WDT B-NP expressed VBD B-VP high JJ B-NP levels NNS I-NP of IN B-PP HB24 NN B-NP mRNA NN I-NP and CC O possessed VBD B-VP an DT B-NP altered JJ I-NP phenotype NN I-NP suggestive JJ B-ADJP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O A DT B-NP number NN I-NP of IN B-PP genes NNS B-NP known VBN B-VP to TO I-VP be VB I-VP induced VBN I-VP following VBG B-PP T NN B-NP cell NN I-NP activation NN I-NP and CC O associated VBN B-VP with IN B-PP cell NN B-NP growth NN I-NP were VBD B-VP increased VBN I-VP in IN B-PP the DT B-NP transfectants NNS I-NP COMMA COMMA O including VBG B-PP c-fos NN B-NP COMMA COMMA O c-myc NN B-NP COMMA COMMA O c-myb NN B-NP COMMA COMMA O HLA-DR NN B-NP COMMA COMMA O lck NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP COMMA COMMA O interleukin-2 NN B-NP and CC O interleukin-2 NN B-NP receptor NN I-NP alpha NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O . . O Analysis NN B-NP of IN B-PP IL-2R NN B-NP alpha NN I-NP expression NN I-NP by IN B-PP transient JJ B-NP transfection NN I-NP of IN B-PP IL-2R NN B-NP alpha NN I-NP promoter NN I-NP constructs NNS I-NP into IN B-PP the DT B-NP HB24 NN I-NP transfectants NNS I-NP revealed VBD B-VP constitutive JJ B-NP expression NN I-NP ( ( O about RB B-NP 60 CD I-NP % NN I-NP of IN B-PP phytohemagglutinin- NN B-NP and CC O phorbol NN B-ADJP ester-activated JJ I-ADJP Jurkat NN B-NP cells NNS I-NP ) ) O that WDT B-NP was VBD B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP kappa NN I-NP B NN I-NP site NN I-NP in IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP promoter NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O as IN B-PP a DT B-NP consequence NN I-NP of IN B-PP the DT B-NP increased VBN I-NP HB24 NN I-NP mRNA NN I-NP levels NNS I-NP COMMA COMMA O the DT B-NP Jurkat NN I-NP HB24 NN I-NP transfectants NNS I-NP proliferated VBD B-VP more RBR B-ADVP rapidly RB I-ADVP than IN B-PP control NN B-NP cell NN I-NP lines NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O stable JJ B-NP expression NN I-NP of IN B-PP HB24 NN B-NP confers VBZ B-VP an DT B-NP activation NN I-NP phenotype NN I-NP on IN B-PP a DT B-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O implicating VBG B-VP this DT B-NP gene NN I-NP as IN B-PP an DT B-NP important JJ I-NP transcriptional JJ I-NP factor NN I-NP during IN B-PP T NN B-NP cell NN I-NP activation NN B-NP and CC O growth NN B-NP . . O Studies NNS B-NP on IN B-PP the DT B-NP biological JJ I-NP activity NN I-NP of IN B-PP triiodothyronine NN B-NP sulfate NN I-NP . . O Hepatic JJ B-NP microsomes NNS I-NP and CC O isolated VBN B-NP hepatocytes NNS I-NP in IN B-PP short JJ B-NP term NN I-NP culture NN I-NP desulfate VBP B-VP T3 NN B-NP sulfate NN I-NP ( ( O T3SO4 NN B-NP ) ) O . . O We PRP B-NP COMMA COMMA O therefore RB B-ADVP COMMA COMMA O wished VBD B-VP to TO I-VP determine VB I-VP whether IN B-SBAR T3SO4 NN B-NP could MD B-VP mimic VB I-VP the DT B-NP action NN I-NP of IN B-PP thyroid NN B-NP hormone NN I-NP in FW B-ADVP vitro FW I-ADVP . . O T3SO4 NN B-NP had VBD B-VP no DT B-NP thyromimetic JJ I-NP effect NN I-NP on IN B-PP the DT B-NP activity NN I-NP of IN B-PP Ca(2+)-ATPase NN B-NP in IN B-PP human JJ B-NP erythrocyte NN I-NP membranes NNS I-NP at IN B-PP doses NNS B-NP up RB B-NP to TO I-NP 10COMMA000 CD I-NP times NNS I-NP the DT I-NP maximally RB I-NP effective JJ I-NP dose NN I-NP of IN B-PP T3 NN B-NP ( ( O 10\/(-10) CD B-NP mol\/L NN I-NP ) ) O . . O In IN B-PP GH4C1 NN B-NP pituitary JJ I-NP cells NNS I-NP COMMA COMMA O T3SO4 NN B-NP failed VBD B-VP to TO I-VP displace VB I-VP {125I}T3 NN B-NP from IN B-PP nuclear JJ B-NP receptors NNS I-NP in IN B-PP intact JJ B-NP cells NNS I-NP or CC O soluble JJ B-NP preparations NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O T3SO4 NN B-NP was VBD B-VP not RB O directly RB B-ADVP thyromimetic JJ B-ADJP in IN B-PP either CC O an DT B-NP isolated VBN I-NP human JJ I-NP membrane NN I-NP system NN I-NP or CC O a DT B-NP pituitary JJ I-NP cell NN I-NP system NN I-NP in IN B-PP which WDT B-NP nuclear JJ B-NP receptor NN I-NP occupancy NN I-NP correlates VBZ B-VP with IN B-PP GH NN B-NP synthesis NN I-NP . . O Thyroid NN B-NP hormones NNS I-NP inhibit VBP B-VP {3H}glycosaminoglycan NN B-NP synthesis NN I-NP by IN B-PP cultured VBN B-NP human JJ I-NP dermal JJ I-NP fibroblasts NNS I-NP COMMA COMMA O and CC O T3SO4 NN B-NP displayed VBN B-VP about IN B-NP 0.5 CD I-NP % NN I-NP the DT B-NP activity NN I-NP of IN B-PP T3 NN B-NP at IN B-PP 72 CD B-NP h NN I-NP . . O Human JJ B-NP fibroblasts NNS I-NP contained VBD B-VP roughly RB B-ADVP the DT B-NP same JJ I-NP level NN I-NP of IN B-PP microsomal JJ B-NP p-nitrophenyl NN I-NP sulfatase NN I-NP activity NN I-NP as IN B-PP that DT B-NP previously RB B-VP observed VBN I-VP in IN B-PP hepatic JJ B-NP microsomes NNS I-NP . . O Propylthiouracil NN B-NP ( ( O 50 CD B-NP mumol\/L NN I-NP ) ) O did VBD B-VP not RB I-VP affect VB I-VP the DT B-NP action NN I-NP of IN B-PP T3SO4 NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR deiodination NN B-NP was VBD B-VP not RB O important JJ B-ADJP for IN B-PP this DT B-NP activity NN I-NP of IN B-PP T3SO4 NN B-NP . . O Thus RB B-ADVP COMMA COMMA O it PRP B-NP appears VBZ B-VP T3SO4 NN B-NP has VBZ B-VP no DT B-NP intrinsic JJ I-NP biological JJ I-NP activity NN I-NP COMMA COMMA O but CC O COMMA COMMA O under IN B-PP certain JJ B-NP circumstances NNS I-NP COMMA COMMA O may MD B-VP be VB I-VP reactivated VBN I-VP by IN B-PP desulfation NN B-NP . . O Nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP contains VBZ B-VP Fos NN B-NP and CC O Jun NN B-NP . . O The DT B-NP nuclear JJ I-NP factor NN I-NP NF-AT NN I-NP ( ( O ref. NN B-NP 1 CD I-NP ) ) O is VBZ B-VP induced VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP stimulated VBN B-VP through IN B-PP the DT B-NP T-cell NN I-NP receptor\/CD3 NN I-NP complex NN I-NP COMMA COMMA O and CC O is VBZ B-VP required VBN I-VP for IN B-PP interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O gene NN B-NP induction NN I-NP . . O Although IN B-SBAR NF-AT NN B-NP has VBZ B-VP not RB I-VP been VBN I-VP cloned VBN I-VP or CC O purified VBN B-VP COMMA COMMA O there EX B-NP is VBZ B-VP evidence NN B-NP that IN B-SBAR it PRP B-NP is VBZ B-VP a DT B-NP major JJ I-NP target NN I-NP for IN B-PP immunosuppression NN B-NP by IN B-PP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O FK506 NN B-NP ( ( O refs NNS B-NP 2-7 CD B-NP ) ) O . . O NF-AT NN B-NP induction NN I-NP may MD B-VP require VB I-VP two CD B-NP activation-dependent JJ I-NP events NNS I-NP : : O the DT B-NP CsA-sensitive JJ I-NP translocation NN I-NP of IN B-PP a DT B-NP pre-existing JJ I-NP component NN I-NP and CC O the DT B-NP CsA-resistant JJ I-NP synthesis NN I-NP of IN B-PP a DT B-NP nuclear JJ I-NP component NN I-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR the DT B-NP newly RB I-NP synthesized VBN I-NP nuclear JJ I-NP component NN I-NP of IN B-PP NF-AT NN B-NP is VBZ B-VP the DT B-NP transcription NN I-NP factor NN I-NP AP-1 NN I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP inducible JJ I-NP nuclear JJ I-NP form NN I-NP of IN B-PP NF-AT NN B-NP contains VBZ B-VP Fos NN B-NP and CC O Jun NN B-NP proteins NNS B-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP identify VBP B-VP a DT B-NP pre-existing JJ I-NP NF-AT-binding JJ I-NP factor NN I-NP that WDT B-NP is VBZ B-VP present JJ B-ADJP in IN B-PP hypotonic JJ B-NP extracts NNS I-NP of IN B-PP unstimulated JJ B-NP T NN I-NP cells NNS I-NP . . O On IN B-PP the DT I-PP basis NN I-PP of IN I-PP binding NN B-NP COMMA COMMA O reconstitution NN B-NP and CC O cotransfection NN B-NP experiments NNS B-NP COMMA COMMA O we PRP B-NP propose VBP B-VP that IN B-SBAR activation NN B-NP of IN B-PP NF-AT NN B-NP occurs VBZ B-VP in IN B-PP at IN B-NP least JJS I-NP two CD I-NP stages NNS I-NP : : O a DT B-NP CsA-sensitive JJ I-NP stage NN I-NP involving VBG B-VP modification NN B-NP and\/or CC O translocation NN B-NP of IN B-PP the DT B-NP pre-existing JJ I-NP NF-AT NN I-NP complex NN I-NP COMMA COMMA O and CC O a DT B-NP CsA-insensitive JJ I-NP stage NN I-NP involving VBG B-VP the DT B-NP addition NN I-NP of IN B-PP newly RB O synthesized VBN O Fos NN B-NP or CC O Fos\/Jun NN B-NP proteins NNS B-NP to TO B-PP the DT B-NP pre-existing JJ I-NP complex NN I-NP . . O Interferon-gamma NN B-NP potentiates VBZ B-VP the DT B-NP antiviral JJ I-NP activity NN I-NP and CC O the DT B-NP expression NN I-NP of IN B-PP interferon-stimulated JJ B-NP genes NNS I-NP induced VBN B-VP by IN B-PP interferon-alpha NN B-NP in IN B-PP U937 NN B-NP cells NNS I-NP . . O Binding NN B-NP of IN B-PP type NN B-NP I CD I-NP interferon NN I-NP ( ( O IFN-alpha\/beta NN B-NP ) ) O to TO B-PP specific JJ B-NP receptors NNS I-NP results VBZ B-VP in IN B-PP the DT B-NP rapid JJ I-NP transcriptional JJ I-NP activation NN I-NP COMMA COMMA O independent JJ B-ADJP of IN B-PP protein NN B-NP synthesis NN I-NP COMMA COMMA O of IN B-PP IFN-alpha-stimulated JJ B-NP genes NNS I-NP ( ( O ISGs NNS B-NP ) ) O in IN B-PP human JJ B-NP fibroblasts NNS I-NP and CC O HeLa NN B-NP and CC O Daudi NN B-NP cell NN B-NP lines NNS I-NP . . O The DT B-NP binding NN I-NP of IN B-PP ISGF3 NN B-NP ( ( O IFN-stimulated JJ B-NP gene NN I-NP factor NN I-NP 3 CD I-NP ) ) O to TO B-PP the DT B-NP conserved VBN I-NP IFN-stimulated JJ B-NP response NN I-NP element NN I-NP ( ( O ISRE NN B-NP ) ) O results VBZ B-VP in IN B-PP transcriptional JJ B-NP activation NN I-NP . . O This DT B-NP factor NN I-NP is VBZ B-VP composed VBN I-VP of IN B-PP a DT B-NP DNA-binding JJ I-NP protein NN I-NP ( ( O ISGF3 NN B-NP gamma NN I-NP ) ) O COMMA COMMA O which WDT B-NP normally RB B-ADVP is VBZ B-VP present JJ B-ADJP in IN B-PP the DT B-NP cytoplasm NN I-NP COMMA COMMA O and CC O other JJ B-NP IFN-alpha-activated JJ I-NP proteins NNS I-NP which WDT B-NP preexist VBP B-VP as IN B-PP latent JJ B-NP cytoplasmic JJ I-NP precursors NNS I-NP ( ( O ISGF3 NN B-NP alpha NN I-NP ) ) O . . O We PRP B-NP have VBP B-VP found VBN I-VP that IN B-SBAR ISG NN B-NP expression NN I-NP in IN B-PP the DT B-NP monocytic JJ I-NP U937 NN I-NP cell NN I-NP line NN I-NP differs VBZ B-VP from IN B-PP most JJS B-NP cell NN I-NP lines NNS I-NP previously RB B-VP examined VBN I-VP . . O U937 NN B-NP cells NNS I-NP express VBP B-VP both CC O type NN B-NP I CD I-NP and CC O type NN B-NP II CD I-NP IFN NN B-NP receptors NNS I-NP COMMA COMMA O but CC O only RB B-NP IFN-alpha NN I-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP inducing VBG B-VP antiviral JJ B-NP protection NN I-NP in IN B-PP these DT B-NP cells NNS I-NP . . O Pretreatment NN B-NP with IN B-PP IFN-gamma NN B-NP potentiates VBZ B-VP the DT B-NP IFN-alpha-induced JJ I-NP protection NN I-NP COMMA COMMA O but CC O IFN-gamma NN B-NP alone RB B-ADVP does VBZ B-VP not RB I-VP have VB I-VP any DT B-NP antiviral JJ I-NP activity NN I-NP . . O ISG15 NN B-NP mRNA NN I-NP accumulation NN I-NP in IN B-PP U937 NN B-NP cells NNS I-NP is VBZ B-VP not RB O detectable JJ B-ADJP before IN B-PP 6 CD B-NP h NN I-NP of IN B-PP IFN-alpha NN B-NP treatment NN I-NP COMMA COMMA O peaks VBZ B-VP at IN B-PP 24 CD B-NP h NN I-NP COMMA COMMA O and CC O requires VBZ B-VP protein NN B-NP synthesis NN I-NP . . O Although IN B-SBAR IFN-gamma NN B-NP alone RB B-ADVP does VBZ B-VP not RB I-VP induce VB I-VP ISG NN B-NP expression NN I-NP COMMA COMMA O IFN-gamma NN B-NP pretreatment NN I-NP markedly RB B-ADVP increases VBZ B-VP and CC O hastens VBZ B-VP ISG NN B-NP expression NN I-NP and CC O transcriptional JJ B-NP induction NN I-NP . . O Nuclear JJ B-NP extracts NNS I-NP assayed VBN B-VP for IN B-PP the DT B-NP presence NN I-NP of IN B-PP ISRE NN B-NP binding NN I-NP factors NNS I-NP by IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP show VBP B-VP that IN B-SBAR ISGF3 NN B-NP is VBZ B-VP induced VBN I-VP by IN B-PP IFN-alpha NN B-NP within IN B-PP 6 CD B-NP h NN I-NP from IN B-PP undetectable JJ B-NP basal JJ I-NP levels NNS I-NP in IN B-PP untreated JJ B-NP U937 NN I-NP cells NNS I-NP . . O Activation NN B-NP of IN B-PP ISGF3 NN B-NP alpha NN I-NP COMMA COMMA O the DT B-NP latent JJ I-NP component NN I-NP of IN B-PP ISGF3 NN B-NP COMMA COMMA O occurs VBZ B-VP rapidly RB B-ADVP . . O However RB B-ADVP COMMA COMMA O the DT B-NP increase NN I-NP in IN B-PP ISGF3 NN B-NP activity NN I-NP ultimately RB B-ADVP correlates VBZ B-VP with IN B-PP the DT B-NP accumulation NN I-NP of IN B-PP ISGF3 NN B-NP gamma NN I-NP induced VBN B-VP by IN B-PP IFN-alpha NN B-NP or CC O IFN-gamma NN B-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O The DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP of IN B-PP cyclosporin NN B-NP A NN I-NP and CC O FK506 NN B-NP . . O CsA NN B-NP and CC O FK506 NN B-NP are VBP B-VP powerful JJ B-NP suppressors NNS I-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP COMMA COMMA O most RBS B-ADVP notably RB I-ADVP of IN B-PP T NN B-NP cells NNS I-NP . . O They PRP B-NP act VBP B-VP at IN B-PP a DT B-NP point NN I-NP in IN B-PP activation NN B-NP that WDT B-NP lies VBZ B-VP between IN B-PP receptor NN B-NP ligation NN I-NP and CC O the DT B-NP transcription NN I-NP of IN B-PP early JJ B-NP genes NNS I-NP . . O Here RB B-ADVP COMMA COMMA O Stuart NNP B-NP Schreiber NNP I-NP and CC O Gerald NNP B-NP Crabtree NNP I-NP review VBP B-VP recent JJ B-NP findings NNS I-NP that WDT B-NP indicate VBP O CsA NN B-NP and CC O FK506 NN B-NP operate VBP B-VP as IN B-PP prodrugs NNS B-NP : : O they PRP B-NP bind VBP B-VP endogenous JJ B-NP intracellular JJ I-NP receptors NNS I-NP COMMA COMMA O the DT B-NP immunophilins NNS I-NP COMMA COMMA O and CC O the DT B-NP resulting VBG I-NP complex NN I-NP targets VBZ B-VP the DT B-NP protein NN I-NP phosphatase NN I-NP COMMA COMMA O calcineurin NN B-NP COMMA COMMA O to TO B-VP exert VB I-VP the DT B-NP immunosuppressive JJ I-NP effect NN I-NP . . O { ( O Plasma NN B-NP cortisol NN I-NP concentration NN I-NP and CC O blood NN B-NP leukocyte NN I-NP content NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP deficiency-cold JJ B-NP vs CC I-NP deficiency-heat JJ I-NP syndromes NNS I-NP } ) O Plasma NN B-NP cortisol NN I-NP concentration NN I-NP and CC O blood NN B-NP leukocyte NN I-NP content NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP ( ( O GCR NN B-NP ) ) O were VBD B-VP assayed VBN I-VP in IN B-PP 20 CD B-NP patients NNS I-NP with IN B-PP deficiency NN B-NP syndromes NNS I-NP COMMA COMMA O 10 CD B-NP cold JJ B-ADJP in IN B-PP property NN B-NP ( ( O deficiency-cold JJ B-ADJP ) ) O COMMA COMMA O the DT B-NP other JJ I-NP 10 CD B-NP hot JJ B-ADJP in IN B-PP property NN B-NP ( ( O deficiency-heat JJ B-ADJP ) ) O COMMA COMMA O and CC O also RB O in IN B-PP 10 CD B-NP healthy JJ I-NP individuals NNS I-NP as IN B-PP normal JJ B-NP control NN I-NP for IN B-PP the DT B-NP purpose NN I-NP of IN B-PP investigating VBG B-VP the DT B-NP nature NN I-NP of IN B-PP cold NN O and CC O heat NN B-NP syndromes NNS B-NP . . O As IN B-PP a DT B-NP result NN I-NP COMMA COMMA O the DT B-NP cases NNS I-NP of IN B-PP deficiency-cold JJ B-NP syndrome NN I-NP ( ( O DCS NN B-NP ) ) O had VBD B-VP a DT B-NP normal JJ I-NP concentration NN I-NP of IN B-PP plasma NN B-NP cortisol NN I-NP but CC O a DT B-NP lowered JJ I-NP content NN I-NP of IN B-PP GCR NN B-NP in IN B-PP leukocytes NNS B-NP when WRB B-ADVP compared VBN B-VP with IN B-PP the DT B-NP normal JJ I-NP control NN I-NP ( ( O P NN B-NP less JJR B-NP than IN I-NP 0.05 CD I-NP ) ) O ; : O the DT B-NP cases NNS I-NP of IN B-PP deficiency-heat JJ B-NP syndrome NN I-NP ( ( O DHS NN B-NP ) ) O had VBD B-VP a DT B-NP higher JJR I-NP concentration NN I-NP of IN B-PP plasma NN B-NP cortisol NN I-NP than IN B-PP the DT B-NP normal JJ I-NP control NN I-NP ( ( O P NN B-NP less JJR B-NP than IN I-NP 0.05 CD I-NP ) ) O and CC O a DT B-NP slightly RB I-NP higher JJR I-NP content NN I-NP of IN B-PP GCR NN B-NP in IN B-PP leukocytes NNS B-NP . . O It PRP B-NP was VBD B-VP concluded VBN I-VP that IN B-SBAR the DT B-NP DCS NN I-NP is VBZ B-VP characterized VBN I-VP by IN B-PP diminished VBN B-NP biological JJ I-NP effects NNS I-NP of IN B-PP adrenocortical JJ B-NP activity NN I-NP COMMA COMMA O while IN O the DT B-NP DHS NN I-NP COMMA COMMA O by IN B-PP augmented JJ B-NP biological JJ I-NP effects NNS I-NP of IN B-PP adrenocortical JJ B-NP activity NN I-NP . . O Specific JJ B-NP NF-kappa NN I-NP B NN I-NP subunits NNS I-NP act VBP B-VP in IN B-PP concert NN I-PP with IN I-PP Tat NN B-NP to TO B-VP stimulate VB I-VP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP transcription NN I-NP . . O NF-kappa NN B-NP B NN I-NP is VBZ B-VP a DT B-NP protein NN I-NP complex NN I-NP which WDT B-NP functions VBZ B-VP in IN B-PP concert NN I-PP with IN I-PP the DT B-NP tat-I NN I-NP gene NN I-NP product NN I-NP to TO B-VP stimulate VB I-VP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O transcription NN B-NP . . O To TO B-VP determine VB I-VP whether IN B-SBAR specific JJ B-NP members NNS I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP family NN I-NP contribute VBP B-VP to TO B-PP this DT B-NP effect NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP abilities NNS I-NP of IN B-PP different JJ B-NP NF-kappa NN I-NP B NN I-NP subunits NNS I-NP to TO B-VP act VB I-VP with IN B-PP Tat-I NN B-NP to TO B-VP stimulate VB I-VP transcription NN B-NP of IN B-PP HIV NN B-NP in IN B-PP Jurkat NN B-NP T-leukemia NN I-NP cells NNS I-NP . . O We PRP B-NP have VBP B-VP found VBN I-VP that IN B-SBAR the DT B-NP p49 NN I-NP ( ( I-NP 100 CD I-NP ) ) I-NP DNA NN I-NP binding NN I-NP subunit NN I-NP COMMA COMMA O together RB B-PP with IN I-PP p65 NN B-NP COMMA COMMA O can MD B-VP act VB I-VP in IN B-PP concert NN I-PP with IN I-PP Tat-I NN B-NP to TO B-VP stimulate VB I-VP the DT B-NP expression NN I-NP of IN B-PP HIV-CAT NN B-NP plasmid NN I-NP . . O Little JJ B-NP effect NN I-NP was VBD B-VP observed VBN I-VP with IN B-PP 50-kDa JJ B-NP forms NNS I-NP of IN B-PP p105 NN B-NP NF-kappa NN I-NP B NN I-NP or CC O rel NN B-NP COMMA COMMA O in IN B-PP combination NN B-NP with IN B-PP p65 NN B-NP or CC O full-length JJ B-NP c-rel NN I-NP COMMA COMMA O which WDT B-NP do VBP B-VP not RB I-VP stimulate VB I-VP the DT B-NP HIV NN I-NP enhancer NN I-NP in IN B-PP these DT B-NP cells NNS I-NP . . O These DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP combination NN I-NP of IN B-PP p49 NN B-NP ( ( I-NP 100 CD I-NP ) ) O and CC O p65 NN B-NP NF-kappa NN I-NP B NN I-NP can MD B-VP act VB I-VP in IN B-PP concert NN I-PP with IN I-PP the DT B-NP tat-I NN I-NP gene NN I-NP product NN I-NP to TO B-VP stimulate VB I-VP the DT B-NP synthesis NN I-NP of IN B-PP HIV NN B-NP RNA NN I-NP . . O Activation NN B-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP enhancer NN I-NP is VBZ B-VP not RB O dependent JJ B-ADJP on IN B-PP NFAT-1 NN B-NP . . O The DT B-NP function NN I-NP of IN B-PP a DT B-NP putative JJ I-NP NFAT-1 NN I-NP site NN I-NP in IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP enhancer NN I-NP has VBZ B-VP been VBN I-VP analyzed VBN I-VP . . O Activation NN B-NP by IN B-PP the DT B-NP T-cell NN I-NP antigen NN I-NP receptor NN I-NP is VBZ B-VP minimal JJ B-ADJP in IN B-PP Jurkat NN B-NP cells NNS I-NP and CC O is VBZ B-VP mediated VBN I-VP by IN B-PP the DT B-NP kappa NN I-NP B NN I-NP sites NNS I-NP . . O The DT B-NP putative JJ I-NP NFAT-1 NN I-NP region NN I-NP is VBZ B-VP not RB I-VP required VBN I-VP for IN B-PP the DT B-NP response NN I-NP to TO B-PP anti-CD3 NN B-NP or CC B-PP to TO B-PP mitogens NNS B-NP in IN B-PP T-cell NN B-NP COMMA COMMA O B-cell NN B-NP COMMA COMMA O or CC O monocyte\/macrophage NN B-NP leukemia NN I-NP lines NNS B-NP COMMA COMMA O nor CC O is VBZ B-VP it PRP B-NP a DT B-NP cis-acting JJ I-NP negative JJ I-NP regulatory JJ I-NP element NN I-NP . . O Protein NN B-NP kinase NN I-NP C NN I-NP activation NN I-NP and CC O protooncogene NN B-NP expression NN I-NP in IN B-PP differentiation\/retrodifferentiation NN B-NP of IN B-PP human JJ B-NP U-937 NN I-NP leukemia NN I-NP cells NNS I-NP . . O Human JJ B-NP U-937 NN I-NP leukemia NN I-NP cells NNS I-NP differentiate VBP B-VP along IN B-PP the DT B-NP monocytic JJ I-NP lineage NN I-NP following VBG B-PP 3-day JJ B-NP exposures NNS I-NP to TO B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( O TPA NN B-NP ) ) O . . O This DT B-NP induction NN I-NP of IN B-PP differentiation NN B-NP is VBZ B-VP accompanied VBN I-VP by IN B-PP adherence NN B-NP and CC O loss NN B-NP of IN B-PP proliferation NN B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP expression\/repression NN B-NP of IN B-PP differentiation-associated JJ B-NP genes NNS I-NP . . O Long JJ B-NP term NN I-NP culture NN I-NP of IN B-PP TPA-differentiated JJ B-NP U-937 NN I-NP cells NNS I-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP phorbol NN B-NP ester NN I-NP for IN B-PP 32-36 CD B-NP days NNS I-NP resulted VBD B-VP in IN B-PP a DT B-NP process NN I-NP of IN B-PP retrodifferentiation NN B-NP . . O The DT B-NP retrodifferentiated VBN I-NP cells NNS I-NP detached VBD B-VP from IN B-PP the DT B-NP substrate NN I-NP and CC O reinitiated VBD B-VP proliferation NN B-NP . . O Other JJ B-NP cellular JJ I-NP parameters NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP glycosidase NN B-NP activities NNS I-NP COMMA COMMA O cytokine NN B-NP release NN I-NP COMMA COMMA O and CC O filament NN B-NP expression NN I-NP COMMA COMMA O returned VBD B-VP to TO B-PP levels NNS B-NP similar JJ B-ADJP to TO B-PP that DT B-NP observed VBN B-VP in IN B-PP uninduced JJ B-NP cells NNS I-NP . . O Treatment NN B-NP of IN B-PP U-937 NN B-NP cells NNS I-NP with IN B-PP TPA NN B-NP resulted VBD B-VP in IN B-PP a DT B-NP rapid JJ I-NP translocation NN I-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O from IN B-PP the DT B-NP cytosol NN I-NP to TO B-PP cell NN B-NP membrane NN I-NP fractions NNS I-NP within IN B-PP 2-8 CD B-NP min NN I-NP . . O Increased VBN B-NP levels NNS I-NP of IN B-PP membrane-associated JJ B-NP PKC NN I-NP activity NN I-NP persisted VBD B-VP until IN B-PP 17-29 CD B-NP days NNS I-NP . . O However RB B-ADVP COMMA COMMA O longer JJR B-NP periods NNS I-NP of IN B-PP incubation NN B-NP were VBD B-VP associated VBN I-VP with IN B-PP a DT B-NP return NN I-NP to TO B-PP the DT B-NP distribution NN I-NP of IN B-PP PKC NN B-NP in IN B-PP control NN B-NP cells NNS I-NP . . O Activation NN B-NP of IN B-PP PKC NN B-NP has VBZ B-VP been VBN I-VP implicated VBN I-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP certain JJ B-NP immediate JJ I-NP early JJ I-NP response NN I-NP genes NNS I-NP COMMA COMMA O and CC O in IN B-PP the DT B-NP present JJ I-NP studies NNS I-NP COMMA COMMA O TPA NN B-NP rapidly RB B-ADVP induced VBD B-VP c-fos NN B-NP and CC O c-jun NN B-NP gene NN B-NP expression NN I-NP . . O Levels NNS B-NP of IN B-PP c-fos NN B-NP and CC O c-jun NN B-NP transcripts NNS B-NP remained VBD B-VP elevated JJ B-ADJP during IN B-PP periods NNS B-NP of IN B-PP PKC NN B-NP activation NN I-NP and CC O also RB O returned VBD B-VP to TO B-PP levels NNS B-NP observed VBN B-VP in IN B-PP control NN B-NP cells NNS I-NP by IN B-PP 30-36 CD B-NP days NNS I-NP COMMA COMMA O when WRB B-ADVP the DT B-NP cells NNS I-NP entered VBD B-VP retrodifferentiation NN B-NP . . O Staurosporine NN B-NP COMMA COMMA O a DT B-NP nonspecific JJ I-NP inhibitor NN I-NP of IN B-PP PKC NN B-NP COMMA COMMA O partially RB B-VP blocked VBD I-VP TPA-induced JJ B-NP adherence NN I-NP and CC O growth NN B-NP inhibition NN I-NP and CC O concomitantly RB B-VP prevented VBD I-VP TPA-induced JJ O c-fos NN B-NP and CC O c-jun NN B-NP gene NN B-NP expression NN I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O The DT B-NP promoter NN I-NP of IN B-PP the DT B-NP CD19 NN I-NP gene NN I-NP is VBZ B-VP a DT B-NP target NN I-NP for IN B-PP the DT B-NP B-cell-specific JJ I-NP transcription NN I-NP factor NN I-NP BSAP NN I-NP . . O The DT B-NP CD19 NN I-NP protein NN I-NP is VBZ B-VP expressed VBN I-VP on IN B-PP the DT B-NP surface NN I-NP of IN B-PP all DT B-NP B-lymphoid JJ I-NP cells NNS I-NP with IN B-PP the DT B-NP exception NN I-NP of IN B-PP terminally RB B-NP differentiated VBN I-NP plasma NN I-NP cells NNS I-NP and CC O has VBZ B-VP been VBN I-VP implicated VBN I-VP as IN B-PP a DT B-NP signal-transducing JJ I-NP receptor NN I-NP in IN B-PP the DT B-NP control NN I-NP of IN B-PP proliferation NN B-NP and CC O differentiation NN B-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP complete JJ B-NP correlation NN I-NP between IN B-PP the DT B-NP expression NN I-NP pattern NN I-NP of IN B-PP the DT B-NP CD19 NN I-NP gene NN I-NP and CC O the DT B-NP B-cell-specific JJ I-NP transcription NN I-NP factor NN I-NP BSAP NN I-NP in IN B-PP a DT B-NP large JJ I-NP panel NN I-NP of IN B-PP B-lymphoid JJ B-NP cell NN I-NP lines NNS I-NP . . O The DT B-NP human JJ I-NP CD19 NN I-NP gene NN I-NP has VBZ B-VP been VBN I-VP cloned VBN I-VP COMMA COMMA O and CC O several JJ B-NP BSAP-binding JJ I-NP sites NNS I-NP have VBP B-VP been VBN I-VP mapped VBN I-VP by IN B-PP in FW B-NP vitro FW I-NP protein-DNA JJ I-NP binding NN I-NP studies NNS I-NP . . O In IN B-PP particular JJ B-NP COMMA COMMA O a DT B-NP high-affinity JJ I-NP BSAP-binding JJ I-NP site NN I-NP instead RB B-CONJP of IN I-CONJP a DT B-NP TATA NN I-NP sequence NN I-NP is VBZ B-VP located JJ B-ADJP in IN B-PP the DT B-NP -30 CD I-NP promoter NN I-NP region NN I-NP upstream JJ B-ADJP of IN B-PP a DT B-NP cluster NN I-NP of IN B-PP heterogeneous JJ B-NP transcription NN I-NP start NN I-NP sites NNS I-NP . . O Moreover RB B-ADVP COMMA COMMA O this DT B-NP site NN I-NP is VBZ B-VP occupied VBN I-VP by IN B-PP BSAP NN B-NP in FW B-ADVP vivo FW I-ADVP in IN B-PP a DT B-NP CD19-expressing JJ I-NP B-cell NN I-NP line NN I-NP but CC B-PP not RB B-PP in IN I-PP plasma NN B-NP or CC O HeLa NN B-NP cells NNS B-NP . . O This DT B-NP high-affinity JJ I-NP site NN I-NP has VBZ B-VP been VBN I-VP conserved VBN I-VP in IN B-PP the DT B-NP promoters NNS I-NP of IN B-PP both CC O human JJ O and CC O mouse NN B-NP CD19 NN B-NP genes NNS I-NP and CC O was VBD B-VP furthermore RB I-VP shown VBN I-VP to TO I-VP confer VB I-VP B-cell NN B-NP specificity NN I-NP to TO B-PP a DT B-NP beta-globin NN I-NP reporter NN I-NP gene NN I-NP in IN B-PP transient JJ B-NP transfection NN I-NP experiments NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O BSAP NN B-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP the DT B-NP only RB I-NP abundant JJ I-NP DNA-binding JJ I-NP activity NN I-NP of IN B-PP B-cell NN B-NP nuclear JJ I-NP extracts NNS I-NP that WDT B-NP interacts VBZ B-VP with IN B-PP the DT B-NP CD19 NN I-NP promoter NN I-NP . . O Together RB B-ADVP COMMA COMMA O this DT B-NP evidence NN I-NP strongly RB B-ADVP implicates VBZ B-VP BSAP NN B-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP CD19 NN I-NP gene NN I-NP . . O Reduced VBN B-NP susceptibility NN I-NP to TO B-PP HIV-1 NN B-NP infection NN I-NP of IN B-PP ethyl-methanesulfonate-treated JJ B-NP CEM NN I-NP subclones NNS I-NP correlates VBZ B-VP with IN B-PP a DT B-NP blockade NN I-NP in IN B-PP their PRP$ B-NP protein NN I-NP kinase NN I-NP C NN I-NP signaling NN I-NP pathway NN I-NP . . O We PRP B-NP have VBP B-VP described VBN I-VP the DT B-NP isolation NN I-NP of IN B-PP chemically RB B-NP induced VBN I-NP CEM NN I-NP subclones NNS I-NP that WDT B-NP express VBP B-VP CD4 NN B-NP receptors NNS I-NP and CC O bind VBP B-VP soluble JJ B-NP gp120 NN I-NP COMMA COMMA O yet RB O show VBP B-VP a DT B-NP markedly RB I-NP reduced VBN I-NP susceptibility NN I-NP to TO B-PP infection NN B-NP with IN B-PP HIV-1 NN B-NP . . O Two CD B-NP subclones NNS I-NP were VBD B-VP found VBN I-VP to TO I-VP have VB I-VP an DT B-NP abnormal JJ I-NP response NN I-NP to TO B-PP the DT O protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O activator NN B-NP PMA NN I-NP . . O PMA NN B-NP treatment NN I-NP induced VBD B-VP CD3 NN B-NP and CC O CD25 NN B-NP ( ( O IL-2R NN B-NP ) ) O receptors NNS B-NP on IN B-PP the DT B-NP parental JJ I-NP line NN I-NP and CC O on IN B-PP other JJ B-NP ethyl-methanesulfonate-derived JJ I-NP subclones NNS I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP on IN I-PP these DT B-NP two CD I-NP mutants NNS I-NP . . O Direct JJ B-NP assays NNS I-NP of IN B-PP PKC NN B-NP activity NN I-NP were VBD B-VP conducted VBN I-VP . . O Total JJ B-NP cellular JJ I-NP PKC NN I-NP enzymatic JJ I-NP activity NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP normal JJ B-ADJP in IN B-PP these DT B-NP subclones NNS I-NP . . O PMA-induced JJ B-NP CD4 NN I-NP down-modulation NN I-NP occurred VBD B-VP normally RB B-ADVP . . O In IN B-PP addition NN B-NP COMMA COMMA O activation NN B-NP of IN B-PP c-raf NN B-NP kinase NN I-NP was VBD B-VP normal JJ B-ADJP . . O Since IN B-SBAR HIV-1 NN B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP contains VBZ B-VP two CD O functional JJ O nuclear JJ B-NP factor NN I-NP kB NN I-NP ( ( O NF-kB NN B-NP ) ) O regulatory JJ B-NP elements NNS I-NP COMMA COMMA O we PRP B-NP studied VBD B-VP the DT B-NP ability NN I-NP of IN B-PP PMA NN B-NP to TO B-VP induce VB I-VP NF-kB NN B-NP binding NN I-NP activity NN I-NP by IN B-PP different JJ B-NP assays NNS I-NP . . O Chloramphenicol NN B-NP acetyl NN I-NP transferase NN I-NP ( ( O CAT NN B-NP ) ) O assays NNS B-NP using VBG B-VP the DT B-NP HIV-1 NN I-NP ( ( I-NP -139 CD I-NP ) ) I-NP long JJ I-NP terminal JJ I-NP repeat-CAT JJ I-NP construct NN I-NP showed VBD B-VP no DT B-NP PMA NN I-NP induction NN I-NP of IN B-PP CAT NN B-NP activity NN I-NP in IN B-PP these DT B-NP subclones NNS I-NP ( ( O unlike IN B-PP the DT B-NP parental JJ I-NP line NN I-NP and CC O other JJ B-NP subclones NNS I-NP ) ) O . . O Okadaic JJ B-NP acid NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP phosphatases NNS B-NP 1 CD B-NP and CC O 2A NN B-NP COMMA COMMA O did VBD B-VP not RB I-VP overcome VB I-VP the DT B-NP defect NN I-NP in IN B-PP these DT B-NP subclones NNS I-NP . . O Gel NN B-NP retardation NN I-NP assays NNS I-NP COMMA COMMA O using VBG B-VP a DT B-NP 32P-probe NN I-NP containing VBG B-VP the DT B-NP HIV-1 NN I-NP NF-kB NN I-NP probe NN I-NP and CC O nuclear JJ B-NP extracts NNS I-NP from IN B-PP PMA-treated JJ B-NP cells NNS I-NP COMMA COMMA O showed VBD B-VP significantly RB B-NP reduced VBN I-NP induction NN I-NP of IN B-PP nuclear JJ B-NP NF-kB NN I-NP binding NN I-NP proteins NNS I-NP in IN B-PP these DT B-NP two CD I-NP subclones NNS I-NP compared VBN B-PP with IN B-PP wild JJ B-NP type NN I-NP CEM NN I-NP and CC O a DT B-NP control NN I-NP subclone NN I-NP . . O Deoxycholate JJ B-NP treatment NN I-NP of IN B-PP cytoplasmic JJ B-NP extracts NNS I-NP from IN B-PP these DT B-NP subclones NNS I-NP released VBD B-VP much JJ B-NP reduced VBN I-NP NF-kB NN I-NP binding NN I-NP proteins NNS I-NP from IN B-PP their PRP$ B-NP cytoplasmic JJ I-NP pools NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O reduced JJ B-NP levels NNS I-NP of IN B-PP PKC-induced JJ B-NP nuclear JJ I-NP NF-kB NN I-NP activity NN I-NP in IN B-PP two CD B-NP T NN I-NP cell NN I-NP subclones NNS I-NP did VBD B-VP not RB I-VP affect VB I-VP their PRP$ B-NP normal JJ I-NP cell NN I-NP growth NN I-NP COMMA COMMA O but CC O correlated VBD B-VP with IN B-PP a DT B-NP pronounced JJ I-NP reduction NN I-NP in IN B-PP their PRP$ B-NP susceptibility NN I-NP to TO B-PP HIV-1 NN B-NP infection NN I-NP . . O Eicosanoids NNS B-NP in IN B-PP breast NN B-NP cancer NN I-NP patients NNS I-NP before IN B-PP and CC B-PP after IN B-PP mastectomy NN B-NP . . O In IN B-PP 19 CD B-NP patients NNS I-NP with IN B-PP a DT B-NP malignant JJ I-NP breast NN I-NP tumor NN I-NP COMMA COMMA O tumor NN B-NP tissue NN I-NP and CC O blood NN B-NP were VBD B-VP taken VBN I-VP to TO B-VP determine VB I-VP the DT B-NP eicosanoid NN B-NP profile NN I-NP and CC O platelet NN B-NP aggregation NN I-NP . . O Values NNS B-NP were VBD B-VP compared VBN I-VP with IN B-PP those DT B-NP of IN B-PP patients NNS B-NP with IN B-PP benign JJ B-NP tumors NNS I-NP ( ( O n NN B-NP = JJ B-VP 4 CD B-NP ) ) O COMMA COMMA O or CC O undergoing VBG B-VP a DT B-NP mammary JJ I-NP reduction NN I-NP ( ( O n NN B-NP = JJ B-VP 7 CD B-NP ) ) O . . O Postoperatively RB B-ADVP COMMA COMMA O blood NN B-NP was VBD B-VP taken VBN I-VP as RB B-PP well RB B-ADVP in IN B-SBAR order NN O to TO O compare VB B-VP pre- JJ B-NP and CC I-NP postoperative JJ I-NP values NNS I-NP . . O Eicosanoids NNS B-NP were VBD B-VP measured VBN I-VP in IN B-PP peripheral JJ B-NP blood NN I-NP monocytes NNS I-NP and CC O mammary JJ B-NP tissue NN I-NP by IN B-PP means NNS I-PP of IN I-PP HPLC NN B-NP ; : O furthermore RBR B-ADVP COMMA COMMA O TXA2 NN B-NP COMMA COMMA O 6-keto-PGF1 NN B-NP alpha NN I-NP COMMA COMMA O and CC O PGE2 NN B-NP were VBD B-VP determined VBN I-VP by IN B-PP RIA NN B-NP . . O Differences NNS B-NP in IN B-PP pre- JJ B-NP and CC I-NP postoperative JJ I-NP values NNS I-NP of IN B-PP cancer NN B-NP patients NNS I-NP were VBD B-VP seen VBN I-VP in IN B-PP plasma NN B-NP RIA NN I-NP values NNS I-NP : : O PGE2 NN B-NP and CC O 6-k-PGF1 NN B-NP alpha NN I-NP were VBD B-VP significantly RB B-ADJP higher JJR I-ADJP preoperatively RB B-ADVP when WRB B-ADVP compared VBN B-VP with IN B-PP postoperatively RB B-ADVP COMMA COMMA O however RB O COMMA COMMA O such JJ B-NP differences NNS I-NP were VBD B-VP seen VBN I-VP in IN B-PP the DT B-NP control NN I-NP groups NNS I-NP as RB B-PP well RB B-ADVP . . O Compared VBN B-PP to TO B-PP benign JJ B-NP tumor NN I-NP or CC O mammary JJ B-NP reduction NN I-NP test NN B-NP material NN I-NP the DT B-NP eicosanoid NN I-NP profile NN I-NP of IN B-PP tissue NN B-NP obtained VBN B-VP from IN B-PP malignant JJ B-NP mammary JJ I-NP tumors NNS I-NP showed VBD B-VP important JJ B-NP differences NNS I-NP . . O Except IN B-PP for IN I-PP PGF2 NN B-NP alpha NN I-NP COMMA COMMA O HHT NN B-NP and CC O 15-HETE NN B-NP no DT B-NP detectable JJ I-NP quantities NNS I-NP of IN B-PP eicosanoids NNS B-NP were VBD B-VP found VBN I-VP in IN B-PP the DT B-NP non-tumor JJ I-NP material NN I-NP COMMA COMMA O whereas IN O in IN B-PP the DT B-NP malignant JJ I-NP tumor NN I-NP material NN I-NP substantial JJ B-NP quantities NNS I-NP of IN B-PP a DT B-NP number NN I-NP of IN B-PP eicosanoid NN B-NP metabolites NNS I-NP were VBD B-VP present JJ B-ADJP . . O Statistically RB B-NP significant JJ I-NP correlations NNS I-NP could MD B-VP be VB I-VP established VBN I-VP between IN B-PP patient\/histopathology NN B-NP data NNS I-NP and CC O the DT B-NP results NNS I-NP of IN B-PP the DT B-NP platelet NN I-NP aggregation NN I-NP assays NNS I-NP COMMA COMMA B-PP e.g. FW I-PP between IN B-PP menopausal JJ B-NP status NN I-NP and CC O ADP NN B-NP aggregation NN I-NP ; : O oestrogen NN B-NP receptor NN I-NP ( ( O +\/- JJ B-NP ) ) O and CC O collagen NN B-NP and CC O arachidonic JJ B-NP acid NN I-NP aggregation NN I-NP COMMA COMMA O inflammatory JJ B-NP cell NN I-NP infiltration NN I-NP score NN I-NP and CC O arachidonic JJ B-NP acid NN I-NP aggregation NN I-NP and CC O fibrosis NN B-NP score NN I-NP and CC O ADP NN B-NP aggregation NN I-NP . . O The DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR eicosanoid NN B-NP synthesis NN I-NP in IN B-PP material NN B-NP from IN B-PP mammary JJ B-NP cancer NN I-NP patients NNS I-NP is VBZ B-VP different JJ B-ADJP from IN B-PP that DT B-NP in IN B-PP benign JJ B-NP mammary JJ I-NP tissue NN I-NP . . O The DT B-NP implications NNS I-NP COMMA COMMA O in IN B-PP particular JJ B-NP COMMA COMMA B-PP in IN I-PP relation NN I-PP to TO I-PP future JJ B-NP prognosis NN I-NP of IN B-PP the DT B-NP patient NN I-NP COMMA COMMA O remain VBP B-VP obscure JJ B-ADJP . . O c-myc NN B-NP mRNA NN I-NP expression NN I-NP in IN B-PP minor JJ B-NP salivary JJ I-NP glands NNS I-NP of IN B-PP patients NNS B-NP with IN B-PP Sjogren NN B-NP 's POS B-NP syndrome NN I-NP . . O c-myc NN B-NP protooncogene NN I-NP is VBZ B-VP implicated VBN I-VP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP B NN B-NP cell NN I-NP lymphoid JJ I-NP malignancies NNS I-NP and CC O high JJ B-NP levels NNS I-NP of IN B-PP c-myc NN B-NP mRNA NN I-NP expression NN I-NP are VBP B-VP observed VBN I-VP in IN B-PP activated VBN B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP . . O Sjogren NN B-NP 's POS B-NP syndrome NN I-NP ( ( O SS NN B-NP ) ) O is VBZ B-VP characterized VBN I-VP by IN B-PP lymphocytic JJ B-NP infiltrates NNS I-NP of IN B-PP exocrine JJ B-NP glands NNS I-NP COMMA COMMA O remarkable JJ B-NP B NN I-NP cell NN I-NP hyperreactivity NN I-NP and CC O a DT B-NP strong JJ I-NP predisposition NN I-NP to TO B-PP B NN B-NP cell NN I-NP neoplasia NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O c-myc NN B-NP protooncogene NN I-NP mRNA NN I-NP expression NN I-NP in IN B-PP 29 CD B-NP labial JJ I-NP minor JJ I-NP salivary JJ I-NP gland NN I-NP biopsies NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP primary JJ B-NP SS NNS I-NP and CC O 15 CD B-NP controls NNS I-NP was VBD B-VP examined VBN I-VP using VBG B-VP in FW B-NP situ FW I-NP hybridization NN I-NP histochemistry NN I-NP . . O Two CD B-NP 40mer JJ I-NP oligonucleotides NNS I-NP from IN B-PP the DT B-NP 1st JJ I-NP and CC O the DT B-NP 2nd JJ I-NP exon NN B-NP of IN B-PP the DT B-NP c-myc NN I-NP gene NN I-NP COMMA COMMA O labeled VBN B-VP with IN B-PP 35S NN B-NP COMMA COMMA O were VBD B-VP used VBN I-VP as IN B-PP probes NNS B-NP . . O To TO B-VP detect VB I-VP the DT B-NP origin NN I-NP of IN B-PP the DT B-NP cell NN I-NP hybridized VBN B-VP with IN B-PP a DT B-NP c-myc NN I-NP probe NN I-NP COMMA COMMA O a DT B-NP combined JJ I-NP immunochemistry NN I-NP in FW I-NP situ FW I-NP hybridization NN I-NP histochemistry NN I-NP technique NN I-NP was VBD B-VP used VBN I-VP . . O High JJ B-NP c-myc NN I-NP mRNA NN I-NP expression NN I-NP was VBD B-VP detected VBN I-VP on IN B-PP acinar JJ B-NP epithelial JJ I-NP cells NNS I-NP . . O c-myc NN B-NP did VBD B-VP not RB I-VP correlate VB I-VP with IN B-PP c-fos NN B-NP and CC O c-jun NN B-NP protein NN B-NP expression NN I-NP . . O Stronger JJR B-NP c-myc NN I-NP mRNA NN I-NP expression NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP labial JJ B-NP salivary JJ I-NP glands NNS I-NP of IN B-PP patients NNS B-NP with IN B-PP longer JJR B-NP disease NN I-NP duration NN I-NP ( ( O p NN B-NP less JJR B-NP than IN I-NP or CC I-NP equal JJ I-NP to TO I-NP 0.002 CD I-NP ) ) O and CC O more RBR B-NP intense JJ I-NP T NN I-NP lymphocyte NN I-NP infiltrates NNS I-NP ( ( O p NN B-NP less JJR B-NP than IN I-NP 0.05 CD I-NP ) ) O although IN B-SBAR these DT B-NP patients NNS I-NP revealed VBD B-VP no DT B-NP hypergammaglobulinemia NN I-NP . . O No DT B-NP correlation NN I-NP was VBD B-VP observed VBN I-VP between IN B-PP c-myc NN B-NP mRNA NN I-NP and CC O B NN B-NP lymphocyte NN I-NP monoclonicity NN B-NP or CC O lymphoma NN B-NP . . O In IN B-PP conclusion NN B-NP COMMA COMMA O strong JJ B-NP c-myc NN I-NP mRNA NN I-NP expression NN I-NP was VBD B-VP observed VBN I-VP on IN B-PP epithelial JJ B-NP cells NNS I-NP of IN B-PP labial JJ B-NP salivary JJ I-NP glands NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP primary JJ B-NP SS NN I-NP . . O Our PRP$ B-NP findings NNS I-NP may MD B-VP indicate VB I-VP the DT B-NP presence NN I-NP of IN B-PP a DT B-NP reactivated VBN I-NP virus NN I-NP hosted VBN B-VP in IN B-PP these DT B-NP cells NNS I-NP . . O Cytoplasmic JJ B-NP domain NN I-NP heterogeneity NN I-NP and CC O functions NNS B-NP of IN B-PP IgG NN B-NP Fc NN I-NP receptors NNS I-NP in IN B-PP B NN B-NP lymphocytes NNS I-NP . . O B NN B-NP lymphocytes NNS I-NP and CC O macrophages NNS B-NP express VBP B-VP closely RB B-NP related JJ I-NP immunoglobulin NN B-NP G NN I-NP ( ( O IgG NN B-NP ) ) O Fc NN B-NP receptors NNS I-NP ( ( O Fc NN O gamma NN O RII NN O ) ) O that WDT B-NP differ VBP B-VP only RB B-ADVP in IN I-ADVP the DT B-NP structures NNS I-NP of IN B-PP their PRP$ B-NP cytoplasmic JJ I-NP domains NNS I-NP . . O Because IN B-PP of IN I-PP cell NN B-NP type-specific JJ I-NP alternative JJ I-NP messenger NN I-NP RNA NN I-NP splicing NN I-NP COMMA COMMA O B-cell NN B-NP Fc NN I-NP gamma NN I-NP RII NN I-NP contains VBZ B-VP an DT B-NP insertion NN I-NP of IN B-PP 47 CD B-NP amino NN I-NP acids NNS I-NP that WDT B-NP participates VBZ B-VP in IN B-PP determining VBG B-VP receptor NN B-NP function NN I-NP in IN B-PP these DT B-NP cells NNS I-NP . . O Transfection NN B-NP of IN B-PP an DT B-NP Fc NN I-NP gamma NN I-NP RII-negative JJ I-NP B-cell NN I-NP line NN I-NP with IN B-PP complementary JJ B-NP DNA NN I-NP 's POS B-NP encoding VBG B-VP the DT B-NP two CD I-NP splice NN I-NP products NNS I-NP and CC O various JJ B-NP receptor NN I-NP mutants NNS I-NP indicated VBD B-VP that IN B-SBAR the DT B-NP insertion NN I-NP was VBD B-VP responsible JJ B-ADJP for IN B-PP preventing VBG B-VP both CC O Fc NN B-NP gamma NN I-NP RII-mediated JJ I-NP endocytosis NN I-NP and CC O Fc NN B-NP gamma NN I-NP RII-mediated JJ I-NP antigen NN I-NP presentation NN I-NP . . O The DT B-NP insertion NN I-NP was VBD B-VP not RB I-VP required VBN I-VP for IN B-PP Fc NN B-NP gamma NN I-NP RII NN I-NP to TO B-VP modulate VB I-VP surface NN B-NP immunoglobulin-triggered JJ I-NP B-cell NN I-NP activation NN I-NP . . O Instead RB B-ADVP COMMA COMMA O regulation NN B-NP of IN B-PP activation NN B-NP involved VBD B-VP a DT B-NP region NN I-NP of IN B-PP the DT B-NP cytoplasmic JJ I-NP domain NN I-NP common JJ B-ADJP to TO B-PP both CC O the DT O lymphocyte NN B-NP and CC O macrophage NN B-NP receptor NN B-NP isoforms NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP insertion NN I-NP did VBD B-VP contribute VB I-VP to TO B-PP the DT B-NP formation NN I-NP of IN B-PP caps NNS B-NP in IN B-PP response NN I-PP to TO I-PP receptor NN B-NP cross-linking NN I-NP COMMA COMMA O consistent JJ B-ADJP with IN B-PP suggestions NNS B-NP that IN B-SBAR the DT O lymphocyte NN B-NP but CC B-CONJP not RB I-CONJP macrophage NN B-NP form NN B-NP of IN B-PP the DT B-NP receptor NN I-NP can MD B-VP associate VB I-VP with IN B-PP the DT B-NP detergent-insoluble JJ I-NP cytoskeleton NN I-NP . . O Every DT B-NP enhancer NN I-NP works VBZ B-VP with IN B-PP every DT B-NP promoter NN I-NP for IN B-PP all PDT B-NP the DT I-NP combinations NNS I-NP tested VBN B-VP : : O could MD O new JJ B-NP regulatory JJ I-NP pathways NNS I-NP evolve VBP B-VP by IN B-PP enhancer NN B-NP shuffling NN I-NP ? . O The DT B-NP promoters NNS B-NP and CC O enhancers NNS B-NP of IN B-PP cell NN B-NP type-specific JJ I-NP genes NNS I-NP are VBP B-VP often RB I-VP conserved VBN I-VP in IN B-PP evolution NN B-NP COMMA COMMA O and CC O hence RB O one NN B-NP might MD B-VP expect VB I-VP that IN B-SBAR a DT B-NP given JJ I-NP enhancer NN I-NP has VBZ B-VP evolved VBN I-VP to TO I-VP work VB I-VP best RBS B-ADVP with IN B-PP its PRP$ B-NP own JJ I-NP promoter NN I-NP . . O While IN B-SBAR this DT B-NP expectation NN I-NP may MD B-VP be VB I-VP realized VBN I-VP in IN B-PP some DT B-NP cases NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP not RB I-VP found VBN I-VP evidence NN B-NP for IN B-PP it PRP B-NP . . O A DT B-NP total NN I-NP of IN B-PP 27 CD B-NP combinations NNS I-NP of IN B-PP different JJ B-NP promoters NNS B-NP and CC O enhancers NNS B-NP were VBD B-VP tested VBN I-VP by IN B-PP transfection NN B-NP into IN B-PP cultured VBN B-NP cells NNS I-NP . . O We PRP B-NP found VBD B-VP that IN B-SBAR the DT B-NP relative JJ I-NP efficiency NN I-NP of IN B-PP the DT B-NP enhancers NNS I-NP is VBZ B-VP approximately RB B-ADVP the DT B-NP same JJ I-NP COMMA COMMA O irrespective JJ B-ADJP of IN B-PP the DT B-NP type NN I-NP of IN B-PP promoter NN B-NP used VBN B-VP COMMA COMMA O i.e. FW O COMMA COMMA O there EX B-NP was VBD B-VP no DT B-NP strong JJ I-NP preference NN I-NP for IN B-PP any DT B-NP given JJ I-NP enhancer\/promoter JJ I-NP combination NN I-NP . . O Notably RB B-ADVP COMMA COMMA O we PRP B-NP do VBP B-VP not RB I-VP see VB I-VP particularly RB B-NP strong JJ I-NP transcription NN I-NP when WRB B-ADVP the DT B-NP immunoglobulin NN I-NP kappa NN I-NP enhancer NN I-NP ( ( O or CC O the DT B-NP immunoglobulin NN I-NP heavy JJ I-NP chain NN I-NP enhancer NN I-NP ) ) O is VBZ B-VP used VBN I-VP to TO B-VP activate VB I-VP a DT B-NP kappa NN I-NP gene NN I-NP promoter NN I-NP . . O We PRP B-NP propose VBP B-VP that IN B-SBAR a DT B-NP generally RB I-NP permissive JJ I-NP enhancer\/promoter JJ I-NP interaction NN I-NP is VBZ B-VP of IN B-PP evolutionary JJ B-NP benefit NN I-NP for IN B-PP higher JJR B-NP eukaryotes NNS I-NP : : O by IN B-PP enhancer NN B-NP shuffling NN I-NP COMMA COMMA O genes NNS B-NP could MD B-VP be VB I-VP easily RB I-VP brought VBN I-VP under IN B-PP a DT B-NP new JJ I-NP type NN I-NP of IN B-PP inducibility\/cell NN B-NP type NN I-NP specificity NN I-NP . . O Heterodimerization NN B-NP and CC O transcriptional JJ B-NP activation NN I-NP in FW B-ADVP vitro FW I-ADVP by IN B-PP NF-kappa NN B-NP B NN I-NP proteins NNS I-NP . . O The DT B-NP NF-kappa NN I-NP B NN I-NP family NN I-NP of IN B-PP transcription NN B-NP proteins NNS I-NP represents VBZ B-VP multiple JJ B-NP DNA NN I-NP binding NN I-NP COMMA COMMA O rel NN B-NP related JJ B-NP polypeptides NNS I-NP that WDT B-NP contribute VBP B-VP to TO B-PP regulation NN B-NP of IN B-PP genes NNS B-NP involved VBN B-VP in IN B-PP immune JJ B-NP responsiveness NN I-NP and CC O inflammation NN B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP activation NN B-NP of IN B-PP the DT B-NP HIV NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP multiple JJ O NF-kappa NN B-NP B NN I-NP related JJ B-NP polypeptides NNS I-NP ranging VBG B-VP from IN B-PP 85 CD I-PP to TO I-PP 45 CD O kDa NN O were VBD B-VP examined VBN I-VP for IN B-PP their PRP$ B-NP capacity NN I-NP to TO B-VP interact VB I-VP with IN B-PP the DT B-NP PRDII NN I-NP regulatory JJ I-NP element NN I-NP of IN B-PP interferon NN B-NP beta NN I-NP and CC O were VBD B-VP shown VBN I-VP to TO I-VP possess VB I-VP distinct JJ B-NP intrinsic JJ I-NP DNA NN I-NP binding NN I-NP affinities NNS I-NP for IN B-PP this DT B-NP NF-kappa NN I-NP B NN I-NP site NN I-NP and CC O form VB B-VP multiple JJ B-NP DNA NN I-NP binding NN I-NP homo- JJ I-NP and CC I-NP heterodimer NN I-NP complexes NNS I-NP in IN B-PP co-renaturation NN B-NP experiments NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O using VBG B-VP DNA NN B-NP templates NNS I-NP containing VBG B-VP two CD B-NP copies NNS I-NP of IN B-PP the DT B-NP PRDII NN I-NP domain NN I-NP linked VBN B-VP to TO B-PP the DT B-NP rabbit NN I-NP beta NN I-NP globin NN I-NP gene NN I-NP COMMA COMMA O the DT B-NP purified VBN I-NP polypeptides NNS I-NP specifically RB B-ADVP stimulated VBD B-VP NF-kappa NN B-NP B NN I-NP dependent JJ B-NP transcription NN I-NP in IN B-PP an DT B-NP in FW I-NP vitro FW I-NP reconstitution NN I-NP assay NN I-NP as IN B-PP heterodimers NNS B-NP but CC B-PP not RB B-PP as IN I-PP p50 NN B-NP homodimers NNS I-NP . . O These DT B-NP experiments NNS I-NP emphasize VBP B-VP the DT B-NP role NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP dimerization NN I-NP as IN B-PP a DT B-NP distinct JJ I-NP level NN I-NP of IN B-PP transcriptional JJ B-NP control NN I-NP that WDT B-NP may MD B-VP permit VB I-VP functional JJ B-NP diversification NN I-NP of IN B-PP a DT B-NP limited JJ I-NP number NN I-NP of IN B-PP regulatory JJ B-NP proteins NNS I-NP . . O Oct2 NN B-NP transactivation NN I-NP from IN B-PP a DT B-NP remote JJ I-NP enhancer NN I-NP position NN I-NP requires VBZ B-VP a DT B-NP B-cell-restricted JJ I-NP activity NN I-NP . . O Previous JJ B-NP cotransfection NN I-NP experiments NNS I-NP had VBD B-VP demonstrated VBN I-VP that IN B-SBAR ectopic JJ B-NP expression NN I-NP of IN B-PP the DT B-NP lymphocyte-specific JJ I-NP transcription NN I-NP factor NN I-NP Oct2 NN I-NP could MD B-VP efficiently RB I-VP activate VB I-VP a DT B-NP promoter NN I-NP containing VBG B-VP an DT B-NP octamer NN I-NP motif NN I-NP . . O Oct2 NN B-NP expression NN I-NP was VBD B-VP unable JJ B-ADJP to TO B-VP stimulate VB I-VP a DT B-NP multimerized JJ I-NP octamer NN I-NP enhancer NN I-NP element NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP COMMA COMMA O however RB B-ADVP . . O We PRP B-NP have VBP B-VP tested VBN I-VP a DT B-NP variety NN I-NP of IN B-PP Oct2 NN B-NP isoforms VBZ I-NP generated VBN B-VP by IN B-PP alternative JJ B-NP splicing NN I-NP for IN B-PP the DT B-NP capability NN I-NP to TO B-VP activate VB I-VP an DT B-NP octamer NN I-NP enhancer NN I-NP in IN B-PP nonlymphoid JJ B-NP cells NNS I-NP and CC O a DT B-NP B-cell NN I-NP line NN I-NP . . O Our PRP$ B-NP analyses NNS I-NP show VBP B-VP that IN B-SBAR several JJ B-NP Oct2 NN I-NP isoforms NNS I-NP can MD B-VP stimulate VB I-VP from IN B-PP a DT B-NP remote JJ I-NP position NN I-NP but CC O that IN B-SBAR this DT B-NP stimulation NN I-NP is VBZ B-VP restricted JJ I-VP to TO B-PP B NN B-NP cells NNS I-NP . . O This DT B-NP result NN I-NP indicates VBZ B-VP the DT B-NP involvement NN I-NP of IN B-PP either CC O a DT B-NP B-cell-specific JJ I-NP cofactor NN I-NP or CC O a DT B-NP specific JJ I-NP modification NN I-NP of IN B-PP a DT B-NP cofactor NN I-NP or CC O the DT B-NP Oct2 NN I-NP protein NN I-NP in IN B-PP Oct2-mediated JJ B-NP enhancer NN I-NP activation NN I-NP . . O Mutational JJ B-NP analyses NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP carboxy-terminal JJ I-NP domain NN I-NP of IN B-PP Oct2 NN B-NP is VBZ B-VP critical JJ B-ADJP for IN B-PP enhancer NN B-NP activation NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O this DT B-NP domain NN I-NP conferred VBD B-VP enhancing NN B-NP activity NN I-NP when WRB O fused VBN B-VP to TO B-PP the DT B-NP Oct1 NN I-NP protein NN I-NP COMMA COMMA O which WDT B-NP by IN B-PP itself PRP B-NP was VBD B-VP unable JJ B-ADJP to TO B-VP stimulate VB I-VP from IN B-PP a DT B-NP remote JJ I-NP position NN I-NP . . O The DT B-NP glutamine-rich JJ I-NP activation NN I-NP domain NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP amino-terminal JJ I-NP portion NN I-NP of IN B-PP Oct2 NN B-NP and CC O the DT B-NP POU NN I-NP domain NN I-NP contribute VBP B-VP only RB B-ADVP marginally RB I-ADVP to TO B-PP the DT B-NP transactivation NN I-NP function NN I-NP from IN B-PP a DT B-NP distal JJ I-NP position NN I-NP . . O Induction NN B-NP of IN B-PP the DT B-NP POU NN I-NP domain NN I-NP transcription NN I-NP factor NN I-NP Oct-2 NN I-NP during IN B-PP T-cell NN B-NP activation NN I-NP by IN B-PP cognate JJ B-NP antigen NN I-NP . . O Oct-2 NN B-NP is VBZ B-VP a DT B-NP transcription NN I-NP factor NN I-NP that WDT B-NP binds VBZ B-VP specifically RB B-PP to TO I-PP octamer NN B-NP DNA NN I-NP motifs NNS I-NP in IN B-PP the DT B-NP promoters NNS I-NP of IN B-PP immunoglobulin NN B-NP and CC O interleukin-2 NN B-NP genes NNS B-NP . . O All DT B-NP tumor NN I-NP cell NN I-NP lines NNS I-NP from IN B-PP the DT B-NP B-cell NN I-NP lineage NN I-NP and CC O a DT B-NP few JJ I-NP from IN B-PP the DT B-NP T-cell NN I-NP lineage NN I-NP express VBP B-VP Oct-2 NN B-NP . . O To TO B-VP address VB I-VP the DT B-NP role NN I-NP of IN B-PP Oct-2 NN B-NP in IN B-PP the DT B-NP T-cell NN I-NP lineage NN I-NP COMMA COMMA O we PRP B-NP studied VBD B-VP the DT B-NP expression NN I-NP of IN B-PP Oct-2 NN B-NP mRNA NN I-NP and CC O protein NN B-NP in IN B-PP nontransformed JJ O human JJ O and CC O mouse NN B-NP T NN B-NP cells NNS I-NP . . O Oct-2 NN B-NP was VBD B-VP found VBN I-VP in IN B-PP CD4+ JJ B-NP and CC I-NP CD8+ JJ I-NP T NN I-NP cells NNS I-NP prepared VBN B-VP from IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP and CC B-PP in IN B-PP mouse NN B-NP lymph NN I-NP node NN I-NP T NN I-NP cells NNS I-NP . . O In IN B-PP a DT B-NP T-cell NN I-NP clone NN I-NP specific JJ B-ADJP for IN B-PP pigeon NN B-NP cytochrome NN I-NP c NN I-NP in IN B-PP the DT I-PP context NN I-PP of IN I-PP I-Ek NN B-NP COMMA COMMA O Oct-2 NN B-NP was VBD B-VP induced VBN I-VP by IN B-PP antigen NN B-NP stimulation NN I-NP COMMA COMMA O with IN B-SBAR the DT B-NP increase NN I-NP in IN B-PP Oct-2 NN B-NP protein NN I-NP seen VBN B-VP first RB B-ADVP at IN B-PP 3 CD B-NP h NN I-NP after IN B-PP activation NN B-NP and CC O continuing VBG B-VP for IN B-PP at IN B-NP least JJS I-NP 24 CD I-NP h NN I-NP . . O Oct-2 NN B-NP mRNA NN I-NP induction NN I-NP during IN B-PP antigen-driven JJ B-NP T-cell NN I-NP activation NN I-NP was VBD B-VP blocked VBN I-VP by IN B-PP cyclosporin NN B-NP A NN I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP by IN B-PP protein NN B-NP synthesis NN I-NP inhibitors NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR Oct-2 NN B-NP participates VBZ B-VP in IN B-PP transcriptional JJ B-NP regulation NN I-NP during IN B-PP T-cell NN B-NP activation NN I-NP . . O The DT B-NP relatively RB I-NP delayed VBN I-NP kinetics NNS I-NP of IN B-PP Oct-2 NN B-NP induction NN I-NP suggests VBZ B-VP that IN B-SBAR Oct-2 NN B-NP mediates VBZ B-VP the DT B-NP changes NNS I-NP in IN B-PP gene NN B-NP expression NN I-NP which WDT B-NP occur VBP B-VP many JJ B-NP hours NNS B-NP or CC O days NNS B-NP following VBG B-PP antigen NN B-NP stimulation NN I-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP . . O { ( O Changes NNS B-NP in IN B-PP plasma NN B-NP interleukin-1 NN I-NP and CC O their PRP$ B-NP possible JJ I-NP relationship NN I-NP with IN B-PP the DT B-NP changes NNS I-NP in IN B-PP glucocorticoid NN B-NP receptor NN I-NP in IN B-PP aged JJ B-NP long-distance JJ I-NP runner NN I-NP } ) O For IN B-PP the DT B-NP study NN I-NP of IN B-PP the DT B-NP changes NNS I-NP in IN B-PP plasma NN B-NP interleukin-1 NN B-NP ( ( O IL-1 NN B-NP ) ) O and CC O their PRP$ B-NP possible JJ I-NP relationship NN I-NP with IN B-PP the DT B-NP changes NNS I-NP in IN B-PP glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O COMMA COMMA O plasma NN B-NP IL-1 NN I-NP and CC O GR NN B-NP in IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP in IN B-PP aged JJ B-NP long-distance JJ I-NP runner NN I-NP were VBD B-VP measured VBN I-VP simultaneously RB B-ADVP . . O The DT B-NP activity NN I-NP of IN B-PP IL-1 NN B-NP was VBD B-VP expressed VBN I-VP as IN B-PP its PRP$ B-NP ability NN I-NP to TO B-VP stimulate VB I-VP 3H-TdR NN B-NP incorporation NN I-NP in IN B-PP the DT B-NP thymocytes NNS I-NP of IN B-PP C57 NN B-NP mice NNS I-NP . . O GR NN B-NP was VBD B-VP determined VBN I-VP by IN B-PP whole JJ B-NP cell NN I-NP assay NN I-NP with IN B-PP 3H-Dex NN B-NP . . O The DT B-NP results NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP activity NN I-NP of IN B-PP plasma NN B-NP IL-1 NN I-NP in IN B-PP aged JJ B-NP long-distance JJ I-NP runner NN I-NP was VBD B-VP 209 CD B-NP % NN I-NP COMMA COMMA O 223 CD B-NP % NN I-NP and CC O 145 CD B-NP % NN I-NP of IN B-PP the DT B-NP control NN I-NP at IN B-PP 14.7-18.7 CD B-NP COMMA COMMA I-NP 3.8-7.0 CD I-NP and CC I-NP 1.5-2.6 CD I-NP KD NN I-NP fractions NNS B-NP . . O The DT B-NP GR NN I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP in IN B-PP aged JJ B-NP runner NN I-NP was VBD B-VP 65 CD B-NP % NN I-NP of IN B-PP the DT B-NP control NN I-NP . . O Possible JJ B-NP relationship NN I-NP between IN B-PP the DT B-NP changes NNS I-NP in IN B-PP IL-1 NN B-NP and CC O GR NN B-NP in IN B-PP aged JJ B-NP long-distance JJ I-NP runner NN I-NP and CC O its PRP$ B-NP physiological JJ I-NP significance NN I-NP are VBP B-VP discussed VBN I-VP . . O Transcription NN B-NP factor NN I-NP AP-2 NN I-NP activates VBZ B-VP gene NN B-NP expression NN I-NP of IN B-PP HTLV-I NN B-NP . . O The DT B-NP HTLV-I NN I-NP LTR NN I-NP contains VBZ B-VP three CD B-NP conserved VBN I-NP regulatory JJ I-NP elements NNS I-NP known VBN B-VP as IN B-PP 21 CD B-NP base NN I-NP pair NN I-NP repeats NNS I-NP which WDT B-NP are VBP B-VP required VBN I-VP for IN B-PP stimulation NN B-NP of IN B-PP gene NN B-NP expression NN I-NP by IN B-PP the DT B-NP transactivator NN I-NP protein NN I-NP tax NN I-NP . . O Mutagenesis NN B-NP indicates VBZ B-VP that IN B-SBAR the DT B-NP 21 CD I-NP bp NN I-NP repeats NNS I-NP can MD B-VP be VB I-VP subdivided VBN I-VP into IN B-PP three CD B-NP motifs NNS I-NP COMMA COMMA O A NN B-NP COMMA COMMA O B NN B-NP and CC O C NN B-NP COMMA COMMA O each DT B-NP of IN B-PP which WDT B-NP influences VBZ B-VP the DT B-NP level NN I-NP of IN B-PP tax NN B-NP activation NN I-NP . . O The DT B-NP A NN I-NP site NN I-NP in IN B-PP the DT B-NP 21 CD I-NP bp NN I-NP repeat NN I-NP has VBZ B-VP strong JJ B-NP homology NN I-NP with IN B-PP previously RB B-NP described VBN I-NP binding VBG I-NP sites NNS I-NP for IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP AP-2 NN I-NP . . O We PRP B-NP demonstrated VBD B-VP that IN B-SBAR AP-2 NN B-NP mRNA NN I-NP was VBD B-VP present JJ B-ADJP in IN B-PP T-lymphocytes NNS B-NP and CC O that IN B-SBAR cellular JJ B-NP factors NNS I-NP from IN B-PP both CC B-NP non-transformed JJ I-NP and CC I-NP transformed VBN I-NP T-lymphocytes NNS I-NP specifically RB B-ADVP bound VBD B-VP to TO B-PP the DT B-NP consensus NN I-NP motif NN I-NP for IN B-PP AP-2 NN B-NP in IN B-PP each DT B-NP 21 CD I-NP bp NN I-NP . . O To TO B-VP determine VB I-VP the DT B-NP role NN I-NP of IN B-PP AP-2 NN B-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP HTLV-I NN I-NP LTR NN I-NP gene NN I-NP expression NN I-NP COMMA COMMA O we PRP B-NP used VBD B-VP an DT B-NP AP-2 NN I-NP cDNA NN I-NP in IN B-PP DNA NN B-NP binding NN I-NP and CC O transient JJ B-NP expression NN I-NP assays NNS B-NP . . O Gel NN B-NP retardation NN I-NP and CC O methylation NN B-NP interference NN I-NP studies NNS B-NP revealed VBD B-VP that IN B-SBAR bacterially RB B-NP produced VBN I-NP AP-2 NN I-NP bound VBD B-VP specifically RB B-ADVP and CC O with IN B-PP high JJ B-NP affinity NN I-NP to TO B-PP all DT B-NP three CD I-NP 21 CD I-NP bp NN I-NP repeats NNS I-NP COMMA COMMA O and CC O that IN B-SBAR it PRP B-NP required VBD B-VP the DT B-NP core NN I-NP sequence NN I-NP AGGC NN I-NP for IN B-PP specific JJ B-NP binding NN I-NP . . O Binding NN B-NP of IN B-PP AP-2 NN B-NP prevented VBD B-VP the DT B-NP subsequent JJ I-NP binding NN I-NP of IN B-PP members NNS B-NP of IN B-PP the DT B-NP CREB\/ATF NN I-NP family NN I-NP to TO B-PP an DT B-NP adjacent JJ I-NP regulatory JJ I-NP motif NN I-NP in IN B-PP the DT B-NP 21 CD I-NP bp NN I-NP repeat NN I-NP . . O Transfection NN B-NP of IN B-PP an DT B-NP AP-2 NN I-NP expression NN I-NP construct NN I-NP into IN B-PP T-lymphocytes NNS B-NP activated VBD B-VP gene NN B-NP expression NN I-NP from IN B-PP the DT B-NP HTLV-I NN I-NP LTR NN I-NP . . O At IN B-NP least JJS I-NP two CD I-NP 21 CD I-NP bp NN I-NP repeats NNS I-NP were VBD B-VP required VBN I-VP for IN B-PP high JJ B-NP levels NNS I-NP of IN B-PP AP-2 NN B-NP activation NN I-NP and CC O mutagenesis NN B-NP of IN B-PP the DT B-NP AP-2 NN I-NP consensus NN I-NP binding NN I-NP sequences NNS I-NP in IN B-PP the DT B-NP 21 CD I-NP bp NN I-NP repeats NNS I-NP eliminate VBP B-VP this DT B-NP activation NN I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Cell NN B-NP cycle-dependent JJ I-NP initiation NN I-NP and CC O lineage-dependent JJ B-NP abrogation NN I-NP of IN B-PP GATA-1 NN B-NP expression NN I-NP in IN B-PP pure JJ B-NP differentiating VBG I-NP hematopoietic JJ I-NP progenitors NNS I-NP . . O The DT B-NP programmed VBN I-NP activation\/repression NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP in IN B-PP early JJ B-NP hematopoietic JJ I-NP differentiation NN I-NP has VBZ B-VP not RB I-VP yet RB I-VP been VBN I-VP explored VBN I-VP . . O The DT B-NP DNA-binding JJ I-NP protein NN I-NP GATA-1 NN I-NP is VBZ B-VP required VBN I-VP for IN B-PP normal JJ B-NP erythroid JJ I-NP development NN I-NP and CC O regulates VBZ B-VP erythroid-expressed JJ B-NP genes NNS I-NP in IN B-PP maturing VBG B-NP erythroblasts NNS I-NP . . O We PRP B-NP analyzed VBD B-VP GATA-1 NN B-NP expression NN I-NP in IN B-PP early JJ B-NP human JJ I-NP adult JJ I-NP hematopoiesis NN I-NP by IN B-PP using VBG B-VP an DT B-NP in FW I-NP vitro FW I-NP system NN I-NP in IN B-PP which WDT B-NP " `` B-NP pure JJ I-NP " '' I-NP early JJ I-NP hematopoietic JJ I-NP progenitors NNS I-NP are VBP B-VP induced VBN I-VP to TO B-PP gradual JJ B-NP and CC I-NP synchronized VBD I-NP differentiation NN I-NP selectively RB B-ADVP along IN B-PP the DT B-NP erythroid JJ I-NP or CC I-NP granulocyte-macrophage JJ I-NP pathway NN I-NP by IN B-PP differential JJ B-NP treatment NN I-NP with IN B-PP hematopoietic JJ B-NP growth NN I-NP factors NNS I-NP . . O The DT B-NP GATA-1 NN I-NP gene NN I-NP COMMA COMMA O though IN B-SBAR virtually RB B-ADJP silent JJ I-ADJP in IN B-PP quiescent JJ B-NP progenitors NNS I-NP COMMA COMMA O is VBZ B-VP activated VBN I-VP after IN B-PP entrance NN B-NP into IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP upon IN B-PP stimulation NN B-NP with IN B-PP hematopoietic JJ B-NP growth NN I-NP factors NNS I-NP . . O Subsequently RB B-ADVP COMMA COMMA O increasing VBG B-NP expression NN I-NP along IN B-PP the DT B-NP erythroid JJ I-NP pathway NN I-NP contrasts VBZ B-VP with IN B-PP an DT B-NP abrupt JJ I-NP downregulation NN I-NP in IN B-PP the DT B-NP granulocyte-macrophage JJ I-NP lineage NN I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP a DT B-NP microenvironment-directed JJ I-NP COMMA COMMA I-NP two-step JJ I-NP model NN I-NP for IN B-PP GATA-1 NN B-NP expression NN I-NP in IN B-PP differentiating VBG B-NP hematopoietic JJ I-NP progenitors NNS I-NP that WDT B-NP involves VBZ B-VP ( ( B-LST i LS I-LST ) ) O cycle-dependent JJ B-NP initiation NN I-NP and CC O ( ( B-LST ii LS I-LST ) ) O lineage-dependent JJ B-NP maintenance NN B-NP or CC O suppression NN B-NP . . O Hypothetically RB B-ADVP COMMA COMMA O on\/off JJ B-NP switches NNS I-NP of IN B-PP lineage-restricted JJ B-NP transactivators NNS I-NP may MD B-VP underlie VB I-VP the DT B-NP binary JJ I-NP fate NN I-NP decisions NNS I-NP of IN B-PP hematopoietic JJ B-NP progenitors NNS I-NP . . O { ( O Age-related JJ B-NP changes NNS I-NP in IN B-PP glucocorticoid NN B-NP and CC O mineralocorticoid NN B-NP receptors NNS B-NP in IN B-PP lymphocytes NNS B-NP of IN B-PP healthy JJ B-NP persons NNS I-NP and CC O patients NNS B-NP with IN B-PP hypertension NN B-NP } ) O It PRP B-NP has VBZ B-VP been VBN I-VP found VBN I-VP that IN B-SBAR the DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP lymphocytes NNS B-NP of IN B-PP the DT B-NP peripheral JJ I-NP blood NN I-NP of IN B-PP healthy JJ B-NP elderly JJ I-NP subjects NNS I-NP increases VBZ B-VP COMMA COMMA O while IN B-SBAR the DT B-NP number NN I-NP of IN B-PP mineralocorticoid NN B-NP receptors NNS I-NP decreases VBZ B-VP . . O The DT B-NP mechanisms NNS I-NP of IN B-PP hormone-receptor NN B-NP interactions NNS I-NP in IN B-PP hypertension NN B-NP are VBP B-VP activated VBN I-VP : : O the DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP and CC O mineralocorticoid NN B-NP binding NN B-NP sites NNS I-NP grows VBZ B-VP in IN B-PP hypertensive JJ B-NP patients NNS I-NP . . O Still RB B-ADVP a DT B-NP more RBR I-NP essential JJ I-NP rise NN I-NP in IN B-PP the DT B-NP number NN I-NP of IN B-PP receptors NNS B-NP is VBZ B-VP observed VBN I-VP in IN B-PP mid-age JJ B-NP hypertensive NN I-NP patients NNS I-NP than IN B-PP in IN B-PP elderly JJ B-NP ones NNS I-NP . . O In FW B-NP vivo FW I-NP footprint NN I-NP analysis NN I-NP of IN B-PP the DT B-NP HLA-DRA NN I-NP gene NN I-NP promoter NN I-NP : : O cell-specific JJ B-NP interaction NN I-NP at IN B-PP the DT B-NP octamer NN I-NP site NN I-NP and CC O up-regulation NN B-NP of IN B-PP X NN B-NP box NN I-NP binding NN I-NP by IN B-PP interferon NN B-NP gamma NN I-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP major JJ I-NP histocompatibility NN I-NP complex NN I-NP class NN I-NP II CD I-NP gene NN I-NP promoter NN I-NP DRA NN I-NP has VBZ B-VP previously RB I-VP identified VBN I-VP at IN B-NP least JJS I-NP five CD I-NP cis-acting JJ I-NP regions NNS I-NP required VBN B-VP for IN B-PP maximal JJ B-NP expression NN I-NP . . O We PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP DRA NN I-NP promoter NN I-NP for IN B-PP protein-DNA JJ B-NP interactions NNS I-NP in IN B-PP the DT B-NP intact JJ I-NP cell NN I-NP COMMA COMMA O which WDT B-NP may MD B-VP mediate VB I-VP transcriptional JJ B-NP activation NN I-NP . . O Using VBG B-VP in FW B-NP vivo FW I-NP genomic JJ I-NP footprinting NN I-NP we PRP B-NP identified VBD B-VP interactions NNS B-NP in IN B-PP B-cell NN B-NP lines NNS I-NP at IN B-PP the DT B-NP octamer NN I-NP site NN I-NP and CC O the DT O Y NN B-NP COMMA COMMA O X1 NN B-NP COMMA COMMA O and CC O X2 NN B-NP boxes NNS B-NP . . O Class NN B-NP II CD I-NP antigen NN I-NP expressing VBG I-NP T-cell NN I-NP lines NNS I-NP maintained VBD B-VP contacts NNS B-NP identical JJ B-ADJP to TO B-PP B-cell NN B-NP lines NNS I-NP COMMA COMMA O while IN B-SBAR class NN B-NP II-negative JJ I-NP T-cell NN I-NP lines NNS I-NP exhibited VBD B-VP no DT B-NP interactions NNS I-NP . . O In IN B-PP lymphoid JJ B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O the DT B-NP octamer NN I-NP site NN I-NP is VBZ B-VP occupied VBN I-VP and CC O required VBN B-VP for IN B-PP maximal JJ B-NP expression NN I-NP . . O This DT B-NP is VBZ B-VP most RBS B-ADVP likely RB I-ADVP due JJ B-PP to TO I-PP the DT B-NP presence NN I-NP of IN B-PP the DT B-NP lymphoid-specific JJ I-NP OTF-2 NN I-NP factor NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP class NN I-NP II-positive JJ I-NP nonlymphoid JJ I-NP glioblastoma NN I-NP cell NN I-NP line NN I-NP does VBZ B-VP not RB I-VP exhibit VB I-VP interactions NNS B-NP at IN B-PP the DT B-NP octamer NN I-NP site NN I-NP despite IN B-PP the DT B-NP presence NN I-NP of IN B-PP the DT B-NP ubiquitous JJ I-NP OTF-1 NN I-NP factor NN I-NP and CC O an DT B-NP open JJ I-NP binding VBG I-NP site NN I-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP DRA NN I-NP promoter NN I-NP discriminates VBZ B-VP against IN B-PP OTF-1 NN B-NP activation NN I-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP DNA NN B-NP binding NN I-NP in IN B-PP the DT B-NP glioblastoma NN I-NP line NN I-NP . . O Interferon NN B-NP gamma NN I-NP induces VBZ B-VP class NN B-NP II CD I-NP expression NN I-NP in IN B-PP this DT B-NP glioblastoma NN I-NP cell NN I-NP line NN I-NP and CC O COMMA COMMA O in IN B-PP parallel NN B-NP COMMA COMMA B-VP up-regulates VBZ I-VP X1 NN B-NP and CC O X2 NN B-NP box NN B-NP protein-DNA JJ I-NP interactions NNS I-NP COMMA COMMA O while IN B-SBAR all DT B-NP other JJ I-NP interactions NNS I-NP remain VBP B-VP unchanged JJ B-ADJP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR interferon NN B-NP gamma NN I-NP functions VBZ B-VP on IN B-PP a DT B-NP poised VBN I-NP promoter NN I-NP by IN B-PP altering VBG B-VP weak JJ B-NP COMMA COMMA I-NP nonproductive JJ I-NP interactions NNS I-NP at IN B-PP the DT B-NP X NN I-NP boxes NNS I-NP to TO B-PP strong JJ B-NP interactions NNS I-NP . . O These DT B-NP findings NNS I-NP provide VBP B-VP direct JJ B-NP in FW I-NP vivo FW I-NP evidence NN I-NP to TO B-VP strongly RB I-VP suggest VB I-VP that IN B-SBAR the DT B-NP modulation NN I-NP of IN B-PP X1 NN B-NP and CC O X2 NN B-NP interactions NNS B-NP is VBZ B-VP an DT B-NP important JJ I-NP constituent NN I-NP of IN B-PP the DT B-NP interferon NN I-NP gamma NN I-NP induction NN I-NP pathway NN I-NP . . O Simple JJ B-NP derivation NN I-NP of IN B-PP TFIID-dependent JJ B-NP RNA NN I-NP polymerase NN I-NP II CD I-NP transcription NN I-NP systems NNS I-NP from IN B-PP Schizosaccharomyces FW B-NP pombe FW I-NP and CC O other JJ B-NP organisms NNS I-NP COMMA COMMA O and CC O factors NNS B-NP required VBN B-VP for IN B-PP transcriptional JJ B-NP activation NN I-NP . . O Resolution NN B-NP of IN B-PP whole JJ B-NP cell NN I-NP extract NN I-NP through IN B-PP two CD B-NP chromatographic JJ I-NP steps NNS I-NP yields VBZ B-VP a DT B-NP single JJ I-NP protein NN I-NP fraction NN I-NP requiring VBG B-VP only RB B-NP the DT I-NP addition NN I-NP of IN B-PP TFIID NN B-NP for IN B-PP the DT B-NP initiation NN I-NP of IN B-PP transcription NN B-NP at IN B-PP RNA NN B-NP polymerase NN I-NP II CD I-NP promoters NNS I-NP . . O This DT B-NP approach NN I-NP allows VBZ B-VP the DT B-NP convenient JJ I-NP generation NN I-NP of IN B-PP RNA NN B-NP polymerase NN I-NP II CD I-NP transcription NN I-NP systems NNS I-NP from IN B-PP Saccharomyces FW B-NP cerevisiae FW I-NP COMMA COMMA O human JJ B-NP lymphocytes NNS I-NP COMMA COMMA O and CC O Schizosaccharomyces FW B-NP pombe FW I-NP . . O TFIIDs NNS B-NP from IN B-PP all DT B-NP three CD I-NP organisms NNS I-NP are VBP B-VP interchangeable JJ B-ADJP among IN B-PP all DT B-NP three CD I-NP systems NNS I-NP . . O The DT O S. FW B-NP cerevisiae FW I-NP and CC O Sch. FW B-NP pombe FW I-NP systems NNS B-NP support VBP B-VP effects NNS B-NP of IN B-PP acidic JJ B-NP activator NN I-NP proteins NNS I-NP COMMA COMMA O provided VBN B-PP a DT B-NP further JJ I-NP protein NN I-NP fraction NN I-NP from IN B-PP S. FW B-NP cerevisiae FW I-NP is VBZ B-VP supplied VBN I-VP . . O This DT B-NP further JJ I-NP fraction NN I-NP is VBZ B-VP distinct JJ B-ADJP from IN B-PP the DT B-NP mediator NN I-NP of IN B-PP transcriptional JJ B-NP activation NN I-NP described VBN B-VP previously RB B-ADVP and CC O represents VBZ B-VP a DT B-NP second JJ I-NP component NN I-NP in IN B-PP addition NN I-PP to TO I-PP general JJ B-NP initiation NN I-NP factors NNS I-NP that WDT B-NP may MD B-VP facilitate VB I-VP a DT B-NP response NN I-NP to TO B-PP acidic JJ B-NP activators NNS I-NP . . O NF-kappa NN B-NP B-dependent JJ I-NP induction NN I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP p50 NN I-NP subunit NN I-NP gene NN I-NP promoter NN I-NP underlies VBZ B-VP self-perpetuation NN B-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP transcription NN I-NP in IN B-PP monocytic JJ B-NP cells NNS I-NP . . O The DT B-NP molecular JJ I-NP mechanisms NNS I-NP underlying VBG B-VP the DT B-NP sustained JJ I-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP observed VBN B-VP in IN B-PP U937 NN B-NP monocytic JJ I-NP cells NNS I-NP chronically RB B-VP infected VBN I-VP with IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O were VBD B-VP studied VBN I-VP . . O The DT B-NP activity NN I-NP of IN B-PP the DT B-NP promoter NN I-NP regulating VBG B-VP the DT B-NP synthesis NN I-NP of IN B-PP the DT B-NP p105 NN I-NP precursor NN I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP p50 NN I-NP subunit NN I-NP was VBD B-VP enhanced VBN I-VP in IN B-PP these DT B-NP cells NNS I-NP . . O Deletions NNS B-NP in IN B-PP this DT B-NP promoter NN I-NP indicated VBD B-VP that IN B-SBAR this DT B-NP upregulation NN I-NP was VBD B-VP mediated VBN I-VP through IN B-PP the DT B-NP NF-kappa NN B-NP B- NN I-NP but CC B-CONJP not RB I-CONJP the DT B-NP AP-1-binding JJ I-NP motif NN B-NP COMMA COMMA O by IN B-PP bona FW B-NP fide FW I-NP p50\/p65 NN I-NP heterodimers NNS I-NP . . O Analysis NN B-NP of IN B-PP cytosolic JJ B-NP extracts NNS I-NP indicated VBD B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP levels NNS I-NP were VBD B-VP increased VBN I-VP in IN B-PP HIV-infected JJ B-NP cells NNS I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP the DT B-NP transient JJ I-NP NF-kappa NN I-NP B NN I-NP activation NN I-NP induced VBN B-VP by IN B-PP phorbol NN B-NP ester NN I-NP COMMA COMMA O the DT B-NP permanent JJ I-NP NF-kappa NN I-NP B NN I-NP translocation NN I-NP induced VBN B-VP by IN B-PP HIV NN B-NP infection NN I-NP was VBD B-VP not RB O dependent JJ B-ADJP on IN B-PP PKC NN B-NP isoenzymes NNS I-NP alpha NN B-NP and CC O beta NN B-NP as IN B-SBAR shown VBN B-VP by IN B-PP the DT B-NP use NN I-NP of IN B-PP a DT B-NP specific JJ I-NP inhibitor NN I-NP ( ( O GF NN B-NP 109203X NN I-NP ) ) O . . O These DT B-NP observations NNS I-NP indicate VBP B-VP that IN B-SBAR during IN B-PP chronic JJ B-NP HIV NN I-NP infection NN I-NP of IN B-PP U937 NN B-NP cells NNS I-NP COMMA COMMA O continuous JJ O NF-kappa NN O B NN O ( ( O p50\/p65 NN B-NP ) ) O translocation NN B-NP results VBZ B-VP in IN B-PP p105 NN B-NP promoter NN I-NP upregulation NN I-NP with IN B-PP subsequent JJ B-NP cytosolic JJ I-NP NF-kappa NN I-NP B NN I-NP accumulation NN I-NP COMMA COMMA O ready JJ B-ADJP for IN B-PP further JJ B-NP translocation NN I-NP . . O This DT B-NP HIV-mediated JJ I-NP mechanism NN I-NP results VBZ B-VP in IN B-PP a DT B-NP self-perpetuating JJ I-NP loop NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP production NN I-NP . . O The DT B-NP development NN I-NP of IN B-PP functionally RB B-NP responsive JJ I-NP T NN I-NP cells NNS I-NP . . O The DT B-NP work NN I-NP reviewed VBN B-VP in IN B-PP this DT B-NP article NN I-NP separates VBZ B-VP T NN B-NP cell NN I-NP development NN I-NP into IN B-PP four CD B-NP phases NNS I-NP . . O First JJ B-ADJP is VBZ B-VP an DT B-NP expansion NN I-NP phase NN I-NP prior RB B-PP to TO I-PP TCR NN B-NP rearrangement NN I-NP COMMA COMMA O which WDT B-NP appears VBZ B-VP to TO I-VP be VB I-VP correlated VBN I-VP with IN B-PP programming NN B-NP of IN B-PP at IN B-NP least JJS I-NP some DT I-NP response NN I-NP genes NNS I-NP for IN B-PP inducibility NN B-NP . . O This DT B-NP phase NN I-NP can MD B-VP occur VB I-VP to TO B-PP some DT B-NP extent NN I-NP outside IN B-ADVP of IN B-PP the DT B-NP thymus NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP profound JJ I-NP T NN I-NP cell NN I-NP deficit NN I-NP of IN B-PP nude JJ B-NP mice NNS I-NP indicates VBZ B-VP that IN B-SBAR the DT B-NP thymus NN I-NP is VBZ B-VP by IN B-PP far RB B-ADVP the DT B-NP most RBS I-NP potent JJ I-NP site NN I-NP for IN B-PP inducing VBG B-VP the DT B-NP expansion NN I-NP per FW B-ADVP se FW I-ADVP COMMA COMMA O even RB B-SBAR if IN I-SBAR other JJ B-NP sites NNS I-NP can MD B-VP induce VB I-VP some DT B-NP response NN I-NP acquisition NN I-NP . . O Second JJ B-ADJP is VBZ B-VP a DT B-NP controlled JJ I-NP phase NN I-NP of IN B-PP TCR NN B-NP gene NN I-NP rearrangement NN I-NP . . O The DT B-NP details NNS I-NP of IN B-PP the DT B-NP regulatory JJ I-NP mechanism NN I-NP that WDT B-NP selects VBZ B-VP particular JJ B-NP loci NNS I-NP for IN B-PP rearrangement NN B-NP are VBP B-VP still RB I-VP not RB I-VP known VBN I-VP . . O It PRP B-NP seems VBZ B-VP that IN B-SBAR the DT B-NP rearrangement NN I-NP of IN B-PP the DT B-NP TCR NN I-NP gamma NN I-NP loci NNS I-NP in IN B-PP the DT B-NP gamma NN I-NP delta NN I-NP lineage NN I-NP may MD B-VP not RB I-VP always RB I-VP take VB I-VP place NN B-NP at IN B-PP a DT B-NP developmental JJ I-NP stage NN I-NP strictly RB B-ADJP equivalent JJ I-ADJP to TO B-PP the DT B-NP rearrangement NN I-NP of IN B-PP TCR NN B-NP beta NN I-NP in IN B-PP the DT B-NP alpha NN I-NP beta NN I-NP lineage NN I-NP COMMA COMMA O and CC O it PRP B-NP is VBZ B-VP not RB O clear JJ B-ADJP just RB B-ADVP how WRB I-ADVP early RB I-ADVP the DT B-NP two CD I-NP lineages NNS I-NP diverge VBP B-VP . . O In IN B-PP the DT B-NP TCR NN I-NP alpha NN I-NP beta NN I-NP lineage NN I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O the DT B-NP final JJ I-NP gene NN I-NP rearrangement NN I-NP events NNS I-NP are VBP B-VP accompanied VBN I-VP by IN B-PP rapid JJ B-NP proliferation NN I-NP and CC O an DT B-NP interruption NN I-NP in IN B-PP cellular JJ B-NP response NN I-NP gene NN I-NP inducibility NN I-NP . . O The DT B-NP loss NN I-NP of IN B-PP conventional JJ B-NP responsiveness NN I-NP is VBZ B-VP probably RB I-VP caused VBN I-VP by IN B-PP alterations NNS B-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP signaling NN B-NP COMMA COMMA O and CC O may MD B-VP be VB I-VP a DT B-NP manifestation NN I-NP of IN B-PP the DT B-NP physiological JJ I-NP state NN I-NP that WDT B-NP is VBZ B-VP a DT B-NP precondition NN I-NP for IN B-PP selection NN B-NP . . O Third JJ B-ADJP is VBZ B-VP the DT B-NP complex JJ I-NP process NN I-NP of IN B-PP selection NN B-NP . . O Whereas IN B-SBAR peripheral JJ B-NP T NN I-NP cells NNS I-NP can MD B-VP undergo VB I-VP forms NNS B-NP of IN B-PP positive JJ B-NP selection NN I-NP ( ( O by IN B-PP antigen-driven JJ B-NP clonal JJ I-NP expansion NN I-NP ) ) O and CC O negative JJ B-NP selection NN I-NP ( ( O by IN B-PP abortive JJ B-NP stimulation NN I-NP leading VBG B-VP to TO B-PP anergy NN B-NP or CC O death NN B-NP ) ) O COMMA COMMA O neither DT B-NP is VBZ B-VP exactly RB B-NP the DT I-NP same JJ I-NP phenomenon NN I-NP that WDT B-NP occurs VBZ B-VP in IN B-PP the DT B-NP thymic JJ I-NP cortex NN I-NP . . O Negative JJ B-NP selection NN I-NP in IN B-PP the DT B-NP cortex NN I-NP appears VBZ B-VP to TO I-VP be VB I-VP a DT B-NP suicidal JJ I-NP inversion NN I-NP of IN B-PP antigen NN B-NP responsiveness NN I-NP : : O instead RB B-PP of IN I-PP turning VBG B-VP on IN B-PRT IL-2 NN B-NP expression NN I-NP COMMA COMMA O the DT B-NP activated VBN I-NP cell NN I-NP destroys VBZ B-VP its PRP$ B-NP own JJ I-NP chromatin NN I-NP . . O The DT B-NP genes NNS I-NP that WDT B-NP need VBP B-VP to TO I-VP be VB I-VP induced VBN I-VP for IN B-PP this DT B-NP response NN I-NP are VBP B-VP not RB I-VP yet RB I-VP identified VBN I-VP COMMA COMMA O but CC O it PRP B-NP is VBZ B-VP unquestionably RB B-ADVP a DT B-NP form NN I-NP of IN B-PP activation NN B-NP . . O It PRP B-NP is VBZ B-VP interesting JJ B-ADJP that IN B-SBAR in IN B-PP humans NNS B-NP and CC O rats NNS B-NP COMMA COMMA O cortical JJ B-NP thymocytes NNS I-NP undergoing VBG B-VP negative JJ B-NP selection NN I-NP can MD B-VP still RB I-VP induce VB I-VP IL-2R NN B-NP alpha NN I-NP expression NN I-NP and CC O even RB B-VP be VB I-VP rescued VBN I-VP in FW B-ADVP vitro FW I-ADVP COMMA COMMA O if IN B-SBAR exogenous JJ B-NP IL-2 NN I-NP is VBZ B-VP provided VBN I-VP . . O Perhaps RB B-ADVP murine JJ B-NP thymocytes NNS I-NP are VBP B-VP denied VBN I-VP this DT B-NP form NN I-NP of IN B-PP rescue NN B-NP because IN B-SBAR they PRP B-NP shut VBD B-VP off RP B-PRT IL-2R NN B-NP beta NN I-NP chain NN I-NP expression NN I-NP at IN B-PP an DT B-NP earlier JJR I-NP stage NN I-NP or CC O because IN B-SBAR they PRP B-NP may MD B-VP be VB I-VP uncommonly RB O Bcl-2 NN B-NP deficient JJ B-ADJP ( ( O cf. VBP B-VP Sentman NNP B-NP et FW I-NP al. FW I-NP COMMA COMMA I-NP 1991 CD I-NP ; : O Strasser NNP B-NP et FW I-NP al. FW I-NP COMMA COMMA I-NP 1991 CD I-NP ) ) O . . O Even RB B-ADVP so RB I-ADVP COMMA COMMA O medullary JJ B-NP thymocytes NNS I-NP remain VBP B-VP at IN B-ADJP least JJS I-ADJP partially RB I-ADJP susceptible JJ I-ADJP to TO B-PP negative JJ B-NP selection NN I-NP even RB B-SBAR as IN I-SBAR they PRP B-NP continue VBP B-VP to TO I-VP mature VB I-VP . . O SRC-related JJ B-NP proto-oncogenes NNS I-NP and CC O transcription NN B-NP factors NNS I-NP in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP : : O modulation NN B-NP by IN B-PP cyclosporin NN B-NP A NN I-NP and CC O FK506 NN B-NP . . O Activation NN B-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP induces VBZ B-VP transcription NN B-NP of IN B-PP genes NNS B-NP encoding VBG B-VP for IN B-PP lymphokines NNS B-NP . . O Interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O gene NN B-NP expression NN I-NP is VBZ B-VP controlled VBN I-VP transcriptionally RB B-ADVP by IN B-PP the DT B-NP cooperative JJ I-NP activity NN I-NP of IN B-PP specific JJ B-NP trans-activating JJ I-NP factors NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP IL-2 NN I-NP enhancer NN I-NP . . O Cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O FK506 NN B-NP inhibit VBP B-VP the DT B-NP production NN I-NP of IN B-PP IL-2 NN B-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP gene NN B-NP transcription NN I-NP . . O A DT B-NP member NN I-NP of IN B-PP the DT B-NP src NN I-NP gene NN I-NP family NN I-NP COMMA COMMA O the DT B-NP lymphocyte-specific JJ I-NP protein NN I-NP tyrosine NN I-NP kinase NN I-NP COMMA COMMA O p56lck NN B-NP COMMA COMMA O has VBZ B-VP been VBN I-VP implicated VBN I-VP in IN B-PP IL-2 NN B-NP production NN I-NP . . O CsA NN B-NP was VBD B-VP found VBN I-VP not RB I-VP to TO I-VP inhibit VB I-VP lck NN B-NP gene NN I-NP expression NN I-NP COMMA COMMA O nor CC O the DT B-NP activity NN I-NP of IN B-PP the DT B-NP lck NN I-NP gene NN I-NP product NN I-NP . . O However RB B-ADVP COMMA COMMA O CsA NN B-NP and CC O FK506 NN B-NP inhibit VBP B-VP the DT B-NP appearance NN I-NP of IN B-PP DNA NN B-NP binding NN I-NP activity NN I-NP of IN B-PP factors NNS B-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT O NF-AT NN B-NP and CC O AP-1 NN B-NP sites NNS B-NP in IN B-PP the DT B-NP IL-2 NN I-NP enhancer NN I-NP . . O Since IN B-SBAR the DT B-NP induction NN I-NP of IN B-PP NF-AT NN B-NP and CC O AP-1 NN B-NP is VBZ B-VP induced VBN I-VP by IN B-PP the DT B-NP same JJ I-NP stimuli NNS I-NP that WDT B-NP stimulate VBP B-VP IL-2 NN B-NP production NN I-NP COMMA COMMA O these DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP immunosuppressant JJ I-NP action NN I-NP of IN B-PP CsA NN B-NP and CC O FK506 NN B-NP is VBZ B-VP exerted VBN I-VP at IN B-PP the DT B-NP level NN I-NP of IN B-PP these DT B-NP trans-activating JJ I-NP factors NNS I-NP . . O TAR-independent JJ B-NP transactivation NN I-NP by IN B-PP Tat NN B-NP in IN B-PP cells NNS B-NP derived VBN B-VP from IN B-PP the DT B-NP CNS NN I-NP : : O a DT B-NP novel JJ I-NP mechanism NN I-NP of IN B-PP HIV-1 NN B-NP gene NN I-NP regulation NN I-NP . . O The DT B-NP Tat NN I-NP protein NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O is VBZ B-VP essential JJ B-ADJP for IN B-PP productive JJ B-NP infection NN I-NP and CC O is VBZ B-VP a DT B-NP potential JJ I-NP target NN I-NP for IN B-PP antiviral JJ B-NP therapy NN I-NP . . O Tat NN B-NP COMMA COMMA O a DT B-NP potent JJ I-NP activator NN I-NP of IN B-PP HIV-1 NN B-NP gene NN I-NP expression NN I-NP COMMA COMMA O serves VBZ B-VP to TO I-VP greatly RB I-VP increase VB I-VP the DT B-NP rate NN I-NP of IN B-PP transcription NN B-NP directed VBN B-VP by IN B-PP the DT B-NP viral JJ I-NP promoter NN I-NP . . O This DT B-NP induction NN I-NP COMMA COMMA O which WDT B-NP seems VBZ B-VP to TO I-VP be VB I-VP an DT B-NP important JJ I-NP component NN I-NP in IN B-PP the DT B-NP progression NN I-NP of IN B-PP acquired VBN B-NP immune JJ I-NP deficiency NN I-NP syndrome NN I-NP ( ( O AIDS NN B-NP ) ) O COMMA COMMA O may MD B-VP be VB I-VP due JJ B-PP to TO I-PP increased VBN B-NP transcriptional JJ I-NP initiation NN I-NP COMMA COMMA O increased VBN B-NP transcriptional JJ I-NP elongation NN I-NP COMMA COMMA O or CC O a DT B-NP combination NN I-NP of IN B-PP these DT B-NP processes NNS I-NP . . O Much JJ B-NP attention NN I-NP has VBZ B-VP been VBN I-VP focused VBN I-VP on IN B-PP the DT B-NP interaction NN I-NP of IN B-PP Tat NN B-NP with IN B-PP a DT B-NP specific JJ I-NP RNA NN I-NP target NN I-NP termed VBN B-VP TAR NN B-NP ( ( O transactivation NN B-NP responsive NN I-NP ) ) O which WDT B-NP is VBZ B-VP present JJ B-ADJP in IN B-PP the DT B-NP leader NN I-NP sequence NN I-NP of IN B-PP all DT B-NP HIV-1 NN I-NP mRNAs NNS I-NP . . O This DT B-NP interaction NN I-NP is VBZ B-VP believed VBN I-VP to TO I-VP be VB I-VP an DT B-NP important JJ I-NP component NN I-NP of IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP transactivation NN B-NP . . O In IN B-PP this DT B-NP report NN I-NP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR in IN B-PP certain JJ B-NP CNS-derived JJ I-NP cells NNS I-NP Tat NN B-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP activating VBG B-VP HIV-1 NN B-NP through IN B-PP a DT B-NP TAR-independent JJ I-NP pathway NN I-NP . . O A DT B-NP Tat-responsive JJ I-NP element NN I-NP is VBZ B-VP found VBN I-VP upstream RB B-ADVP within IN B-PP the DT B-NP viral JJ I-NP promoter NN I-NP that WDT B-NP in IN B-PP glial-derived JJ B-NP cell NN I-NP lines NNS I-NP allows VBZ B-VP transactivation NN B-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP TAR NN B-NP . . O Deletion NN B-NP mapping NN I-NP and CC O hybrid NN B-NP promoter NN I-NP constructs NNS I-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP newly RB I-NP identified VBN I-NP Tat-responsive JJ I-NP element NN I-NP corresponds VBZ B-VP to TO B-PP a DT B-NP sequence NN I-NP within IN B-PP the DT B-NP viral JJ I-NP long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O previously RB B-VP identified VBN I-VP as IN B-PP the DT B-NP HIV-1 NN I-NP enhancer NN I-NP COMMA COMMA O or CC O NF-kappa NN B-NP B NN I-NP domain NN I-NP . . O DNA NN B-NP band-shift JJ I-NP analysis NN I-NP reveals VBZ B-VP NF-kappa NN B-NP B NN I-NP binding NN I-NP activity NN I-NP in IN B-PP glial JJ B-NP cells NNS I-NP that WDT B-NP differs VBZ B-VP from IN B-PP that DT B-NP present JJ B-ADJP in IN B-PP T NN B-NP lymphoid JJ I-NP cells NNS I-NP . . O Further RB B-ADVP COMMA COMMA O we PRP B-NP observe VBP B-VP that IN B-SBAR TAR-deleted JJ B-NP mutants NNS I-NP of IN B-PP HIV-1 NN B-NP demonstrate VBP B-VP normal JJ B-NP late JJ I-NP gene NN I-NP expression NN I-NP in IN B-PP glial JJ B-NP cells NNS I-NP as IN B-SBAR evidenced VBN B-VP by IN B-PP syncytia NN B-NP formation NN B-NP and CC O production NN B-NP of IN B-PP viral JJ B-NP p24 NN I-NP antigen NN I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Bcl-2 NN B-NP : : O a DT B-NP repressor NN I-NP of IN B-PP lymphocyte NN B-NP death NN I-NP . . O The DT B-NP genes NNS B-NP and CC O mechanisms NNS B-NP that WDT B-NP control VBP B-VP programmed VBN B-NP cell NN I-NP death NN I-NP are VBP B-VP currently RB B-ADVP the DT B-NP subject NN I-NP of IN B-PP intense JJ B-NP study NN I-NP . . O The DT B-NP bcl-2 NN I-NP gene NN I-NP COMMA COMMA O a DT B-NP repressor NN I-NP of IN B-PP lymphocyte NN B-NP death NN I-NP COMMA COMMA O is VBZ B-VP perhaps RB B-ADVP the DT B-NP best JJS I-NP understood VBN I-NP of IN B-PP the DT O programmed VBN B-NP cell NN I-NP death NN I-NP associated JJ B-NP genes NNS I-NP . . O Here RB B-ADVP COMMA COMMA O Stanley NNP B-NP Korsmeyer NNP I-NP provides VBZ B-VP a DT B-NP brief JJ I-NP overview NN I-NP of IN B-PP bcl-2 NN B-NP COMMA COMMA O concentrating VBG B-VP on IN B-PP its PRP$ B-NP roles NNS I-NP in IN B-PP B- NN B-NP and CC O T-cell NN B-NP development NN B-NP and CC B-PP in IN B-PP oncogenesis NN B-NP . . O Mitogen NN B-NP stimulation NN I-NP of IN B-PP T-cells NNS B-NP increases VBZ B-VP c-Fos NN B-NP and CC O c-Jun NN B-NP protein NN B-NP levels NNS I-NP COMMA COMMA O AP-1 NN B-NP binding NN I-NP and CC O AP-1 NN B-NP transcriptional JJ I-NP activity NN I-NP . . O We PRP B-NP have VBP B-VP analysed VBN I-VP the DT B-NP effect NN I-NP of IN B-PP mitogenic JJ B-NP lectins NNS I-NP on IN B-PP c-Fos NN B-NP and CC O c-Jun NN B-NP protein NN B-NP levels NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP on IN B-PP activator NN B-NP protein-1 NN I-NP ( ( O AP-1 NN B-NP ) ) O binding NN B-NP and CC O enhancer NN B-NP activity NN I-NP in IN B-PP Jurkat NN B-NP T-cells NNS I-NP . . O Both CC O c-Fos NN B-NP and CC O c-Jun NN B-NP protein NN B-NP levels NNS I-NP were VBD B-VP increased VBN I-VP after IN B-PP Con NN B-NP A NN I-NP and CC O PHA NN B-NP stimulation NN B-NP . . O Since IN B-SBAR T-cell NN B-NP stimulation NN I-NP increases VBZ B-VP both CC O intracellular JJ O Ca2+ NN B-NP and CC O cAMP NN B-NP levels NNS B-NP and CC O activates VBZ B-VP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O COMMA COMMA O the DT B-NP possible JJ I-NP involvement NN I-NP of IN B-PP these DT B-NP intracellular JJ I-NP messengers NNS I-NP in IN B-PP c-Fos NN B-NP and CC O c-Jun NN B-NP induction NN B-NP was VBD B-VP tested VBN I-VP . . O PMA NN B-NP COMMA COMMA O which WDT B-NP directly RB B-ADVP activates VBZ B-VP PKC NN B-NP COMMA COMMA O mimicked VBD B-VP the DT B-NP effect NN I-NP of IN B-PP the DT B-NP lectins NNS I-NP on IN B-PP c-Fos NN B-NP and CC O c-Jun NN B-NP COMMA COMMA O but CC O elevation NN B-NP of IN B-PP either CC O intracellular JJ O Ca2+ NN B-NP or CC O cAMP NN B-NP levels NNS B-NP had VBD B-VP little JJ B-NP or CC I-NP no DT I-NP effect NN I-NP . . O The DT B-NP mitogen-induced JJ I-NP increase NN I-NP of IN B-PP c-Fos NN B-NP and CC O c-Jun NN B-NP immunoreactivity NN B-NP was VBD B-VP inhibited VBN I-VP by IN B-PP H-7 NN B-NP COMMA COMMA O a DT B-NP kinase NN I-NP inhibitor NN I-NP with IN B-PP relatively RB B-NP high JJ I-NP specificity NN I-NP for IN B-PP PKC NN B-NP COMMA COMMA O and CC O less RBR B-ADVP efficiently RB I-ADVP by IN B-PP H-8 NN B-NP COMMA COMMA O a DT B-NP structurally RB I-NP related JJ I-NP kinase NN I-NP inhibitor NN I-NP less RBR B-ADJP active JJ I-ADJP on IN B-PP PKC NN B-NP COMMA COMMA O but CC O more RBR B-ADJP active JJ I-ADJP on IN B-PP cyclic JJ B-NP nucleotide-dependent JJ I-NP kinases NNS I-NP . . O Con NN B-NP A NN I-NP stimulation NN I-NP was VBD B-VP found VBN I-VP to TO I-VP increase VB I-VP both CC O binding NN B-NP of IN B-PP AP-1 NN B-NP to TO B-PP the DT B-NP AP-1 NN I-NP consensus NN I-NP sequence NN I-NP COMMA COMMA O TRE NN B-NP COMMA COMMA O and CC O AP-1 NN B-NP enhancer NN I-NP activity NN I-NP COMMA COMMA O in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O PMA NN B-NP was VBD B-VP also RB I-VP found VBN I-VP to TO I-VP increase VB I-VP the DT B-NP AP-1 NN I-NP enhancer NN I-NP activity NN I-NP COMMA COMMA O whereas IN O elevation NN B-NP of IN B-PP Ca2+ NN B-NP or CC O cAMP NN B-NP had VBD B-VP only RB B-NP minor JJ I-NP effects NNS I-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR stimulation NN B-NP with IN B-PP mitogenic JJ B-NP lectins NNS I-NP is VBZ B-VP sufficient JJ B-ADJP to TO B-VP increase VB I-VP both CC O c-Fos NN B-NP and CC O c-Jun NN B-NP protein NN B-NP levels NNS I-NP COMMA COMMA O AP-1 NN B-NP binding NN I-NP and CC O AP-1 NN B-NP enhancer NN I-NP activity NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP and CC O that IN B-SBAR they PRP B-NP act VBP B-VP via IN B-PP mechanisms NNS B-NP that WDT B-NP could MD B-VP involve VB I-VP the DT B-NP activation NN I-NP of IN B-PP PKC NN B-NP . . O Functional JJ B-NP interaction NN I-NP between IN B-PP the DT B-NP two CD I-NP zinc NN I-NP finger NN I-NP domains NNS I-NP of IN B-PP the DT B-NP v-erb NN I-NP A NN I-NP oncoprotein NN I-NP . . O The DT B-NP v-erb NN I-NP A NN I-NP oncogene NN I-NP of IN B-PP avian JJ B-NP erythroblastosis NN I-NP virus NN I-NP is VBZ B-VP a DT B-NP mutated VBN I-NP and CC I-NP virally RB I-NP transduced VBN I-NP copy NN I-NP of IN B-PP a DT B-NP host NN I-NP cell NN I-NP gene NN I-NP encoding VBG B-VP a DT B-NP thyroid NN I-NP hormone NN I-NP receptor NN I-NP . . O The DT B-NP protein NN I-NP expressed VBN B-VP by IN B-PP the DT B-NP v-erb NN I-NP A NN I-NP oncogene NN I-NP binds VBZ B-VP to TO B-PP DNA NN B-NP and CC O acts VBZ B-VP as IN B-PP a DT B-NP dominant JJ I-NP negative JJ I-NP inhibitor NN I-NP of IN B-PP both CC O the DT B-NP thyroid NN I-NP hormone NN I-NP receptor NN I-NP and CC O the DT B-NP closely RB I-NP related JJ I-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP . . O The DT B-NP v-erb NN I-NP A NN I-NP protein NN I-NP has VBZ B-VP sustained VBN I-VP two CD B-NP amino NN I-NP acid NN I-NP alterations NNS I-NP within IN B-PP its PRP$ B-NP DNA-binding JJ I-NP domain NN I-NP relative JJ B-PP to TO I-PP that DT B-NP of IN B-PP c-erb NN B-NP A NN I-NP COMMA COMMA O one CD B-NP of IN B-PP which WDT B-NP COMMA COMMA O at IN B-PP serine NN B-NP 61 CD I-NP COMMA COMMA O is VBZ B-VP known VBN I-VP to TO I-VP be VB I-VP important JJ B-ADJP for IN B-PP v-erb NN B-NP A NN I-NP function NN I-NP in IN B-PP the DT B-NP neoplastic JJ I-NP cell NN I-NP . . O We PRP B-NP report VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP second JJ I-NP alteration NN I-NP COMMA COMMA O at IN B-PP threonine NN B-NP 78 CD I-NP COMMA COMMA O also RB B-ADVP plays VBZ B-VP an DT B-NP important JJ I-NP COMMA COMMA I-NP although IN I-NP more RBR I-NP indirect JJ I-NP COMMA COMMA I-NP role NN I-NP : : O alteration NN B-NP of IN B-PP the DT B-NP sequence NN I-NP at IN B-PP threonine NN B-NP 78 CD I-NP such JJ B-SBAR that IN I-SBAR it PRP B-NP resembles VBZ B-VP that DT B-NP of IN B-PP c-erb NN B-NP A NN I-NP can MD B-VP act VB I-VP as IN B-PP an DT B-NP intragenic JJ I-NP suppressor NN I-NP and CC O can MD B-VP partially RB I-VP restore VB I-VP function NN B-NP to TO B-PP a DT B-NP v-erb NN I-NP A NN I-NP protein NN I-NP rendered VBN B-VP defective JJ B-ADJP due JJ B-PP to TO I-PP a DT B-NP mutation NN I-NP at IN B-PP position NN B-NP 61 CD I-NP . . O Threonine NN B-NP 78 CD I-NP lies VBZ B-VP within IN B-PP the DT B-NP D-box NN I-NP of IN B-PP the DT B-NP v-erb NN I-NP A NN I-NP protein NN I-NP COMMA COMMA O a DT B-NP region NN I-NP thought VBN B-VP to TO I-VP mediate VB I-VP receptor-receptor JJ B-NP dimerizations NNS I-NP COMMA COMMA O and CC O is VBZ B-VP not RB O in IN B-PP physical JJ B-NP proximity NN I-NP to TO B-PP the DT B-NP serine NN I-NP at IN B-PP position NN B-NP 61 CD I-NP . . O It PRP B-NP therefore RB B-ADVP appears VBZ B-VP that IN B-SBAR an DT B-NP indirect JJ I-NP interaction NN I-NP occurs VBZ B-VP between IN B-PP these DT B-NP two CD I-NP sites NNS I-NP and CC O that IN B-SBAR this DT B-NP interaction NN I-NP is VBZ B-VP crucial JJ B-ADJP for IN B-PP v-erb NN B-NP A NN I-NP function NN I-NP . . O Pax-5 NN B-NP encodes VBZ B-VP the DT B-NP transcription NN I-NP factor NN I-NP BSAP NN I-NP and CC O is VBZ B-VP expressed VBN I-VP in IN B-PP B NN B-NP lymphocytes NNS I-NP COMMA COMMA O the DT B-NP developing VBG I-NP CNS NNS I-NP COMMA COMMA O and CC O adult JJ B-NP testis NN I-NP . . O BSAP NN B-NP has VBZ B-VP been VBN I-VP identified VBN I-VP previously RB B-ADVP as IN B-PP a DT B-NP transcription NN I-NP factor NN I-NP that WDT B-NP is VBZ B-VP expressed VBN I-VP at IN B-PP early JJ B-NP COMMA COMMA I-NP but CC I-NP not RB I-NP late JJ I-NP COMMA COMMA I-NP stages NNS I-NP of IN B-PP B-cell NN B-NP differentiation NN I-NP . . O Biochemical JJ B-NP purification NN I-NP and CC O cDNA NN B-NP cloning NN I-NP has VBZ B-VP now RB I-VP revealed VBN I-VP that IN B-SBAR BSAP NN B-NP belongs VBZ B-VP to TO B-PP the DT B-NP family NN I-NP of IN B-PP paired JJ B-NP domain NN I-NP proteins NNS I-NP . . O BSAP NN B-NP is VBZ B-VP encoded VBN I-VP by IN B-PP the DT B-NP Pax-5 NN I-NP gene NN I-NP and CC O has VBZ B-VP been VBN I-VP highly RB I-VP conserved VBN I-VP between IN B-PP human JJ B-NP and CC O mouse NN B-NP . . O An DT B-NP intact JJ I-NP paired JJ I-NP domain NN I-NP was VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP both CC O necessary JJ B-ADJP and CC O sufficient JJ B-ADJP for IN B-PP DNA NN B-NP binding NN I-NP of IN B-PP BSAP NN B-NP . . O Binding VBG B-NP studies NNS I-NP with IN B-PP several JJ B-NP BSAP NN I-NP recognition NN I-NP sequences NNS I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP sequence NN I-NP specificity NN I-NP of IN B-PP BSAP NN B-NP differs VBZ B-VP from IN B-PP that DT B-NP of IN B-PP the DT B-NP distantly RB I-NP related JJ I-NP paired JJ I-NP domain NN I-NP protein NN I-NP Pax-1 NN I-NP . . O During IN B-PP embryogenesis NN B-NP COMMA COMMA O the DT B-NP BSAP NN I-NP gene NN I-NP is VBZ B-VP transiently RB I-VP expressed VBN I-VP in IN B-PP the DT B-NP mesencephalon NN B-NP and CC O spinal JJ B-NP cord NN I-NP with IN B-PP a DT B-NP spatial JJ I-NP and CC I-NP temporal JJ I-NP expression NN I-NP pattern NN I-NP that WDT B-NP is VBZ B-VP distinct JJ B-ADJP from IN B-PP that DT B-NP of IN B-PP other JJ B-NP Pax NN I-NP genes NNS I-NP in IN B-PP the DT B-NP developing VBG I-NP central JJ B-NP nervous JJ I-NP system NN I-NP ( ( O CNS NN B-NP ) ) O . . O Later RB B-ADVP COMMA COMMA O the DT B-NP expression NN I-NP of IN B-PP the DT B-NP BSAP NN I-NP gene NN I-NP shifts VBZ B-VP to TO B-PP the DT B-NP fetal JJ I-NP liver NN I-NP where WRB B-ADVP it PRP B-NP correlates VBZ B-VP with IN B-PP the DT B-NP onset NN I-NP of IN B-PP B NN B-NP lymphopoiesis NN I-NP . . O BSAP NN B-NP expression NN I-NP persists VBZ B-VP in IN B-PP B NN B-NP lymphocytes NNS I-NP and CC O is VBZ B-VP also RB I-VP seen VBN I-VP in IN B-PP the DT B-NP testis NN I-NP of IN B-PP the DT B-NP adult JJ I-NP mouse NN I-NP . . O All DT B-NP of IN B-PP this DT B-NP evidence NN I-NP indicates VBZ B-VP that IN B-SBAR the DT B-NP transcription NN I-NP factor NN I-NP BSAP NN I-NP may MD B-VP not RB B-CONJP only RB I-CONJP play VB B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP B-cell NN B-NP differentiation NN I-NP but CC B-CONJP also RB I-CONJP in IN B-PP neural JJ B-NP development NN I-NP and CC O spermatogenesis NN B-NP . . O Okadaic JJ B-NP acid NN I-NP is VBZ B-VP a DT B-NP potent JJ I-NP inducer NN I-NP of IN B-PP AP-1 NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP COMMA COMMA O and CC O tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP in IN B-PP human JJ B-NP B NN I-NP lymphocytes NNS I-NP . . O Treatment NN B-NP of IN B-PP human JJ B-NP B NN I-NP lymphocytes NNS I-NP with IN B-PP an DT B-NP optimal JJ I-NP concentration NN I-NP of IN B-PP okadaic JJ B-NP acid NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP phosphatases NNS B-NP 1 CD B-NP and CC O 2A NN B-NP COMMA COMMA O resulted VBD B-VP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O AP-1 NN B-NP and CC O a DT B-NP marked JJ I-NP increase NN I-NP in IN B-PP NF-kappa NN B-NP B NN I-NP levels NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O no DT B-NP effect NN I-NP on IN B-PP the DT B-NP levels NNS I-NP of IN B-PP the DT B-NP octamer NN I-NP binding NN I-NP proteins NNS I-NP COMMA COMMA O Oct-1 NN B-NP or CC O Oct-2 NN B-NP COMMA COMMA O were VBD B-VP found VBN I-VP . . O Since IN B-SBAR both CC O AP-1 NN B-NP and CC O NF-kappa NN B-NP B NN I-NP have VBP B-VP been VBN I-VP reported VBN I-VP to TO I-VP be VB I-VP important JJ B-ADJP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP the DT O tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O gene NN B-NP we PRP B-NP examined VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP okadaic JJ B-NP acid NN I-NP on IN B-PP TNF-alpha NN B-NP mRNA NN I-NP levels NNS I-NP . . O Treatment NN B-NP with IN B-PP okadaic JJ B-NP acid NN I-NP resulted VBD B-VP in IN B-PP a DT B-NP striking JJ I-NP increase NN I-NP in IN B-PP TNF-alpha NN B-NP mRNA NN I-NP transcripts NNS I-NP within IN B-PP 1 CD B-NP h NN I-NP of IN B-PP stimulation NN B-NP and CC O large JJ B-NP amounts NNS I-NP of IN B-PP TNF-alpha NN B-NP were VBD B-VP released VBN I-VP into IN B-PP the DT B-NP culture NN I-NP media NNS I-NP . . O Although IN B-SBAR okadaic JJ B-NP acid NN I-NP provides VBZ B-VP a DT B-NP potent JJ I-NP inductive JJ I-NP signal NN I-NP for IN B-PP AP-1 NN B-NP and CC O NF-kappa NN B-NP B NN I-NP it PRP B-NP did VBD B-VP not RB I-VP induce VB I-VP either CC O B NN B-NP cell NN I-NP proliferation NN I-NP or CC O immunoglobulin NN B-NP secretion NN I-NP . . O A DT B-NP novel JJ I-NP Ets-related JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O Elf-1 NN B-NP COMMA COMMA O binds VBZ B-VP to TO B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 2 CD I-NP regulatory JJ I-NP elements NNS I-NP that WDT B-NP are VBP B-VP required VBN I-VP for IN B-PP inducible JJ B-NP trans JJ I-NP activation NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O Human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O and CC O HIV-2 NN B-NP are VBP B-VP structurally RB B-NP related JJ I-NP retroviruses NNS I-NP which WDT B-NP both DT O cause VBP B-VP AIDS NN B-NP in IN B-PP humans NNS B-NP . . O Although IN B-SBAR both DT B-NP viruses NNS I-NP establish VBP B-VP latency NN B-NP in IN B-PP quiescent JJ B-NP human-peripheral-blood JJ I-NP T NN I-NP cells NNS I-NP COMMA COMMA O the DT B-NP asymptomatic JJ I-NP phase NN I-NP of IN B-PP HIV-2 NN B-NP infection NN I-NP may MD B-VP be VB I-VP more JJR B-ADJP prolonged JJ I-ADJP than IN B-PP that DT B-NP of IN B-PP HIV-1 NN B-NP . . O The DT B-NP latent JJ I-NP phases NNS I-NP of IN B-PP both CC O HIV-1 NN B-NP and CC O HIV-2 NN B-NP infection NN B-NP have VBP B-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP disrupted VBN I-VP by IN B-PP T-cell NN B-NP activation NN I-NP COMMA COMMA O a DT B-NP process NN I-NP that WDT B-NP requires VBZ B-VP host NN B-NP cell NN I-NP transcription NN I-NP factors NNS I-NP . . O In IN B-PP the DT B-NP case NN I-NP of IN B-PP HIV-1 NN B-NP COMMA COMMA O the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP is VBZ B-VP sufficient JJ B-ADJP for IN B-PP inducible JJ B-NP transcriptional JJ I-NP activation NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O factors NNS B-NP in IN B-PP addition NN I-PP to TO I-PP NF-kappa NN B-NP B NN I-NP are VBP B-VP required VBN I-VP to TO I-VP activate VB I-VP HIV-2 NN B-NP transcription NN I-NP in IN B-PP infected JJ B-NP T NN I-NP cells NNS I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR a DT B-NP novel JJ I-NP Ets-related JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O Elf-1 NN B-NP COMMA COMMA O binds VBZ B-VP specifically RB B-ADVP to TO B-PP two CD B-NP purine-rich JJ I-NP motifs NNS I-NP in IN B-PP the DT B-NP HIV-2 NN I-NP enhancer NN I-NP . . O Mutagenesis NN B-NP experiments NNS I-NP demonstrated VBD B-VP that IN B-SBAR these DT B-NP Elf-1 NN I-NP binding NN I-NP sites NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP induction NN B-NP of IN B-PP HIV-2 NN B-NP transcription NN I-NP following VBG B-PP T-cell-receptor-mediated JJ B-NP T-cell NN I-NP activation NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O Elf-1 NN B-NP is VBZ B-VP the DT B-NP only JJ I-NP factor NN I-NP present JJ B-ADJP in IN B-PP activated VBN B-NP T-cell NN I-NP nuclear JJ I-NP extracts NNS I-NP that WDT B-NP binds VBZ B-VP to TO B-PP these DT B-NP sites NNS I-NP in IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O Elf-1 NN B-NP is VBZ B-VP a DT B-NP novel JJ I-NP transcription NN I-NP factor NN I-NP that WDT B-NP appears VBZ B-VP to TO I-VP be VB I-VP required VBN I-VP for IN B-PP the DT B-NP T-cell-receptor-mediated JJ I-NP trans JJ I-NP activation NN I-NP of IN B-PP HIV-2 NN B-NP gene NN I-NP expression NN I-NP . . O These DT B-NP results NNS I-NP may MD B-VP explain VB I-VP differences NNS B-NP in IN B-PP the DT B-NP clinical JJ I-NP spectra NNS I-NP of IN B-PP diseases NNS B-NP caused VBN B-VP by IN B-PP HIV-1 NN B-NP and CC O HIV-2 NN B-NP and CC O may MD B-VP also RB I-VP have VB I-VP implications NNS B-NP for IN B-PP the DT B-NP design NN I-NP of IN B-PP therapeutic JJ B-NP approaches NNS I-NP to TO B-PP HIV-2 NN B-NP infection NN I-NP . . O Human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP Nef NN I-NP protein NN I-NP inhibits VBZ B-VP NF-kappa NN B-NP B NN I-NP induction NN I-NP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP . . O Human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O can MD B-VP establish VB I-VP a DT B-NP persistent JJ I-NP and CC I-NP latent JJ I-NP infection NN I-NP in IN B-PP CD4+ JJ B-NP T NN I-NP lymphocytes NNS I-NP ( ( O W.C.Greene NNP B-NP COMMA COMMA O N.Engl.J. NNP B-NP Med.324 NNP I-NP : : I-NP 308-317 CD I-NP COMMA COMMA O 1991 CD B-NP ; : O S.M.Schnittman NNP B-NP COMMA COMMA O M.C.Psallidopoulos NNP B-NP COMMA COMMA O H.C. NNP B-NP Lane NNP I-NP COMMA COMMA O L.Thompson NNP B-NP COMMA COMMA O M.Baseler NNP B-NP COMMA COMMA O F.Massari NNP B-NP COMMA COMMA O C.H.Fox NNP B-NP COMMA COMMA O N.P.Salzman NNP B-NP COMMA COMMA O and CC O A.S.Fauci NNP B-NP COMMA COMMA O Science NNP B-NP 245 CD I-NP : : I-NP 305-308 CD I-NP COMMA COMMA O 1989 CD B-NP ) ) O . . O Production NN B-NP of IN B-PP HIV-1 NN B-NP from IN B-PP latently RB B-NP infected JJ I-NP cells NNS I-NP requires VBZ B-VP host NN B-NP cell NN I-NP activation NN I-NP by IN B-PP T-cell NN B-NP mitogens NNS I-NP ( ( O T.Folks NNP B-NP COMMA COMMA O D.M.Powell NNP B-NP COMMA COMMA O M.M.Lightfoote NNP B-NP COMMA COMMA O S.Benn NNP B-NP COMMA COMMA O M.A. NNP B-NP Martin NNP I-NP COMMA COMMA O and CC O A.S.Fauci NNP B-NP COMMA COMMA O Science NNP B-NP 231 CD I-NP : : I-NP 600-602 CD I-NP COMMA COMMA O 1986 CD B-NP ; : O D.Zagury NNP B-NP COMMA COMMA O J. NNP B-NP Bernard NNP I-NP COMMA COMMA O R.Leonard NNP B-NP COMMA COMMA O R.Cheynier NNP B-NP COMMA COMMA O M.Feldman NNP B-NP COMMA COMMA O P.S.Sarin NNP B-NP COMMA COMMA O and CC O R.C. NNP B-NP Gallo NNP I-NP COMMA COMMA O Science NNP B-NP 231 CD I-NP : : I-NP 850-853 CD I-NP COMMA COMMA O 1986 CD B-NP ) ) O . . O This DT B-NP activation NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP the DT B-NP host NN I-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP { ( O G.Nabel NNP B-NP and CC O D.Baltimore NNP B-NP COMMA COMMA O Nature NNP B-NP ( ( I-NP London NNP I-NP ) ) I-NP 326 CD I-NP : : I-NP 711-717 CD I-NP COMMA COMMA O 1987 CD B-NP } ) O . . O We PRP B-NP report VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP HIV-1-encoded JJ I-NP Nef NN I-NP protein NN I-NP inhibits VBZ B-VP the DT B-NP induction NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP DNA-binding JJ I-NP activity NN I-NP by IN B-PP T-cell NN B-NP mitogens NNS I-NP . . O However RB B-ADVP COMMA COMMA O Nef NN B-NP does VBZ B-VP not RB I-VP affect VB I-VP the DT B-NP DNA-binding JJ I-NP activity NN I-NP of IN B-PP other JJ B-NP transcription NN I-NP factors NNS I-NP implicated VBN B-VP in IN B-PP HIV-1 NN B-NP regulation NN I-NP COMMA COMMA O including VBG B-PP SP-1 NN B-NP COMMA COMMA O USF NN B-NP COMMA COMMA O URS NN B-NP COMMA COMMA O and CC O NF-AT NN B-NP . . O Additionally RB B-ADVP COMMA COMMA O Nef NN B-NP inhibits VBZ B-VP the DT B-NP induction NN I-NP of IN B-PP HIV-1- NN B-NP and CC O interleukin NN B-ADJP 2-directed JJ I-ADJP gene NN B-NP expression NN I-NP COMMA COMMA O and CC O the DT B-NP effect NN I-NP on IN B-PP HIV-1 NN B-NP transcription NN I-NP depends VBZ B-VP on IN B-PP an DT B-NP intact JJ I-NP NF-kappa NN I-NP B-binding JJ I-NP site NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR defective JJ B-NP recruitment NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP may MD B-VP underlie VB I-VP Nef NN B-NP 's POS B-NP negative JJ I-NP transcriptional JJ I-NP effects NNS I-NP on IN B-PP the DT O HIV-1 NN B-NP and CC O interleukin NN B-NP 2 CD I-NP promoters NNS B-NP . . O Further JJ B-NP evidence NN I-NP suggests VBZ B-VP that IN B-SBAR Nef NN B-NP inhibits VBZ B-VP NF-kappa NN B-NP B NN I-NP induction NN I-NP by IN B-PP interfering VBG B-VP with IN B-PP a DT B-NP signal NN I-NP derived VBN B-VP from IN B-PP the DT B-NP T-cell NN I-NP receptor NN I-NP complex NN I-NP . . O { ( O Effect NN B-NP of IN B-PP antihypertensive JJ B-NP therapy NN I-NP with IN B-PP captopril NN B-NP on IN B-PP gluco- JJ B-NP and CC O mineralocorticoid NN B-NP receptors NNS B-NP of IN B-PP peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP in IN B-PP hypertensive JJ B-NP patients NNS I-NP of IN B-PP various JJ B-NP age NN I-NP } ) O Binding NN B-NP of IN B-PP 3H-dexamethasone NN B-NP and CC O 3H-aldosterone NN B-NP by IN B-PP peripheral JJ B-NP lymphocyte NN I-NP receptors NNS I-NP was VBD B-VP investigated VBN I-VP in IN B-PP healthy JJ B-NP persons NNS I-NP and CC O hypertensive JJ B-NP patients NNS I-NP before IN B-PP and CC B-PP after IN B-PP 2-week JJ B-NP captopril NN I-NP treatment NN I-NP . . O The DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP and CC O mineralocorticoid NN B-NP binding NN B-NP sites NNS I-NP was VBD B-VP increased VBN I-VP in IN B-PP hypertensives NNS B-NP vs CC O normotensives NNS B-NP . . O The DT B-NP treatment NN I-NP with IN B-PP the DT B-NP ACE NN I-NP inhibitor NN I-NP captopril NN I-NP led VBD B-VP to TO B-PP activation NN B-NP of IN B-PP hormone-receptor NN B-NP interactions NNS I-NP . . O There EX B-NP was VBD B-VP a DT B-NP more RBR I-NP marked JJ I-NP rise NN I-NP of IN B-PP the DT B-NP number NN I-NP of IN B-PP receptors NNS B-NP in IN B-PP middle-aged JJ O ( ( O 44-55 CD B-NP years NNS I-NP ) ) O hypertensives NNS B-NP vs CC O elderly JJ O ( ( O 61-80 CD B-NP years NNS I-NP ) ) O subjects NNS B-NP after IN B-PP captopril NN B-NP treatment NN I-NP . . O Leukotriene NN B-NP B4 NN I-NP transcriptionally RB B-ADVP activates VBZ B-VP interleukin-6 NN B-NP expression NN I-NP involving VBG B-VP NK-chi NN B-NP B NN I-NP and CC O NF-IL6 NN B-NP . . O Leukotriene NN B-NP B4 NN I-NP ( ( O LTB4 NN B-NP ) ) O is VBZ B-VP a DT B-NP notable JJ I-NP participant NN I-NP in IN B-PP inflammation NN B-NP and CC O chemotaxis NN B-NP . . O It PRP B-NP is VBZ B-VP COMMA COMMA O however RB B-ADVP COMMA COMMA O still RB B-ADJP unclear JJ I-ADJP whether IN B-SBAR LTB4 NN B-NP acts VBZ B-VP in IN B-PP this DT B-NP regard NN I-NP directly RB B-ADVP or CC B-ADVP indirectly RB B-ADVP by IN B-PP stimulating VBG B-VP the DT B-NP release NN I-NP of IN B-PP chemotactic JJ B-NP and CC I-NP inflammatory JJ I-NP cytokines NNS I-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR LTB4 NN B-NP induces VBZ B-VP synthesis NN B-NP of IN B-PP interleukin NN B-NP ( ( O IL NN B-NP ) ) O -6 CD B-NP by IN B-PP human JJ B-NP blood NN I-NP monocytes NNS I-NP through IN B-PP transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT B-NP IL-6 NN I-NP gene NN I-NP . . O We PRP B-NP furthermore RB B-ADVP demonstrate VBP B-VP that IN B-SBAR this DT B-NP process NN I-NP involves VBZ B-VP activation NN B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-chi NN I-NP B NN I-NP and CC O COMMA COMMA O to TO B-PP a DT B-NP lesser JJR I-NP extent NN I-NP COMMA COMMA O of IN B-PP NF-IL6 NN B-NP COMMA COMMA O while IN B-SBAR the DT B-NP activity NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP AP-1 NN I-NP COMMA COMMA O shown VBN B-VP to TO I-VP otherwise RB I-VP confer VB I-VP IL-6 NN B-NP inducibility NN I-NP COMMA COMMA O appeared VBD B-VP to TO I-VP be VB I-VP unaffected JJ I-VP by IN B-PP LTB4 NN B-NP . . O Involvement NN B-NP of IN B-PP NF-chi NN B-NP B NN I-NP and CC O NF-IL6 NN B-NP in IN B-PP induction NN B-NP of IN B-PP IL-6 NN B-NP transcription NN I-NP by IN B-PP monocytes NNS B-NP was VBD B-VP demonstrated VBN I-VP using VBG B-VP deleted JJ B-NP forms NNS I-NP of IN B-PP the DT B-NP IL-6 NN I-NP promoter NN I-NP . . O Activation NN B-NP of IN B-PP the DT B-NP IL-6 NN I-NP promoter NN I-NP by IN B-PP LTB4 NN B-NP was VBD B-VP not RB B-CONJP only RB I-CONJP associated VBN B-VP with IN B-PP accumulation NN B-NP of IN B-PP the DT B-NP respective JJ I-NP transcripts NNS I-NP but CC O resulted VBD B-VP in IN B-PP synthesis NN B-NP of IN B-PP functional JJ B-NP IL-6 NN I-NP protein NN I-NP as RB B-PP well RB B-ADVP . . O In IN B-PP addition NN B-NP COMMA COMMA O LTB4 NN B-NP mediated VBD B-VP transactivation NN B-NP of IN B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP construct NN I-NP containing VBG B-VP the DT B-NP NF-chi NN I-NP B NN I-NP or CC O the DT B-NP NF-IL6 NN I-NP enhancer NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP the DT B-NP AP-1 NN I-NP enhancer NN I-NP . . O The DT B-NP signaling NN I-NP events NNS I-NP mediating VBG B-VP this DT B-NP effect NN I-NP appeared VBD B-VP to TO I-VP involve VB I-VP the DT B-NP release NN I-NP of IN B-PP H2O2 NN B-NP COMMA COMMA O since IN B-SBAR LTB4 NN B-NP failed VBD B-VP to TO I-VP induce VB I-VP NF-chi NN B-NP B NN I-NP or CC O NF-IL6 NN B-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP the DT B-NP scavenger NN I-NP of IN B-PP H2O2 NN B-NP COMMA COMMA O N-acetyl-L-cysteine NN B-NP . . O Estrogen NN B-NP binding NN I-NP sites NNS I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP monocytes NNS I-NP and CC O effects NNS B-NP of IN B-PP danazol NN B-NP on IN B-PP their PRP$ B-NP sites NNS I-NP in FW B-ADVP vitro FW I-ADVP . . O 1 LS B-LST . . O This DT B-NP study NN I-NP was VBD B-VP designed VBN I-VP to TO B-VP investigate VB I-VP the DT B-NP presence NN I-NP of IN B-PP estrogen NN O type NN B-NP I CD I-NP ( ( O high JJ B-NP affinity NN I-NP COMMA COMMA O low JJ B-NP capacity NN I-NP ) ) O and CC O type NN B-NP II CD I-NP ( ( O low JJ B-NP affinity NN I-NP COMMA COMMA O high JJ B-NP capacity NN I-NP ) ) O binding NN B-NP sites NNS I-NP in IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP monocytes NNS I-NP and CC O the DT B-NP effects NNS I-NP of IN B-PP danazol NN B-NP on IN B-PP these DT B-NP sites NNS I-NP . . O 2 LS B-LST . . O These DT B-NP two CD I-NP types NNS I-NP of IN B-PP estrogen NN B-NP binding NN I-NP sites NNS I-NP existed VBD B-VP in IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP monocytes NNS I-NP . . O 3 LS B-LST . . O Danazol NN B-NP bound VBD B-VP to TO B-PP these DT B-NP sites NNS I-NP in IN B-PP high JJ B-NP concentration NN I-NP ( ( O 10(-6) CD B-NP M NN I-NP COMMA COMMA O clinical JJ B-ADJP serum NN B-NP concentration NN I-NP during IN B-PP danazol NN B-NP therapy NN I-NP ) ) O and CC O decreased VBD B-VP the DT B-NP number NN I-NP of IN B-PP both DT B-NP sites NNS I-NP . . O 4 LS B-LST . . O It PRP B-NP is VBZ B-VP suggested VBN I-VP that IN B-SBAR danazol NN B-NP has VBZ B-VP an DT B-NP anti-estrogenic JJ I-NP action NN I-NP to TO B-PP the DT B-NP monocytes NNS I-NP through IN B-PP the DT B-NP competition NN B-NP and CC O suppression NN B-NP of IN B-PP estrogen NN B-NP binding NN I-NP sites NNS I-NP as IN B-SBAR seen VBN B-VP in IN B-PP the DT B-NP estrogen NN I-NP target NN I-NP organ NN I-NP . . O { ( O Mechanism NN B-NP of IN B-PP action NN B-NP of IN B-PP steroid NN B-NP hormones NNS I-NP . . I-NP I LS I-NP . . I-NP Estrogens NNS I-NP } ) O The DT B-NP steroid NN I-NP hormone NN I-NP are VBP B-VP very RB B-NP versatile JJ I-NP molecules NNS I-NP : : O although IN B-SBAR they PRP B-NP are VBP B-VP related JJ B-ADJP among IN B-PP them PRP B-NP by IN B-PP their PRP$ B-NP chemical JJ I-NP structure NN I-NP COMMA COMMA O they PRP B-NP have VBP B-VP very RB B-NP diverse JJ I-NP functions NNS I-NP and CC O including VBG B-PP antagonic JJ B-NP . . O Their PRP$ B-NP action NN I-NP mechanism NN I-NP is VBZ B-VP not RB I-VP completely RB I-VP cleared VBN I-VP . . O The DT B-NP estrogens NNS I-NP participate VBP B-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP practically RB B-NP all PDT I-NP the DT I-NP reproductive JJ I-NP and CC I-NP sexual JJ I-NP events NNS I-NP of IN B-PP the DT B-NP female NN I-NP COMMA COMMA O although IN B-SBAR the DT B-NP intracellular JJ I-NP actions NNS I-NP by IN B-PP which WDT B-NP they PRP B-NP take VBP B-VP place NN B-NP are VBP B-VP not RB I-VP well RB I-VP known VBN I-VP and CC O the DT B-NP proposed JJ I-NP models NNS I-NP do VBP B-VP not RB I-VP adequately RB I-VP satisfy VB I-VP the DT B-NP questions NNS I-NP . . O Currently RB B-ADVP it PRP B-NP is VBZ B-VP accepted VBN I-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP cytoplasmic JJ I-NP and\/or CC I-NP nuclear JJ I-NP receptor NN I-NP COMMA COMMA O without IN B-PP explaining VBG B-VP satisfactorily RB B-ADVP how WRB B-ADVP the DT B-NP hormones NNS I-NP come VBN B-VP to TO B-PP the DT B-NP nucleus NN I-NP . . O The DT B-NP endocrine JJ I-NP events NNS I-NP that WDT B-NP are VBP O rapidly RB B-ADVP expressed VBN B-VP ( ( O seconds NNS B-NP ) ) O are VBP B-VP due JJ B-PP to TO I-PP a DT B-NP possible JJ I-NP interaction NN I-NP with IN B-PP cellular JJ B-NP membrane NN I-NP . . O The DT B-NP purpose NN I-NP of IN B-PP this DT B-NP review NN I-NP is VBZ B-VP to TO B-VP analyze VB I-VP and CC O concilliate VB B-VP the DT B-NP reported VBN I-NP data NNS I-NP on IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP of IN B-PP estrogens NNS B-NP . . O Stable JJ B-NP expression NN I-NP of IN B-PP transdominant JJ B-NP Rev NN I-NP protein NN I-NP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP inhibits VBZ B-VP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP replication NN I-NP . . O The DT O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O Rev NN B-NP protein NN I-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP viral JJ B-NP structural JJ I-NP protein NN I-NP expression NN I-NP ( ( O Gag NN B-NP COMMA COMMA O Pol NN B-NP COMMA COMMA O and CC O Env NN B-NP ) ) O and CC B-PP COMMA COMMA I-PP hence RB I-PP COMMA COMMA O for IN B-PP viral JJ B-NP replication NN I-NP . . O In IN B-PP transient JJ B-NP transfection NN I-NP assays NNS I-NP COMMA COMMA O mutant JJ B-NP forms NNS I-NP of IN B-PP Rev NN B-NP have VBP B-VP been VBN I-VP identified VBN I-VP that WDT B-NP inhibit VBP B-VP wild-type JJ B-NP Rev NN I-NP activity NN I-NP and CC O therefore RB O suppress VBP B-VP viral JJ B-NP replication NN I-NP . . O To TO B-VP determine VB I-VP whether IN B-SBAR such JJ B-NP transdominant JJ I-NP Rev NN I-NP proteins NNS I-NP could MD B-VP provide VB I-VP long-term JJ B-NP protection NN I-NP against IN B-PP HIV NN B-NP infection NN I-NP without IN B-PP affecting VBG B-VP T NN B-NP cell NN I-NP function NN I-NP COMMA COMMA O T NN B-NP leukemia NN I-NP cell NN I-NP lines NNS I-NP were VBD B-VP stably RB I-VP transduced VBN I-VP with IN B-PP a DT B-NP retroviral JJ I-NP vector NN I-NP encoding VBG B-VP a DT B-NP transdominant JJ I-NP mutant NN I-NP of IN B-PP the DT B-NP Rev NN I-NP protein NN I-NP COMMA COMMA O M10 NN B-NP . . O While IN B-SBAR all PDT B-NP the DT I-NP M10-expressing JJ I-NP cell NN I-NP lines NNS I-NP remained VBD B-VP infectable JJ B-ADJP by IN B-PP HIV-1 NN B-NP COMMA COMMA O these DT B-NP same JJ I-NP cells NNS I-NP failed VBD B-VP to TO I-VP support VB I-VP a DT B-NP productive JJ I-NP replication NN I-NP cycle NN I-NP when WRB B-ADVP infected VBN B-VP with IN B-PP a DT B-NP cloned VBN I-NP isolate NN I-NP of IN B-PP HIV-1 NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O two CD B-NP out IN I-NP of IN I-NP three CD I-NP M10-expressing JJ I-NP CEM NN I-NP clones NNS I-NP were VBD B-VP also RB B-ADJP resistant JJ I-ADJP to TO B-PP highly RB B-NP productive JJ I-NP infection NN I-NP by IN B-PP a DT B-NP heterogeneous JJ I-NP HIV-1 NN I-NP pool NN I-NP . . O Expression NN B-NP of IN B-PP M10 NN B-NP did VBD B-VP not RB I-VP affect VB I-VP induction NN B-NP of IN B-PP HIV NN B-NP transcription NN I-NP mediated VBN B-VP by IN B-PP the DT B-NP kappa NN I-NP B NN I-NP regulatory JJ I-NP element NN I-NP or CC O Tat NN B-NP . . O Importantly RB B-ADVP COMMA COMMA O constitutive JJ B-NP expression NN I-NP of IN B-PP Rev NN B-NP M10 NN I-NP did VBD B-VP not RB I-VP alter VB I-VP the DT B-NP secretion NN I-NP of IN B-PP interleukin NN B-NP 2 CD I-NP in IN B-PP response NN I-PP to TO I-PP mitogen NN B-NP stimulation NN I-NP of IN B-PP EL-4 NN B-NP and CC O Jurkat NN B-NP cells NNS B-NP . . O The DT B-NP inhibition NN I-NP of IN B-PP HIV NN B-NP infection NN I-NP in IN B-PP cells NNS B-NP stably RB B-VP expressing VBG I-VP a DT B-NP transdominant JJ I-NP Rev NN I-NP protein NN I-NP COMMA COMMA O in IN B-PP the DT I-PP absence NN I-PP of IN I-PP any DT B-NP deleterious JJ I-NP effect NN I-NP on IN B-PP T NN B-NP cell NN I-NP function NN I-NP COMMA COMMA O suggests VBZ B-VP that IN B-SBAR such PDT B-NP a DT I-NP strategy NN I-NP could MD B-VP provide VB I-VP a DT B-NP therapeutic JJ I-NP effect NN I-NP in IN B-PP the DT B-NP T NN I-NP lymphocytes NNS I-NP of IN B-PP acquired VBN B-NP immunodeficiency NN I-NP syndrome NN I-NP patients NNS I-NP . . O Glucocorticoid NN B-NP receptor NN I-NP in IN B-PP patients NNS B-NP with IN B-PP lupus NN B-NP nephritis NN I-NP : : O relationship NN B-NP between IN B-PP receptor NN B-NP levels NNS I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP and CC O effect NN B-NP of IN B-PP glucocorticoid NN B-NP therapy NN I-NP . . O We PRP B-NP investigated VBD B-VP the DT B-NP clinical JJ I-NP significance NN I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP determination NN I-NP in IN B-PP 20 CD B-NP patients NNS I-NP with IN B-PP systemic JJ B-NP lupus NN I-NP erythematosus NN I-NP ( ( O SLE NN B-NP ) ) O who WP B-NP afterwards RB B-ADVP developed VBD B-VP nephrotic JJ B-NP syndrome NN I-NP . . O Glucocorticoid NN B-NP receptor NN I-NP concentrations NNS I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP ( ( O MNL NNS B-NP ) ) O in IN B-PP these DT B-NP patients NNS I-NP were VBD B-VP comparable JJ B-ADJP with IN B-PP those DT B-NP in IN B-PP both CC O other JJ B-NP patients NNS I-NP with IN B-PP SLE NN B-NP and CC O healthy JJ B-NP persons NNS I-NP . . O Improvement NN B-NP in IN B-PP urinary JJ B-NP protein NN I-NP excretion NN I-NP and CC B-PP in IN B-PP disease NN B-NP activity NN I-NP COMMA COMMA O which WDT B-NP was VBD B-VP scored VBN I-VP according VBG B-PP to TO B-PP the DT B-NP SLE NNP I-NP Disease NNP I-NP Activity NNP I-NP Index NNP I-NP system NN I-NP of IN B-PP the DT B-NP University NNP I-NP of IN B-PP Toronto NNP B-NP COMMA COMMA O closely RB B-ADVP related JJ B-VP to TO B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP concentrations NNS I-NP in IN B-PP MNL NN B-NP isolated VBN B-VP from IN B-PP the DT B-NP corresponding JJ I-NP patients NNS I-NP . . O In IN B-PP summary NN B-NP COMMA COMMA O glucocorticoid NN B-NP receptor NN I-NP determination NN I-NP in IN B-PP patients NNS B-NP with IN B-PP lupus NN B-NP nephritis NN I-NP may MD B-VP be VB I-VP a DT B-NP predictive JJ I-NP clue NN I-NP for IN B-PP assessing VBG B-VP responsiveness NN B-NP to TO B-PP glucocorticoid NN B-NP therapy NN I-NP . . O Selection NN B-NP of IN B-PP optimal JJ B-NP kappa NN I-NP B\/Rel NN I-NP DNA-binding JJ I-NP motifs NNS I-NP : : O interaction NN B-NP of IN B-PP both DT B-NP subunits NNS I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP with IN B-PP DNA NN B-NP is VBZ B-VP required VBN I-VP for IN B-PP transcriptional JJ B-NP activation NN I-NP . . O Analysis NN B-NP of IN B-PP the DT O p50 NN B-NP and CC O p65 NN B-NP subunits NNS B-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP complex NN I-NP has VBZ B-VP revealed VBN I-VP that IN B-SBAR both DT B-NP proteins NNS I-NP can MD B-VP interact VB I-VP with IN B-PP related JJ B-NP DNA NN I-NP sequences NNS I-NP through IN B-PP either CC O homo- JJ B-NP or CC O heterodimer NN B-NP formation NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O the DT B-NP product NN I-NP of IN B-PP the DT B-NP proto-oncogene NN I-NP c-rel NN I-NP can MD B-VP bind VB I-VP to TO B-PP similar JJ B-NP DNA NN I-NP motifs NNS I-NP by IN B-PP itself PRP B-NP or CC B-PP as IN B-PP a DT B-NP heterodimer NN I-NP with IN B-PP p50 NN B-NP or CC O p65 NN B-NP . . O However RB B-ADVP COMMA COMMA O these DT B-NP studies NNS I-NP have VBP B-VP used VBN I-VP a DT B-NP limited JJ I-NP number NN I-NP of IN B-PP known JJ B-NP kappa NN I-NP B NN I-NP DNA NN I-NP motifs NNS I-NP COMMA COMMA O and CC O the DT B-NP question NN I-NP of IN B-PP the DT B-NP optimal JJ I-NP DNA NN I-NP sequences NNS I-NP preferred VBN B-VP by IN B-PP each DT B-NP homodimer NN I-NP has VBZ B-VP not RB I-VP been VBN I-VP addressed VBN I-VP . . O Using VBG B-VP purified VBN O recombinant JJ O p50 NN B-NP COMMA COMMA O p65 NN B-NP COMMA COMMA O and CC O c-Rel NN B-NP proteins NNS B-NP COMMA COMMA O optimal JJ B-NP DNA-binding JJ I-NP motifs NNS I-NP were VBD B-VP selected VBN I-VP from IN B-PP a DT B-NP pool NN I-NP of IN B-PP random JJ B-NP oligonucleotides NNS I-NP . . O Alignment NN B-NP of IN B-PP the DT B-NP selected VBN I-NP sequences NNS I-NP allowed VBD B-VP us PRP B-NP to TO B-VP predict VB I-VP a DT B-NP consensus NN I-NP sequence NN I-NP for IN B-PP binding NN B-NP of IN B-PP the DT B-NP individual JJ I-NP homodimeric JJ I-NP Rel-related JJ I-NP proteins NNS I-NP COMMA COMMA O and CC O DNA-protein NN B-NP binding NN I-NP analysis NN I-NP of IN B-PP the DT B-NP selected VBN I-NP DNA NN I-NP sequences VBZ I-NP revealed VBD B-VP sequence NN B-NP specificity NN I-NP of IN B-PP the DT B-NP proteins NNS I-NP . . O Contrary JJ B-PP to TO I-PP previous JJ B-NP assumptions NNS I-NP COMMA COMMA O we PRP B-NP observed VBD B-VP that IN B-SBAR p65 NN B-NP homodimers NNS I-NP can MD B-VP interact VB I-VP with IN B-PP a DT B-NP subset NN I-NP of IN B-PP DNA NN B-NP sequences VBZ I-NP not RB B-VP recognized VBN I-VP by IN B-PP p50 NN B-NP homodimers NNS I-NP . . O Differential JJ B-NP binding NN I-NP affinities NNS I-NP were VBD B-VP also RB I-VP obtained VBN I-VP with IN B-PP p50- NN B-NP and CC O c-Rel-selected JJ B-ADJP sequences NNS B-NP . . O Using VBG B-VP either CC O a DT O p50- NN B-NP or CC O p65-selected JJ B-ADJP kappa NN B-NP B NN I-NP motif NN I-NP COMMA COMMA O which WDT B-NP displayed VBD B-VP differential JJ B-NP binding NN I-NP with IN B-PP respect NN I-PP to TO I-PP the DT B-NP other JJ I-NP protein NN I-NP COMMA COMMA O little JJ B-NP to TO I-NP no DT I-NP binding NN I-NP was VBD B-VP observed VBN I-VP with IN B-PP the DT B-NP heterodimeric JJ I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP . . O Similarly RB B-ADVP COMMA COMMA O in IN B-PP transfection NN B-NP experiments NNS I-NP in IN B-PP which WDT B-NP the DT B-NP selective JJ I-NP kappa NN I-NP B NN I-NP binding NN I-NP sites NNS I-NP were VBD B-VP used VBN I-VP to TO B-VP drive VB I-VP the DT B-NP expression NN I-NP of IN B-PP a DT B-NP chloramphenicol NN I-NP acetyltransferase NN I-NP reporter NN I-NP construct NN I-NP COMMA COMMA O the DT O p65- NN B-NP and CC O p50-selected JJ B-ADJP motifs NNS B-NP were VBD B-VP activated VBN I-VP only RB B-PP in IN I-PP the DT I-PP presence NN I-PP of IN I-PP p65 NN B-NP and CC O p50\/65 NN B-NP ( ( O a DT B-NP chimeric JJ I-NP protein NN I-NP with IN B-PP the DT B-NP p50 NN B-NP DNA NN I-NP binding NN I-NP domain NN I-NP and CC O p65 NN B-NP activation NN I-NP domain NN I-NP ) ) O expression NN B-NP vectors NNS I-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O and CC O neither DT B-NP demonstrated VBD B-VP a DT B-NP significant JJ I-NP response NN I-NP to TO B-PP stimuli NNS B-NP that WDT B-NP induce VBP B-VP NF-kappa NN B-NP B NN I-NP activity NN I-NP . . O These DT B-NP findings NNS I-NP demonstrate VBP B-VP that IN B-SBAR interaction NN B-NP of IN B-PP both DT B-NP subunits NNS I-NP of IN B-PP the DT B-NP heterodimeric JJ I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP with IN B-PP DNA NN B-NP is VBZ B-VP required VBN I-VP for IN B-PP DNA NN B-NP binding NN I-NP and CC O transcriptional JJ B-NP activation NN I-NP and CC O suggest VBP B-VP that IN B-SBAR transcriptional JJ B-NP activation NN I-NP mediated VBN B-VP by IN B-PP the DT B-NP individual JJ I-NP rel-related JJ I-NP proteins NNS I-NP will MD B-VP differ VB I-VP dramatically RB B-ADVP COMMA COMMA O depending VBG B-PP on IN B-PP the DT B-NP specific JJ I-NP kappa NN I-NP B NN I-NP motifs NNS I-NP present JJ B-ADJP . . O Characterization NN B-NP of IN B-PP a DT B-NP new JJ I-NP tissue-specific JJ I-NP transcription NN I-NP factor NN I-NP binding VBG B-VP to TO B-PP the DT B-NP simian JJ I-NP virus NN I-NP 40 CD I-NP enhancer NN I-NP TC-II NN I-NP ( ( I-NP NF-kappa NN I-NP B NN I-NP ) ) I-NP element NN I-NP . . O We PRP B-NP have VBP O biochemically RB B-ADVP and CC O functionally RB B-ADVP characterized VBN B-VP a DT B-NP new JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O NP-TCII NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP present JJ B-ADJP in IN B-PP nuclei NNS B-NP from IN B-PP unstimulated JJ O T NN B-NP and CC O B NN B-NP lymphocytes NNS B-NP but CC O is VBZ B-VP not RB I-VP found VBN I-VP in IN B-PP nonhematopoietic JJ B-NP cells NNS I-NP . . O This DT B-NP factor NN I-NP has VBZ B-VP a DT B-NP DNA-binding JJ I-NP specificity NN I-NP similar JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP but CC O is VBZ B-VP unrelated JJ B-ADJP to TO B-PP this DT B-NP or CC I-NP other JJ I-NP Rel NN I-NP proteins NNS I-NP by IN B-PP functional JJ B-NP and CC I-NP biochemical JJ I-NP criteria NNS I-NP . . O It PRP B-NP can MD B-VP also RB I-VP be VB I-VP distinguished VBN I-VP from IN B-PP other JJ B-NP previously RB I-NP described VBN I-NP lymphocyte-specific JJ I-NP DNA-binding JJ I-NP proteins NNS I-NP . . O The DT B-NP candidate NN I-NP oncoprotein NN I-NP Bcl-3 NN I-NP is VBZ B-VP an DT B-NP antagonist NN I-NP of IN B-PP p50\/NF-kappa NN B-NP B-mediated JJ I-NP inhibition NN I-NP . . O The DT B-NP candidate NN I-NP oncogene NN I-NP bcl-3 NN I-NP was VBD B-VP discovered VBN I-VP as IN B-PP a DT B-NP translocation NN I-NP into IN B-PP the DT B-NP immunoglobulin NN I-NP alpha-locus NN I-NP in IN B-PP some DT B-NP cases NNS I-NP of IN B-PP B-cell NN B-NP chronic JJ I-NP lymphocytic JJ I-NP leukaemias NNS I-NP . . O The DT B-NP protein NN I-NP Bcl-3 NN I-NP contains VBZ B-VP seven CD B-NP so-called JJ I-NP ankyrin NN I-NP repeats NNS I-NP . . O Similar JJ B-NP repeat NN I-NP motifs NNS I-NP are VBP B-VP found VBN I-VP in IN B-PP a DT B-NP number NN I-NP of IN B-PP diverse JJ B-NP regulatory JJ I-NP proteins NNS I-NP but CC O the DT B-NP motifs NNS I-NP of IN B-PP Bcl-3 NN B-NP are VBP B-VP most RBS B-ADJP closely RB I-ADJP related JJ I-ADJP to TO B-PP those DT B-NP found VBN B-VP in IN B-PP I NN B-NP kappa NN I-NP B NN I-NP proteins NNS I-NP in IN B-PP which WDT B-NP the DT B-NP ankyrin NN I-NP repeat NN I-NP domain NN I-NP is VBZ B-VP thought VBN I-VP to TO I-VP be VB I-VP directly RB I-VP involved VBN I-VP in IN B-PP inhibition NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activity NN I-NP . . O No DT B-NP biological JJ I-NP function NN I-NP has VBZ B-VP yet RB I-VP been VBN I-VP described VBN I-VP for IN B-PP Bcl-3 NN B-NP COMMA COMMA O but CC O it PRP B-NP was VBD B-VP noted VBN I-VP recently RB B-ADVP that IN B-SBAR Bcl-3 NN B-NP interferes VBZ B-VP with IN B-PP DNA-binding NN B-NP of IN B-PP the DT B-NP p50 NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in FW B-ADVP vitro FW I-ADVP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR Bcl-3 NN B-NP can MD B-VP aid VB I-VP kappa NN B-NP B NN I-NP site-dependent JJ I-NP transcription NN I-NP in FW B-ADVP vivo FW I-ADVP by IN B-PP counteracting VBG B-VP the DT B-NP inhibitory JJ I-NP effects NNS I-NP of IN B-PP p50\/NF-kappa NN B-NP B NN I-NP homodimers NNS I-NP . . O Bcl-3 NN B-NP may MD B-VP therefore RB I-VP aid VB I-VP activation NN B-NP of IN B-PP select JJ B-NP NF-kappa NN I-NP B-regulated JJ I-NP genes NNS I-NP COMMA COMMA O including VBG B-PP those DT B-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP . . O A DT B-NP microtitre NN I-NP assay NN I-NP system NN I-NP for IN B-PP glucocorticoid NN B-NP receptors NNS I-NP : : O decreased VBN B-NP receptor NN I-NP concentration NN I-NP in IN B-PP myocardial JJ B-NP infarction NN I-NP . . O A DT B-NP major JJ I-NP difficulty NN I-NP in IN B-PP determination NN B-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP sites NNS I-NP is VBZ B-VP the DT B-NP very RB I-NP complicated JJ I-NP assay NN I-NP procedure NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP describe VBP B-VP a DT B-NP microtitre NN I-NP assay NN I-NP system NN I-NP for IN B-PP glucocorticoid NN B-NP receptors NNS I-NP which WDT B-NP is VBZ B-VP a DT B-NP whole-cell JJ I-NP competitive JJ I-NP binding NN I-NP radioassay NN I-NP using VBG B-VP {3H}-dexamethasone NN B-NP as IN B-PP radioligand NN B-NP . . O This DT B-NP modification NN I-NP of IN B-PP a DT B-NP previously RB I-NP described VBN I-NP protocol NN I-NP simplifies VBZ B-VP and CC O reduces VBZ B-VP laboratory NN B-NP work NN I-NP and CC O allows VBZ B-VP assay NN B-NP reproducibility NN I-NP to TO B-VP be VB I-VP controlled VBN I-VP more RBR B-ADVP reliably RB I-ADVP . . O Thus RB B-VP enabled VBN I-VP to TO I-VP perform VB I-VP the DT B-NP test NN I-NP on IN B-PP multiple JJ B-NP blood NN I-NP samples NNS I-NP in IN B-PP parallel NN B-NP COMMA COMMA O we PRP B-NP investigated VBD B-VP cardiac JJ B-NP infarction NN I-NP patients NNS I-NP over IN B-PP a DT B-NP 12-day JJ I-NP period NN I-NP to TO B-VP test VB I-VP if IN B-SBAR glucocorticoid NN B-NP receptor NN I-NP binding NN I-NP is VBZ B-VP altered VBN I-VP in IN B-PP this DT B-NP ' `` I-NP stressful JJ I-NP ' '' I-NP disease NN I-NP . . O On IN B-PP the DT B-NP first JJ I-NP day NN I-NP of IN B-PP the DT B-NP disease NN I-NP COMMA COMMA O glucocorticoid NN B-NP receptor NN I-NP capacity NN I-NP was VBD B-VP significantly RB I-VP decreased VBN I-VP without IN B-PP alteration NN B-NP of IN B-PP the DT B-NP receptor-ligand JJ I-NP affinity NN I-NP COMMA COMMA O whereas IN O on IN B-PP days NNS B-NP 4 CD B-NP and CC O 12 CD B-NP the DT B-NP number NN I-NP of IN B-PP receptor NN B-NP sites NNS I-NP was VBD B-VP normal JJ B-ADJP again RB B-ADVP . . O This DT B-NP result NN I-NP fits VBZ B-VP well RB B-ADVP into IN B-PP the DT B-NP general JJ I-NP observation NN I-NP of IN B-PP stress-induced JJ B-NP down-regulation NN I-NP of IN B-PP immune JJ B-NP responses NNS I-NP . . O Regulation NN B-NP of IN B-PP c-jun NN B-NP expression NN I-NP during IN B-PP induction NN B-NP of IN B-PP monocytic JJ B-NP differentiation NN I-NP by IN B-PP okadaic JJ B-NP acid NN I-NP . . O The DT B-NP present JJ I-NP work NN I-NP has VBZ B-VP examined VBN I-VP the DT B-NP effects NNS I-NP of IN B-PP okadaic JJ B-NP acid NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP type NN O 1 CD B-NP and CC O 2A NN B-NP protein NN B-NP phosphatases NNS I-NP COMMA COMMA O on IN B-PP the DT B-NP regulation NN I-NP of IN B-PP c-jun NN B-NP expression NN I-NP during IN B-PP monocytic JJ B-NP differentiation NN I-NP of IN B-PP U-937 NN B-NP leukemia NN I-NP cells NNS I-NP . . O The DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR okadaic JJ B-NP acid NN I-NP treatment NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP induction NN B-NP of IN B-PP a DT B-NP differentiated VBN I-NP monocyte NN I-NP phenotype NN I-NP characterized VBN B-VP by IN B-PP : : O ( ( B-LST a LS I-LST ) ) O growth NN B-NP arrest NN I-NP ; : O ( ( B-LST b LS I-LST ) ) O increases NNS B-NP in IN B-PP Mac-1 NN B-NP cell NN I-NP surface NN I-NP antigen NN I-NP expression NN I-NP ; : O ( ( B-LST c LS I-LST ) ) O down-regulation NN B-NP of IN B-PP c-myc NN B-NP transcripts NNS I-NP ; : O and CC O ( ( B-LST d LS I-LST ) ) O induction NN B-NP of IN B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP gene NN I-NP expression NN I-NP . . O This DT B-NP induction NN I-NP of IN B-PP monocytic JJ B-NP differentiation NN I-NP was VBD B-VP associated VBN I-VP with IN B-PP transient JJ B-NP increases NNS I-NP in IN B-PP c-jun NN B-NP mRNA NN I-NP levels NNS I-NP COMMA COMMA O which WDT B-NP were VBD B-VP maximal JJ B-ADJP at IN B-PP 6 CD B-NP h NN I-NP . . O Similar JJ B-NP effects NNS I-NP were VBD B-VP obtained VBN I-VP for IN B-PP the DT B-NP c-fos NN I-NP gene NN I-NP . . O Run-on JJ B-NP analysis NN I-NP demonstrated VBD B-VP detectable JJ B-NP levels NNS I-NP of IN B-PP c-jun NN B-NP transcription NN I-NP in IN B-PP U-937 NN B-NP cells NNS I-NP and CC O that IN B-SBAR this DT B-NP rate NN I-NP is VBZ B-VP increased VBN I-VP approximately RB B-ADVP 40-fold RB I-ADVP following VBG B-PP okadaic JJ B-NP acid NN I-NP exposure NN I-NP . . O c-jun NN B-NP mRNA NN I-NP levels NNS I-NP were VBD B-VP superinduced VBN I-VP in IN B-PP cells NNS B-NP treated VBN B-VP with IN B-PP both CC O okadaic JJ B-NP acid NN I-NP and CC O cycloheximide NN B-NP COMMA COMMA O whereas IN O inhibition NN B-NP of IN B-PP protein NN B-NP synthesis NN I-NP had VBD B-VP little JJ O COMMA COMMA O if IN B-SBAR any DT B-ADJP COMMA COMMA O effect NN B-NP on IN B-PP okadaic JJ B-NP acid-induced JJ I-NP c-jun NN I-NP transcription NN I-NP . . O The DT B-NP half-life NN I-NP of IN B-PP c-jun NN B-NP mRNA NN I-NP was VBD B-VP similar JJ B-ADJP ( ( O 45-50 CD B-NP min NN I-NP ) ) O in IN B-PP both CC B-NP untreated JJ I-NP and CC I-NP okadaic JJ I-NP acid-induced JJ I-NP cells NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O treatment NN B-NP with IN B-PP both DT B-NP okadaic JJ B-NP acid NN I-NP and CC O cycloheximide NN B-NP was VBD B-VP associated VBN I-VP with IN B-PP stabilization NN B-NP ( ( O t NN B-NP 1\/2 CD I-NP = JJ B-VP 90 CD B-NP min NN I-NP ) ) O of IN B-PP c-jun NN B-NP transcripts NNS I-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O these DT B-NP findings NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP induction NN I-NP of IN B-PP c-jun NN B-NP transcription NN I-NP by IN B-PP okadaic JJ B-NP acid NN I-NP is VBZ B-VP controlled VBN I-VP primarily RB B-ADVP by IN B-PP a DT B-NP transcriptional JJ I-NP mechanism NN I-NP . . O Since IN B-SBAR previous JJ B-NP studies NNS I-NP have VBP B-VP demonstrated VBN I-VP that IN B-SBAR the DT B-NP c-jun NN I-NP gene NN I-NP is VBZ B-VP autoinduced VBN I-VP by IN B-PP Jun\/AP-1 NN B-NP COMMA COMMA O we PRP B-NP also RB B-ADVP studied VBD B-VP transcription NN B-NP of IN B-PP c-jun NN O promoter NN O ( ( O positions NNS B-NP -132\/+170 CD B-NP ) ) O -reporter JJ B-NP gene NN I-NP constructs NNS I-NP with IN B-PP and CC B-PP without IN B-PP a DT B-NP mutated VBN I-NP AP-1 NN I-NP element NN I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Activation NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP by IN B-PP interleukin NN B-NP 2 CD I-NP in IN B-PP human JJ B-NP blood NN I-NP monocytes NNS I-NP . . O We PRP B-NP report VBP B-VP here RB B-ADVP that IN B-SBAR interleukin NN B-NP 2 CD I-NP ( ( O IL-2 NN B-NP ) ) O acts VBZ B-VP on IN B-PP human JJ B-NP blood NN I-NP monocytes NNS I-NP by IN B-PP enhancing VBG B-VP binding NN B-NP activity NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP to TO B-PP its PRP$ B-NP consensus NN I-NP sequence NN I-NP in IN B-PP the DT B-NP 5' JJ I-NP regulatory JJ I-NP enhancer NN I-NP region NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP receptor NN I-NP alpha NN I-NP chain NN I-NP ( ( O p55 NN B-NP ) ) O . . O Similarly RB B-ADVP COMMA COMMA O IL-2 NN B-NP activates VBZ B-VP NF-kappa NN B-NP B NN I-NP in IN B-PP the DT B-NP human JJ I-NP monocytic JJ I-NP cell NN I-NP line NN I-NP U NN I-NP 937 CD I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP in IN I-PP resting VBG B-NP human JJ I-NP T-cells NNS I-NP . . O This DT B-NP effect NN I-NP is VBZ B-VP detectable JJ B-ADJP within IN B-PP 15 CD B-NP min NN I-NP and CC O peaks VBZ B-VP 1 CD B-NP h NN I-NP after IN B-PP exposure NN B-NP to TO B-PP IL-2 NN B-NP . . O Enhanced VBN B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP activity NN I-NP is VBZ B-VP followed VBN I-VP by IN B-PP functional JJ B-NP activation NN I-NP in IN B-PP that IN B-NP inducibility NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP receptor NN I-NP alpha NN I-NP chain NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP enhanced VBN B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP and CC O that IN B-NP a DT B-NP heterologous JJ I-NP promoter NN I-NP containing VBG B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP consensus NN I-NP sequence NN I-NP ( ( O -291 CD B-NP to TO O -245 CD B-NP ) ) O of IN B-PP the DT B-NP IL-2 NN I-NP receptor NN I-NP alpha NN I-NP chain NN I-NP gene NN I-NP is VBZ B-VP activated VBN I-VP . . O In IN B-PP addition NN B-NP COMMA COMMA O IL-2 NN B-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP increasing VBG B-VP transcript NN B-NP levels NNS I-NP of IN B-PP the DT B-NP p50 NN I-NP gene NN I-NP coding VBG B-VP for IN B-PP the DT B-NP p50 NN I-NP subunit NN I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O whereas IN O mRNA NN B-NP levels NNS I-NP of IN B-PP the DT B-NP p65 NN I-NP NF-kappa NN I-NP B NN I-NP gene NN I-NP remained VBD B-VP unchanged JJ B-ADJP . . O Single JJ B-NP point NN I-NP estimation NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP lymphocytes NNS B-NP of IN B-PP normal JJ B-NP subjects NNS I-NP and CC B-PP of IN B-PP children NNS B-NP under IN B-PP long JJ B-NP term NN I-NP glucocorticoid NN I-NP treatment NN I-NP . . O A DT B-NP single JJ I-NP point NN I-NP assay NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP ( ( O GR NN B-NP ) ) O in IN B-PP human JJ B-NP lymphocytes NNS I-NP based VBN B-PP on IN B-PP the DT B-NP measurement NN I-NP of IN B-PP specific JJ B-NP dexamethasone NN I-NP binding NN I-NP has VBZ B-VP been VBN I-VP developed VBN I-VP and CC O compared VBN B-VP with IN B-PP a DT B-NP common JJ I-NP multi-point JJ I-NP Scatchard NN I-NP analysis NN I-NP . . O The DT B-NP assay NN I-NP conditions NN I-NP - : O concentration NN B-NP of IN B-PP the DT B-NP ligand NN I-NP 20 CD B-NP nmol\/l NN I-NP COMMA COMMA O incubation NN B-NP time NN I-NP 2 CD I-NP h NN I-NP and CC O the DT B-NP cell NN I-NP count NN I-NP 2-6 CD I-NP mil. CD I-NP cells\/tube NNS I-NP in IN B-PP the DT B-NP assay NN I-NP volume NN I-NP 0.25 CD I-NP ml NN I-NP were VBD B-VP found VBN I-VP to TO I-VP be VB I-VP optimal JJ B-ADJP . . O An DT B-NP attempt NN I-NP was VBD B-VP also RB I-VP undertaken VBN I-VP to TO B-VP use VB I-VP a DT B-NP cell NN I-NP harvester NN I-NP for IN B-PP the DT B-NP separation NN I-NP of IN B-PP cells NNS B-NP from IN B-PP unbound JJ B-NP ligand NN I-NP . . O Though IN B-SBAR specifically RB B-NP bound VBN I-NP dexamethasone NN I-NP measured VBN B-VP by IN B-PP whole-cell JJ B-NP assay NN I-NP and CC O that DT B-NP using VBG B-VP cell NN B-NP harvester NN I-NP correlated VBD B-VP well RB B-ADVP COMMA COMMA O almost RB B-PP by IN I-PP one CD B-NP order NN I-NP lower JJR B-NP values NNS I-NP obtained VBN B-VP with IN B-PP the DT B-NP latter JJ I-NP method NN I-NP render VBP B-VP it PRP B-NP non-applicable JJ B-ADJP for IN B-PP receptor NN B-NP quantitation NN I-NP . . O The DT B-NP results NNS I-NP from IN B-PP 9 CD B-NP healthy JJ I-NP volunteers NNS I-NP ( ( O average JJ B-NP GR NN I-NP concentration NN I-NP 7131 CD B-NP +\/- CC I-NP 1256 CD I-NP sites\/cell NNS I-NP ) ) O correlated VBD B-VP excellently RB B-ADVP with IN B-PP those DT B-NP obtained VBN B-VP by IN B-PP the DT B-NP Scatchard NN I-NP analysis NN I-NP . . O The DT B-NP single JJ I-NP point NN I-NP assay NN I-NP has VBZ B-VP been VBN I-VP also RB I-VP applied VBN I-VP for IN B-PP determination NN B-NP of IN B-PP GH NN B-NP in IN B-PP 10 CD B-NP children NNS I-NP treated VBN B-VP with IN B-PP large JJ B-NP doses NNS I-NP of IN B-PP prednisone NN B-NP . . O The DT B-NP average JJ I-NP values NNS I-NP from IN B-PP healthy JJ B-NP volunteers NNS I-NP did VBD B-VP not RB I-VP differ VB I-VP significantly RB B-ADVP from IN B-PP those DT B-NP found VBN B-VP in IN B-PP these DT B-NP children NNS I-NP COMMA COMMA O though RB O much RB B-NP broader JJR I-NP range NN I-NP was VBD B-VP found VBN I-VP in IN B-PP patients NNS B-NP . . O A DT B-NP novel JJ I-NP B NN I-NP cell-derived JJ I-NP coactivator NN I-NP potentiates VBZ B-VP the DT B-NP activation NN I-NP of IN B-PP immunoglobulin NN B-NP promoters NNS I-NP by IN B-PP octamer-binding JJ B-NP transcription NN I-NP factors NNS I-NP . . O A DT B-NP novel JJ I-NP B NN I-NP cell-restricted JJ I-NP activity NN I-NP COMMA COMMA O required VBN B-VP for IN B-PP high JJ B-NP levels NNS I-NP of IN B-PP octamer\/Oct-dependent JJ B-NP transcription NN I-NP from IN B-PP an DT O immunoglobulin NN B-NP heavy JJ I-NP chain NN I-NP ( ( O IgH NN B-NP ) ) O promoter NN B-NP COMMA COMMA O was VBD B-VP detected VBN I-VP in IN B-PP an DT B-NP in FW I-NP vitro FW I-NP system NN I-NP consisting VBG B-VP of IN B-PP HeLa NN B-NP cell-derived JJ I-NP extracts NNS I-NP complemented VBN B-VP with IN B-PP fractionated VBN B-NP B NN I-NP cell NN I-NP nuclear JJ I-NP proteins NNS I-NP . . O The DT B-NP factor NN I-NP responsible JJ B-ADJP for IN B-PP this DT B-NP activity NN I-NP was VBD B-VP designated VBN I-VP Oct NN B-NP coactivator NN I-NP from IN B-PP B NN B-NP cells NNS I-NP ( ( O OCA-B NN B-NP ) ) O . . O OCA-B NN B-NP stimulates VBZ B-VP the DT B-NP transcription NN I-NP from IN B-PP an DT B-NP IgH NN I-NP promoter NN I-NP in IN B-PP conjunction NN I-PP with IN I-PP either CC O Oct-1 NN B-NP or CC O Oct-2 NN B-NP but CC O shows VBZ B-VP no DT B-NP significant JJ I-NP effect NN I-NP on IN B-PP the DT B-NP octamer\/Oct-dependent JJ I-NP transcription NN I-NP of IN B-PP the DT B-NP ubiquitously RB I-NP expressed VBN I-NP histone NN I-NP H2B NN I-NP promoter NN I-NP and CC O the DT B-NP transcription NN I-NP of IN B-PP USF- NN B-NP and CC O Sp1-regulated JJ B-ADJP promoters NNS B-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O our PRP$ B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR OCA-B NN B-NP is VBZ B-VP a DT O tissue- NN B-NP COMMA COMMA O promoter- NN B-NP COMMA COMMA O and CC O factor-specific JJ B-ADJP coactivator NN B-NP and CC O that IN B-SBAR OCA-B NN B-NP may MD B-VP be VB I-VP a DT B-NP major JJ I-NP determinant NN I-NP for IN B-PP B NN B-NP cell-specific JJ I-NP activation NN I-NP of IN B-PP immunoglobulin NN B-NP promoters NNS I-NP . . O In IN B-PP light NN I-PP of IN I-PP the DT B-NP evidence NN I-NP showing VBG B-VP physical JJ B-NP and CC I-NP functional JJ I-NP interactions NNS I-NP between IN B-PP Oct NN B-NP factors NNS I-NP and CC O OCA-B NN B-NP COMMA COMMA O we PRP B-NP propose VBP B-VP a DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP for IN B-PP OCA-B NN B-NP and CC O discuss VBP B-VP the DT B-NP implications NNS I-NP of IN B-PP OCA-B NN B-NP for IN B-PP the DT B-NP transcriptional JJ I-NP regulation NN I-NP of IN B-PP other JJ B-NP tissue-specific JJ I-NP promoters NNS I-NP . . O The DT B-NP regulation NN I-NP of IN B-PP the DT B-NP human JJ I-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP promoter NN I-NP region NN I-NP in IN B-PP macrophage NN B-NP COMMA COMMA O T NN B-NP cell NN I-NP COMMA COMMA O and CC O B NN B-NP cell NN I-NP lines NNS B-NP . . O The DT B-NP 1311-base JJ I-NP pair NN I-NP human JJ I-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP ( ( I-NP TNF NN I-NP ) ) I-NP alpha NN I-NP promoter NN I-NP region NN I-NP was VBD B-VP fused VBN I-VP to TO B-PP the DT O luciferase NN B-NP ( ( O Luc NN B-NP ) ) O reporter NN B-NP gene NN I-NP and CC O studied VBN B-VP in IN B-PP a DT B-NP transient JJ I-NP transfection NN I-NP system NN I-NP in IN B-PP three CD B-NP TNF NN I-NP producing NN I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O the DT B-NP U937 NN I-NP macrophage NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O the DT B-NP MLA NN I-NP 144 CD I-NP T NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O and CC O the DT B-NP 729-6 CD I-NP B NN I-NP cell NN I-NP line NN I-NP . . O This DT B-NP full JJ I-NP length NN I-NP promoter NN I-NP construct NN I-NP can MD B-VP be VB I-VP induced VBN I-VP by IN B-PP phorbol NN B-NP 13-myristate NN I-NP acetate NN I-NP ( ( O PMA NN B-NP ) ) O in IN B-PP each DT B-NP of IN B-PP these DT B-NP cell NN I-NP types NNS I-NP . . O Analysis NN B-NP of IN B-PP a DT B-NP series NN I-NP of IN B-PP 5'-truncations NNS B-NP showed VBD B-VP several JJ B-NP peaks NNS I-NP of IN B-PP basal JJ B-NP and CC I-NP PMA NN I-NP induced JJ I-NP activity NN I-NP suggesting VBG B-VP the DT B-NP presence NN I-NP of IN B-PP several JJ B-NP positive JJ I-NP and CC I-NP negative JJ I-NP regulatory JJ I-NP elements NNS I-NP . . O A DT B-NP PMA NN I-NP responsive JJ I-NP element NN I-NP was VBD B-VP localized JJ I-VP to TO B-PP a DT B-NP region NN I-NP between IN B-PP -95 CD B-NP and CC O -36 CD B-NP bp NN B-NP relative JJ B-ADJP to TO B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP . . O Within IN B-PP this DT B-NP region NN I-NP COMMA COMMA O single JJ B-NP AP-2- NN I-NP and CC I-NP AP-1-like JJ I-NP consensus NN I-NP sequences NNS I-NP were VBD B-VP noted VBN I-VP . . O These DT O AP-2 NN B-NP and CC O AP-1 NN B-NP sites NNS B-NP were VBD B-VP each DT O modified VBN B-VP with IN B-PP a DT B-NP double JJ I-NP point NN I-NP mutation NN I-NP . . O A DT O modest JJ O ( ( O 20-50 CD B-NP % NN I-NP ) ) O reduction NN B-NP in IN B-PP TNF NN B-NP promoter NN I-NP activity NN I-NP was VBD B-VP observed VBN I-VP with IN B-PP the DT B-NP AP-2 NN I-NP site NN I-NP mutation NN I-NP . . O However RB B-ADVP COMMA COMMA O mutation NN B-NP of IN B-PP the DT B-NP AP-1 NN I-NP site NN I-NP markedly RB B-ADVP diminished VBD B-VP both CC B-NP the DT I-NP basal JJ I-NP and CC I-NP PMA-activated JJ I-NP promoter NN I-NP activity NN I-NP . . O Also RB B-ADVP co-transfections NNS B-NP of IN B-PP the DT B-NP wild-type JJ I-NP promoter NN I-NP construct NN I-NP with IN B-PP an DT B-NP AP-1\/c-jun NN I-NP expression NN I-NP vector NN I-NP resulted VBD B-VP in IN B-PP augmented JJ B-NP basal JJ I-NP and CC I-NP PMA-induced JJ I-NP promoter NN I-NP activity NN I-NP . . O Redox NN B-NP status NN I-NP of IN B-PP cells NNS B-NP influences VBZ B-VP constitutive JJ B-NP or CC I-NP induced VBN I-NP NF-kappa NN I-NP B NN I-NP translocation NN I-NP and CC O HIV NN B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP activity NN I-NP in IN B-PP human JJ O T NN B-NP and CC O monocytic JJ B-ADJP cell NN B-NP lines NNS I-NP . . O We PRP B-NP have VBP B-VP tested VBN I-VP the DT B-NP hypothesis NN I-NP that IN B-SBAR cellular JJ B-NP activation NN I-NP events NNS I-NP occurring VBG B-VP in IN B-PP T NN B-NP lymphocytes NNS I-NP and CC O monocytes NNS B-NP and CC O mediated VBN B-VP through IN B-PP translocation NN B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP are VBP B-VP dependent JJ B-ADJP upon IN B-PP the DT B-NP constitutive JJ I-NP redox NN I-NP status NN I-NP of IN B-PP these DT B-NP cells NNS I-NP . . O We PRP B-NP used VBD B-VP phenolic JJ B-NP COMMA COMMA I-NP lipid-soluble JJ I-NP COMMA COMMA I-NP chain-breaking JJ I-NP antioxidants NNS I-NP ( ( O butylated VBN B-NP hydroxyanisole NN I-NP ( ( O BHA NN B-NP ) ) O COMMA COMMA O nordihydroquairetic JJ B-NP acid NN I-NP COMMA COMMA O or CC O alpha-tocopherol NN B-NP ( ( O vitamin NN B-NP E NN I-NP ) ) O to TO B-VP show VB I-VP that IN B-SBAR peroxyl JJ B-NP radical JJ I-NP scavenging NN I-NP in IN B-PP unstimulated JJ O and CC O PMA- NN B-NP or CC O TNF-stimulated JJ B-ADJP cells NNS B-NP blocks VBZ B-VP the DT B-NP functions NNS I-NP depending VBG B-PP on IN B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP . . O BHA NN B-NP was VBD B-VP found VBN I-VP to TO I-VP suppress VB I-VP not RB B-CONJP only RB I-CONJP PMA- NN B-NP or CC O TNF-induced JJ B-ADJP COMMA COMMA O but CC B-CONJP also RB I-CONJP constitutive JJ B-ADJP COMMA COMMA B-NP HIV-enhancer JJ I-NP activity NN I-NP concomitant JJ B-ADJP to TO B-PP an DT B-NP inhibition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP binding NN I-NP activity NN I-NP in IN B-PP both CC O lymphoblastoid JJ O T NN O ( ( O J.Jhan NN B-NP ) ) O and CC O monocytic JJ O ( ( O U937 NN B-NP ) ) O cell NN B-NP lines NNS I-NP . . O This DT B-NP was VBD B-VP also RB B-ADVP true JJ B-ADJP for IN B-PP KBF NN B-NP ( ( O p50 NN B-NP homodimer NN I-NP ) ) O binding NN B-NP activity NN I-NP in IN B-PP U937 NN B-NP cells NNS I-NP . . O Secretion NN B-NP of IN B-PP TNF NN B-NP COMMA COMMA O the DT B-NP product NN I-NP of IN B-PP another DT B-NP NF-kappa NN I-NP B-dependent JJ I-NP gene NN I-NP COMMA COMMA O was VBD B-VP abolished VBN I-VP by IN B-PP BHA NN B-NP in IN B-PP PMA-stimulated JJ B-NP U937 NN I-NP cells NNS I-NP . . O The DT B-NP anti-oxidative JJ I-NP effect NN I-NP of IN B-PP BHA NN B-NP was VBD B-VP accompanied VBN I-VP by IN B-PP an DT B-NP increase NN I-NP in IN B-PP thiol NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP glutathione NN B-NP COMMA COMMA O content NN B-NP in IN B-PP stimulated VBN B-NP and CC I-NP unstimulated JJ I-NP T NN I-NP cell NN I-NP COMMA COMMA O whereas IN O TNF NN B-NP stimulation NN I-NP itself PRP B-NP barely RB B-ADVP modified VBD B-VP the DT B-NP cellular JJ I-NP thiol NN I-NP level NN I-NP . . O Oxidative JJ B-NP stress NN I-NP obtained VBN B-VP by IN B-PP the DT B-NP addition NN I-NP of IN B-PP H2O2 NN B-NP to TO B-PP the DT B-NP culture NN I-NP medium NN I-NP of IN B-PP J.Jhan NN B-NP or CC O U937 NN B-NP cells NNS B-NP could MD B-VP not RB O by IN B-PP itself PRP B-NP induce VB B-VP NF-kappa NN B-NP B NN I-NP activation NN I-NP . . O These DT B-NP observations NNS I-NP suggest VBP B-VP that IN B-SBAR TNF NN B-NP and CC O PMA NN B-NP do VBP B-VP not RB I-VP lead VB I-VP to TO B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP through IN B-PP induction NN B-NP of IN B-PP changes NNS B-NP in IN B-PP the DT B-NP cell NN I-NP redox NN I-NP status NN I-NP . . O Rather RB B-ADVP COMMA COMMA O TNF NN B-NP and CC O PMA NN B-NP can MD B-VP exert VB I-VP their PRP$ B-NP effect NN I-NP only RB B-SBAR if IN I-SBAR cells NNS B-NP are VBP B-VP in IN B-PP an DT B-NP appropriate JJ I-NP redox NN I-NP status NN I-NP COMMA COMMA O because IN B-SBAR prior JJ B-NP modification NN I-NP toward IN B-PP reduction NN B-NP with IN B-PP BHA NN B-NP treatment NN I-NP prevents VBZ B-VP this DT I-VP activation NN I-VP . . O It PRP B-NP appears VBZ B-VP that IN B-SBAR a DT B-NP basal JJ I-NP redox NN I-NP equilibrium NN I-NP tending VBG B-VP toward IN B-PP oxidation NN B-NP is VBZ B-VP a DT B-NP prerequisite NN I-NP for IN B-PP full JJ B-NP activation NN I-NP of IN B-PP transduction NN B-NP pathways NNS I-NP regulating VBG B-VP the DT B-NP activity NN I-NP of IN B-PP NF-kappa NN B-NP B-dependent JJ I-NP genes NNS I-NP . . O Expression NN B-NP of IN B-PP c-fos NN B-NP COMMA COMMA O c-jun NN B-NP and CC O jun NN B-NP B NN I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP from IN B-PP young JJ B-NP and CC I-NP elderly JJ I-NP adults NNS I-NP . . O The DT B-NP expression NN I-NP of IN B-PP c-fos NN B-NP COMMA COMMA O c-jun NN B-NP and CC O jun NN B-NP B NN I-NP proto-oncogenes NNS B-NP was VBD B-VP studied VBN I-VP in IN B-PP phytohemagglutinin NN B-NP ( ( O PHA NN B-NP ) ) O activated VBN B-NP peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP ( ( O PBL NN B-NP ) ) O from IN B-PP young JJ B-NP and CC I-NP aged JJ I-NP humans NNS I-NP . . O Specific JJ B-NP mRNAs NNS I-NP for IN B-PP c-fos NN B-NP and CC O c-jun NN B-NP were VBD B-VP detectable JJ B-ADJP within IN B-PP 30 CD B-NP min NN I-NP after IN B-PP cell NN B-NP activation NN I-NP and CC O reached VBD B-VP maximal JJ B-NP levels NNS I-NP within IN B-PP 2 CD B-NP h NN I-NP . . O Both CC O c-fos NN B-NP and CC O jun NN B-NP B NN I-NP mRNAs NNS B-NP decreased VBD B-VP to TO B-PP pre-activation NN B-NP levels NNS I-NP within IN B-PP 6 CD B-NP h NN I-NP COMMA COMMA O while IN B-SBAR c-jun NN B-NP mRNA NN I-NP remained VBD B-VP elevated JJ B-ADJP . . O In IN B-PP PHA-activated JJ B-NP PBL NN I-NP COMMA COMMA O no DT B-NP age-related JJ I-NP differences NNS I-NP were VBD B-VP observed VBN I-VP in IN B-PP c-fos NN B-NP or CC O jun NN B-NP B NN I-NP mRNA NN B-NP expression NN I-NP . . O However RB B-ADVP COMMA COMMA O c-jun NN B-NP mRNA NN I-NP levels NNS I-NP decreased VBD B-VP significantly RB B-ADVP ( ( O 1.73 CD B-NP +\/- CC I-NP 0.08 CD I-NP vs. CC O 1.16 CD B-NP +\/- CC I-NP 0.09 CD I-NP arbitrary JJ B-NP units NNS I-NP COMMA COMMA O P NN B-NP < VBG B-VP 0.01 CD B-NP COMMA COMMA O young JJ B-ADJP vs. CC O old JJ B-ADJP ) ) O in IN B-PP PBL NN B-NP from IN B-PP elderly JJ B-NP individuals NNS I-NP activated VBN B-VP with IN B-PP PHA NN B-NP . . O Because IN B-SBAR previous JJ B-NP work NN I-NP has VBZ B-VP demonstrated VBN I-VP that IN B-SBAR T NN B-NP cells NNS I-NP from IN B-PP elderly JJ B-NP individuals NNS I-NP may MD B-VP display VB I-VP normal JJ B-NP proliferative JJ I-NP responses NNS I-NP when WRB B-ADVP activated VBN B-VP via IN B-PP the DT B-NP anti-CD2 JJ I-NP pathway NN I-NP COMMA COMMA O c-jun NN B-NP and CC O jun NN B-NP B NN I-NP mRNA NN B-NP expression NN I-NP was VBD B-VP also RB I-VP studied VBN I-VP in IN B-PP anti-CD2-activated JJ B-NP purified VBN I-NP T NN I-NP cells NNS I-NP . . O No DT B-NP age-related JJ I-NP differences NNS I-NP were VBD B-VP found VBN I-VP in IN B-PP the DT B-NP expression NN I-NP of IN B-PP either DT B-NP of IN B-PP these DT B-NP two CD I-NP proto-oncogenes NNS I-NP by IN B-PP anti-CD2 NN B-NP activated JJ I-NP T NN I-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP decreased VBN I-NP IL-2 NN I-NP production NN I-NP and CC O proliferative JJ B-NP response NN I-NP displayed VBN B-VP by IN B-PP PHA-activated JJ B-NP PBL NN I-NP from IN B-PP elderly JJ B-NP adults NNS I-NP may MD B-VP be VB I-VP related JJ B-ADJP to TO B-PP age-related JJ B-NP changes NNS I-NP in IN B-PP c-jun NN B-NP mRNA NN I-NP expression NN I-NP and CC B-PP in IN B-PP the DT B-NP ratio NN I-NP of IN B-PP c-fos NN B-NP to TO B-PP c-jun NN B-NP mRNA NN B-NP . . O Characterization NN B-NP of IN B-PP a DT B-NP novel JJ I-NP T NN I-NP lymphocyte NN I-NP protein NN I-NP which WDT B-NP binds VBZ B-VP to TO B-PP a DT B-NP site NN I-NP related JJ B-ADJP to TO B-PP steroid\/thyroid JJ B-NP hormone NN B-NP receptor NN I-NP response NN I-NP elements NNS I-NP in IN B-PP the DT B-NP negative JJ I-NP regulatory JJ I-NP sequence NN I-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP identified VBN I-VP a DT B-NP T NN I-NP lymphocyte NN I-NP protein NN I-NP which WDT B-NP binds VBZ B-VP to TO B-PP a DT B-NP site NN I-NP within IN B-PP the DT B-NP LTR NN I-NP of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O and CC O exerts VBZ B-VP an DT B-NP inhibitory JJ I-NP effect NN I-NP on IN B-PP virus NN B-NP gene NN I-NP expression NN I-NP . . O The DT B-NP palindromic JJ I-NP site NN I-NP ( ( O site NN B-NP B NN I-NP ) ) O recognized VBN B-VP by IN B-PP this DT B-NP protein NN I-NP is VBZ B-VP related JJ B-ADJP to TO B-PP the DT B-NP palindromic JJ I-NP binding VBG I-NP sites NNS I-NP of IN B-PP members NNS B-NP of IN B-PP the DT O steroid\/thyroid JJ B-NP hormone NN B-NP receptor NN I-NP family NN I-NP . . O Here RB B-ADVP we PRP B-NP characterize VBP B-VP the DT B-NP T NN I-NP cell NN I-NP protein NN I-NP binding VBG B-VP to TO B-PP this DT B-NP site NN I-NP as IN B-PP a DT B-NP 100 CD I-NP kD NN I-NP protein NN I-NP which WDT B-NP is VBZ B-VP most RBS B-ADJP abundant JJ I-ADJP in IN B-PP T NN B-NP cells NNS I-NP and CC O which WDT B-NP binds VBZ B-VP to TO B-PP site NN B-NP B NN I-NP as IN B-PP a DT B-NP 200 CD I-NP kD NN I-NP complex NN I-NP . . O This DT B-NP protein NN I-NP is VBZ B-VP distinct JJ B-ADJP from IN B-PP other JJ B-NP members NNS I-NP of IN B-PP the DT O steroid\/thyroid JJ B-NP hormone NN B-NP receptor NN I-NP family NN I-NP including VBG B-PP the DT B-NP COUP NN I-NP protein NN I-NP which WDT B-NP has VBZ B-VP a DT B-NP closely RB I-NP related JJ I-NP DNA NN I-NP binding NN I-NP specificity NN I-NP . . O A DT B-NP mechanism NN I-NP for IN B-PP the DT B-NP antiinflammatory JJ I-NP effects NNS I-NP of IN B-PP corticosteroids NNS B-NP : : O the DT B-NP glucocorticoid NN I-NP receptor NN I-NP regulates VBZ B-VP leukocyte NN B-NP adhesion NN I-NP to TO B-PP endothelial JJ B-NP cells NNS I-NP and CC O expression NN B-NP of IN B-PP endothelial-leukocyte JJ B-NP adhesion NN I-NP molecule NN I-NP 1 CD I-NP and CC O intercellular JJ B-NP adhesion NN I-NP molecule NN I-NP 1 CD I-NP . . O Corticosteroids NNS B-NP are VBP B-VP the DT B-NP preeminent JJ I-NP antiinflammatory JJ I-NP agents NNS I-NP although IN B-SBAR the DT B-NP molecular JJ I-NP mechanisms NNS I-NP that WDT B-NP impart VBP B-VP their PRP$ B-NP efficacy NN I-NP have VBP B-VP not RB I-VP been VBN I-VP defined VBN I-VP . . O The DT B-NP endothelium NN I-NP plays VBZ B-VP a DT B-NP critical JJ I-NP role NN I-NP in IN B-PP inflammation NN B-NP by IN B-PP directing VBG B-VP circulating VBG B-NP leukocytes NNS I-NP into IN B-PP extravascular JJ B-NP tissues NNS I-NP by IN B-PP expressing VBG B-VP adhesive JJ B-NP molecules NNS I-NP for IN B-PP leukocytes NNS B-NP { ( O e.g. FW B-PP COMMA COMMA O endothelial-leukocyte JJ B-NP adhesion NN I-NP molecule NN I-NP 1 CD I-NP ( ( O ELAM-1 NN B-NP ) ) O and CC O intercellular JJ B-NP adhesion NN I-NP molecule NN I-NP 1 CD I-NP ( ( O ICAM-1 NN B-NP ) ) O } ) O . . O We PRP B-NP therefore RB B-ADVP determined VBD B-VP whether IN B-SBAR corticosteroids NNS B-NP suppress VBP B-VP inflammation NN B-NP by IN B-PP inhibiting VBG B-VP endothelial JJ B-NP expression NN I-NP of IN B-PP adhesion NN B-NP molecules NNS I-NP for IN B-PP neutrophils NNS B-NP ( ( O polymorphonuclear JJ B-NP leukocytes NNS I-NP ) ) O . . O Preincubation NN B-NP of IN B-PP endothelial JJ B-NP cells NNS I-NP with IN B-PP endotoxin NN B-NP { ( O lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O COMMA COMMA O 1 CD B-NP microgram\/ml NN I-NP } ) O led VBD B-VP to TO B-PP a DT B-NP 4-fold JJ I-NP increase NN I-NP in IN B-PP subsequent JJ B-NP adherence NN I-NP of IN B-PP polymorphonuclear JJ B-NP leukocytes NNS I-NP ( ( O P NN B-NP < VBG B-VP 0.0001 CD B-NP COMMA COMMA O n NN B-NP = JJ B-VP 10 CD B-NP ) ) O to TO B-PP endothelial JJ B-NP cells NNS I-NP COMMA COMMA O an DT B-NP increase NN I-NP that WDT B-NP was VBD B-VP markedly RB I-VP attenuated VBN I-VP when WRB B-ADVP endothelial JJ B-NP cells NNS I-NP were VBD B-VP treated VBN I-VP with IN B-PP dexamethasone NN B-NP ( ( O IC50 NN B-NP < VBG B-VP 1 CD B-NP nM NN I-NP COMMA COMMA O P NN B-NP < VBG B-VP 0.0001 CD B-NP COMMA COMMA O n NN B-NP = VBG B-VP 6 CD B-NP or CC O 7 CD B-NP ) ) O during IN B-PP preincubation NN B-NP with IN B-PP LPS NN B-NP . . O Moreover RB B-ADVP COMMA COMMA O the DT B-NP steroid NN I-NP receptor NN I-NP agonist NN I-NP cortisol NN I-NP ( ( O 10 CD B-NP microM NN I-NP ) ) O COMMA COMMA O but CC B-CONJP not RB I-CONJP its PRP$ B-NP inactive JJ I-NP metabolite NN I-NP tetrahydrocortisol NN I-NP ( ( O 10 CD B-NP microM NN I-NP ) ) O COMMA COMMA O diminished VBD B-VP LPS-induced JJ B-NP endothelial JJ I-NP cell NN I-NP adhesiveness NN I-NP . . O Further JJ B-NP evidence NN I-NP that IN B-SBAR the DT B-NP action NN I-NP of IN B-PP dexamethasone NN B-NP was VBD B-VP mediated VBN I-VP through IN B-PP ligation NN B-NP of IN B-PP corticosteroid NN B-NP receptors NNS I-NP { ( O human JJ B-NP glucocorticoid NN I-NP receptors NNS I-NP ( ( O hGRs NNS B-NP ) ) O } ) O was VBD B-VP provided VBN I-VP by IN B-PP experiments NNS B-NP utilizing VBG B-VP the DT B-NP steroid NN I-NP antagonist NN I-NP RU-486 NN I-NP . . O RU-486 NN B-NP ( ( O 10 CD B-NP microM NN I-NP ) ) O COMMA COMMA O which WDT B-NP prevents VBZ B-VP translocation NN B-NP of IN B-PP ligated VBN B-NP hGR NN I-NP to TO B-PP the DT B-NP nucleus NN I-NP by IN B-PP inhibiting VBG B-VP dissociation NN B-NP of IN B-PP hGR NN B-NP from IN B-PP heat NN B-NP shock NN I-NP protein NN I-NP 90 CD I-NP COMMA COMMA O completely RB B-ADVP aborted VBD B-VP the DT B-NP effect NN I-NP of IN B-PP dexamethasone NN B-NP on IN B-PP adhesiveness NN B-NP of IN B-PP endothelial JJ B-NP cells NNS I-NP ( ( O P NN B-NP < VBG B-VP 0.0005 CD B-NP COMMA COMMA O n NN B-NP = JJ B-VP 3 CD B-NP ) ) O . . O Treatment NN B-NP of IN B-PP endothelial JJ B-NP cells NNS I-NP with IN B-PP LPS NN B-NP ( ( O 1 CD B-NP microgram\/ml NN I-NP ) ) O stimulated VBD B-VP transcription NN B-NP of IN B-PP ELAM-1 NN B-NP COMMA COMMA O as IN B-SBAR shown VBN B-VP by IN B-PP Northern NN B-NP blot NN I-NP analysis NN I-NP COMMA COMMA O and CC O expression NN B-NP of IN B-PP membrane-associated JJ B-NP ELAM-1 NN B-NP and CC O ICAM-1 NN B-NP COMMA COMMA O as IN B-SBAR shown VBN B-VP by IN B-PP quantitative JJ B-NP immunofluorescence NN I-NP ( ( O both DT B-NP P NN I-NP < VBG B-VP 0.001 CD B-NP COMMA COMMA O n NN B-NP = VBG B-VP 9 CD B-NP ) ) O . . O Dexamethasone NN B-NP markedly RB B-ADVP inhibited VBD B-VP LPS-stimulated JJ B-NP accumulation NN I-NP of IN B-PP mRNA NN B-NP for IN B-PP ELAM-1 NN B-NP and CC O expression NN B-NP of IN B-PP ELAM-1 NN B-NP and CC O ICAM-1 NN B-NP ( ( O IC50 NN B-NP < VBG B-VP 10 CD B-NP nM NN I-NP COMMA COMMA O both DT B-NP P NN I-NP < VBG B-VP 0.001 CD B-NP COMMA COMMA O n NN B-NP = VBG B-VP 4-9 CD B-NP ) ) O ; : O inhibition NN B-NP of IN B-PP expression NN B-NP by IN B-PP dexamethasone NN B-NP was VBD B-VP reversed VBN I-VP by IN B-PP RU-486 NN B-NP ( ( O both DT B-NP P NN I-NP < VBG B-VP 0.005 CD B-NP COMMA COMMA O n NN B-NP = VBG B-VP 4-6 CD B-NP ) ) O . . O As IN B-SBAR in IN B-PP the DT B-NP adhesion NN I-NP studies NNS I-NP COMMA COMMA O cortisol NN B-NP but CC B-CONJP not RB I-CONJP tetrahydrocortisol NN B-NP inhibited VBD B-VP expression NN B-NP of IN B-PP ELAM-1 NN B-NP and CC O ICAM-1 NN B-NP ( ( O both DT B-NP P NN I-NP < VBG B-VP 0.005 CD B-NP COMMA COMMA O n NN B-NP = JJ B-VP 3 CD B-NP or CC O 4 CD B-NP ) ) O . . O In IN B-PP contrast NN B-NP COMMA COMMA O sodium NN B-NP salicylate NN I-NP ( ( O 1 CD B-NP mM NN I-NP ) ) O inhibited VBD B-VP neither CC O adhesion NN B-NP nor CC O expression NN B-NP of IN B-PP these DT B-NP adhesion NN I-NP molecules NNS I-NP . . O These DT B-NP studies NNS I-NP suggest VBP B-VP that IN B-SBAR antagonism NN B-NP by IN B-PP dexamethasone NN B-NP of IN B-PP endotoxin-induced JJ B-NP inflammation NN I-NP is VBZ B-VP a DT B-NP specific JJ I-NP instance NN I-NP of IN B-PP the DT B-NP general JJ I-NP biological JJ I-NP principle NN I-NP that IN B-SBAR the DT B-NP glucocorticoid NN I-NP receptor NN I-NP is VBZ B-VP a DT B-NP hormone-dependent JJ I-NP regulator NN I-NP of IN B-PP transcription NN B-NP . . O Membrane NN B-NP receptors NNS I-NP for IN B-PP aldosterone NN B-NP : : O a DT B-NP novel JJ I-NP pathway NN I-NP for IN B-PP mineralocorticoid NN B-NP action NN I-NP . . O Rapid JJ B-NP nongenomic JJ I-NP in FW I-NP vitro FW I-NP effects NNS I-NP of IN B-PP aldosterone NN B-NP on IN B-PP intracellular JJ B-NP electrolytes NNS I-NP COMMA COMMA O cell NN B-NP volume NN I-NP COMMA COMMA O and CC O Na(+)-H+ JJ B-NP antiport NN I-NP have VBP B-VP been VBN I-VP found VBN I-VP in IN B-PP human JJ B-NP mononuclear JJ I-NP leukocytes NNS I-NP ( ( O HML NN B-NP ) ) O . . O Binding NN B-NP of IN B-PP 125I-labeled JJ B-NP aldosterone NN I-NP to TO B-PP plasma NN B-NP membranes NNS I-NP of IN B-PP HML NN B-NP shares VBZ B-VP important JJ B-NP features NNS I-NP with IN B-PP these DT B-NP functional JJ I-NP data NNS I-NP . . O This DT B-NP includes VBZ B-VP a DT B-NP very RB I-NP low JJ I-NP apparent JJ I-NP dissociation NN B-NP constant NN I-NP ( ( O Kd NN B-NP ) ) O of IN B-PP 0.1 CD B-NP nM NN I-NP for IN B-PP both CC O aldosterone NN B-NP and CC O the DT B-NP effect NN I-NP on IN B-PP the DT B-NP Na(+)-H(+)-antiport NN I-NP COMMA COMMA O a DT B-NP high JJ I-NP turnover NN I-NP rate NN I-NP COMMA COMMA O and CC O the DT B-NP almost RB I-NP exclusive JJ I-NP binding NN I-NP selectivity NN I-NP for IN B-PP aldosterone NN B-NP . . O Dexamethasone NN B-NP COMMA COMMA O RU NN B-NP 26988 CD I-NP COMMA COMMA O corticosterone NN B-NP COMMA COMMA O ouabain NN B-NP COMMA COMMA O amiloride NN B-NP COMMA COMMA O and CC O 18-hydroxyprogesterone NN B-NP were VBD B-VP inactive JJ B-ADJP as IN B-PP ligands NNS B-NP . . O Deoxycorticosterone NN B-NP acetate NN I-NP had VBD B-VP an DT B-NP intermediate JJ I-NP activity NN I-NP with IN B-PP an DT B-NP apparent JJ I-NP Kd NN I-NP of IN B-PP 100 CD B-NP nM NN I-NP . . O These DT B-NP findings NNS I-NP are VBP B-VP the DT B-NP first JJ I-NP to TO B-VP demonstrate VB I-VP membrane NN B-NP binding NN I-NP of IN B-PP aldosterone NN B-NP being VBG B-VP compatible JJ B-ADJP with IN B-PP major JJ B-NP aspects NNS I-NP of IN B-PP its PRP$ B-NP nongenomic JJ I-NP effects NNS I-NP . . O Reticuloendotheliosis NN B-NP virus NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP elements NNS I-NP are VBP B-VP efficient JJ B-NP promoters NNS I-NP in IN B-PP cells NNS B-NP of IN B-PP various JJ B-NP species NNS B-NP and CC O tissue NN B-NP origin NN B-NP COMMA COMMA O including VBG B-PP human JJ B-NP lymphoid JJ I-NP cells NNS I-NP . . O Promiscuous JJ B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP the DT B-NP reticuloendotheliosis NN I-NP virus NN I-NP ( ( O REV NN B-NP ) ) O long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O was VBD B-VP detected VBN I-VP in IN B-PP transient JJ B-NP expression NN I-NP assays NNS I-NP using VBG B-VP LTR-chloramphenicol NN B-NP acetyltransferase-encoding JJ I-NP gene NN I-NP chimeras NNS I-NP COMMA COMMA O and CC O cells NNS B-NP of IN B-PP diverse JJ B-NP species NNS B-NP and CC O tissue NN B-NP type NN B-NP ; : O levels NNS B-NP of IN B-PP expression NN B-NP from IN B-PP two CD B-NP different JJ I-NP REV NN I-NP LTRs NNS I-NP correlate VBP B-VP with IN B-PP reports NNS B-NP of IN B-PP pathogenicity NN B-NP of IN B-PP the DT B-NP respective JJ I-NP viruses NNS I-NP in FW B-ADVP vivo FW I-ADVP . . O REVs NNS B-NP do VBP B-VP not RB I-VP encode VB I-VP a DT B-NP transactivator NN I-NP targeted VBN B-VP to TO B-PP the DT B-NP viral JJ I-NP LTR NN I-NP COMMA COMMA O and CC O cells NNS B-NP infected VBN B-VP with IN B-PP Marek NN B-NP 's POS B-NP disease NN I-NP virus NN I-NP COMMA COMMA O a DT B-NP herpesvirus NN I-NP with IN B-PP an DT B-NP overlapping VBG I-NP host NN I-NP range NN I-NP COMMA COMMA O do VBP B-VP not RB I-VP express VB I-VP factors NNS B-NP that WDT B-NP preferentially RB B-ADVP enhance VBP B-VP expression NN B-NP from IN B-PP REV NN B-NP or CC O avian JJ B-NP sarcoma\/leukemia NN I-NP virus NN I-NP LTRs NNS I-NP . . O REV NN B-NP LTRs NNS I-NP work VBP B-VP efficiently RB B-ADVP in IN B-PP human JJ B-NP lymphoid JJ I-NP cells NNS I-NP COMMA COMMA O and CC O are VBP B-VP viable JJ B-NP alternatives NNS I-NP to TO B-PP promoters NNS B-NP commonly RB B-VP used VBN I-VP for IN B-PP expression NN B-NP of IN B-PP cloned VBN B-NP genes NNS I-NP . . O They PRP B-NP may MD B-VP also RB I-VP prove VB I-VP useful JJ B-ADJP in IN B-PP the DT B-NP identification NN I-NP of IN B-PP new JJ B-NP COMMA COMMA I-NP ubiquitous JJ I-NP cellular JJ I-NP transcription NN I-NP factors NNS I-NP . . O Natural JJ B-NP variants NNS I-NP of IN B-PP the DT B-NP HIV-1 NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP : : O analysis NN B-NP of IN B-PP promoters NNS B-NP with IN B-PP duplicated JJ B-NP DNA NN I-NP regulatory JJ I-NP motifs NNS I-NP . . O Sequence NN B-NP variation NN I-NP in IN B-PP the DT O long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O region NN B-NP of IN B-PP HIV-1 NN B-NP was VBD B-VP analyzed VBN I-VP in IN B-PP viral JJ B-NP isolates NNS I-NP of IN B-PP 17 CD B-NP infected JJ I-NP individuals NNS I-NP . . O Two CD B-NP classes NNS I-NP of IN B-PP LTR NN B-NP size NN I-NP variants NNS I-NP were VBD B-VP found VBN I-VP . . O One CD B-NP HIV-1 NN I-NP variant NN I-NP was VBD B-VP detected VBN I-VP containing VBG B-VP an DT B-NP additional JJ I-NP binding VBG I-NP site NN I-NP for IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP Sp1 NN I-NP . . O Another DT B-NP LTR NN I-NP size NN I-NP variation NN I-NP was VBD B-VP observed VBN I-VP in IN B-PP four CD B-NP patients NNS I-NP in IN B-PP a DT B-NP region NN I-NP just RB B-ADJP upstream JJ I-ADJP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP enhancer NN I-NP . . O This DT B-NP variation NN I-NP was VBD B-VP the DT B-NP result NN I-NP of IN B-PP a DT B-NP duplication NN I-NP of IN B-PP a DT B-NP short JJ I-NP DNA NN I-NP sequence NN I-NP ( ( O CTG-motif NN B-NP ) ) O . . O Cell NN B-NP culture NN I-NP experiments NNS I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP natural JJ I-NP variant NN I-NP with IN B-PP four CD B-NP Sp1 NN I-NP sites NNS I-NP had VBD B-VP a DT B-NP slightly RB I-NP higher JJR I-NP promoter NN B-NP activity NN I-NP and CC O viral JJ B-NP replication NN I-NP rate NN I-NP than IN B-PP the DT B-NP isogenic JJ I-NP control NN I-NP LTR NN I-NP with IN B-PP three CD B-NP Sp1 NN I-NP sites NNS I-NP . . O No DT B-NP positive JJ I-NP effect NN I-NP of IN B-PP the DT B-NP duplicated JJ I-NP CTG-motif NN I-NP could MD B-VP be VB I-VP detected VBN I-VP . . O In IN B-SBAR order NN O to TO O measure VB B-VP small JJ B-NP differences NNS I-NP in IN B-PP virus NN B-NP production NN I-NP more RBR B-ADVP accurately RB I-ADVP COMMA COMMA O equal JJ B-NP amounts NNS I-NP of IN B-PP a DT B-NP size NN I-NP variant NN I-NP and CC O the DT B-NP wild-type JJ I-NP plasmid NN I-NP were VBD B-VP cotransfected VBN I-VP into IN B-PP T-cells NNS B-NP . . O The DT B-NP virus NN I-NP with IN B-PP four CD B-NP Sp1 NN I-NP sites NNS I-NP did VBD B-VP outgrow VB I-VP the DT B-NP three CD I-NP Sp1 NN I-NP virus NN I-NP in IN B-PP 35 CD B-NP days NNS I-NP of IN B-PP culture NN B-NP and CC O CTG-monomer NN B-NP virus NN I-NP outcompeted VBD B-VP the DT B-NP CTG-dimer NN I-NP virus NN I-NP in IN B-PP 42 CD B-NP days NNS I-NP . . O Based VBN B-PP on IN B-PP these DT B-NP results NNS I-NP we PRP B-NP estimate VBP B-VP a DT B-NP 5-10 CD I-NP % NN I-NP difference NN I-NP in IN B-PP virus NN B-NP production NN I-NP of IN B-PP the DT B-NP LTR NN I-NP variants NNS I-NP when WRB B-ADVP compared VBN B-VP to TO B-PP that DT B-NP of IN B-PP wild-type NN B-NP . . O SCL NN B-NP and CC O related JJ B-NP hemopoietic JJ I-NP helix-loop-helix JJ I-NP transcription NN I-NP factors NNS I-NP . . O The DT O helix-loop-helix JJ O ( ( O HLH JJ B-ADJP ) ) O proteins NNS B-NP are VBP B-VP a DT B-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP that WDT B-NP include VBP B-VP proteins NNS B-NP critical JJ B-ADJP to TO B-PP differentiation NN B-NP and CC O development NN B-NP in IN B-PP species NNS B-NP ranging VBG B-VP from IN B-PP plants NNS B-NP to TO B-PP mammals NNS B-NP . . O Five CD B-NP members NNS I-NP of IN B-PP this DT B-NP family NN I-NP ( ( O MYC NN B-NP COMMA COMMA O SCL NN B-NP COMMA COMMA O TAL-2 NN B-NP COMMA COMMA O LYL-1 NN B-NP and CC O E2A NN B-NP ) ) O are VBP B-VP implicated VBN I-VP in IN B-PP oncogenic JJ B-NP events NNS I-NP in IN B-PP human JJ B-NP lymphoid JJ I-NP tumors NNS I-NP because IN B-PP of IN I-PP their PRP$ B-NP consistent JJ I-NP involvement NN I-NP in IN B-PP chromosomal JJ B-NP translocations NNS I-NP . . O Although IN B-SBAR activated VBN B-VP in IN B-PP T NN B-NP cell NN I-NP leukemias NNS I-NP COMMA COMMA O expression NN B-NP of IN B-PP SCL NN B-NP and CC O LYL-1 NN B-NP is VBZ B-VP low JJ B-ADJP or CC O undetectable JJ B-ADJP in IN B-PP normal JJ B-NP T NN I-NP cell NN I-NP populations NNS I-NP . . O SCL NN B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP erythroid JJ O COMMA COMMA O megakaryocyte NN B-NP and CC O mast NN B-NP cell NN I-NP populations NNS B-NP ( ( O the DT B-NP same JJ I-NP cell NN I-NP lineages NNS I-NP as IN B-PP GATA-1 NN B-NP COMMA COMMA O a DT B-NP zinc-finger NN I-NP transcription NN I-NP factor NN I-NP ) ) O . . O In IN B-PP addition NN B-NP COMMA COMMA O both CC O SCL NN B-NP and CC O GATA-1 NN B-NP undergo VBP B-VP coordinate JJ B-NP modulation NN I-NP during IN B-PP chemically RB B-NP induced VBN I-NP erythroid JJ I-NP differentiation NN I-NP of IN B-PP mouse NN B-NP erythroleukemia NN I-NP cells NNS I-NP and CC O are VBP B-VP down-modulated VBN I-VP during IN B-PP myeloid JJ B-NP differentiation NN I-NP of IN B-PP human JJ B-NP K562 NN I-NP cells NNS I-NP COMMA COMMA O thus RB B-ADVP implying VBG B-VP a DT B-NP role NN I-NP for IN B-PP SCL NN B-NP in IN B-PP erythroid JJ B-NP differentiation NN I-NP events NNS I-NP . . O However RB B-ADVP COMMA COMMA O in IN B-PP contrast NN I-PP to TO I-PP GATA-1 NN B-NP COMMA COMMA O SCL NN B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP the DT B-NP developing VBG I-NP brain NN I-NP . . O Studies NNS B-NP of IN B-PP the DT B-NP function NN I-NP of IN B-PP SCL NN B-NP suggest VBP B-VP it PRP B-NP is VBZ B-VP also RB B-ADJP important JJ I-ADJP in IN B-PP proliferation NN B-NP and CC O self-renewal JJ B-ADJP events NNS B-NP in IN B-PP erythroid JJ B-NP cells NNS I-NP . . O Transcription NN B-NP of IN B-PP the DT B-NP hypersensitive JJ I-NP site NN I-NP HS2 NN I-NP enhancer NN I-NP in IN B-PP erythroid JJ B-NP cells NNS I-NP . . O In IN B-PP the DT B-NP human JJ I-NP genome NN I-NP COMMA COMMA O the DT B-NP erythroid-specific JJ I-NP hypersensitive JJ I-NP site NN I-NP HS2 NN I-NP enhancer NN I-NP regulates VBZ B-VP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP downstream JJ I-NP beta-like JJ I-NP globin NN I-NP genes NNS I-NP 10-50 CD B-NP kilobases NNS I-NP away RB B-ADVP . . O The DT B-NP mechanism NN I-NP of IN B-PP HS2 NN B-NP enhancer NN I-NP function NN I-NP is VBZ B-VP not RB I-VP known VBN I-VP . . O The DT B-NP present JJ I-NP study NN I-NP employs VBZ B-VP RNA NN B-NP protection NN I-NP assays NNS I-NP to TO B-VP analyze VB I-VP the DT B-NP transcriptional JJ I-NP status NN I-NP of IN B-PP the DT B-NP HS2 NN I-NP enhancer NN I-NP in IN B-PP transfected VBN O recombinant JJ O chloramphenicol NN B-NP acetyltransferase NN I-NP ( ( O CAT NN B-NP ) ) O plasmids NNS B-NP . . O In IN B-PP erythroid JJ B-NP K562 NN I-NP cells NNS I-NP in IN B-PP which WDT B-NP the DT B-NP HS2 NN I-NP enhancer NN I-NP is VBZ B-VP active JJ B-ADJP COMMA COMMA O the DT B-NP HS2 NN I-NP sequence NN I-NP directs VBZ B-VP the DT B-NP synthesis NN I-NP of IN B-PP long JJ B-NP enhancer NN I-NP transcripts NNS I-NP that WDT B-NP are VBP B-VP initiated VBN I-VP apparently RB B-ADVP from IN B-PP within IN B-PP the DT B-NP enhancer NN I-NP and CC O elongated VBN B-VP through IN B-PP the DT B-NP intervening VBG I-NP DNA NN I-NP into IN B-PP the DT B-NP cis-linked JJ I-NP CAT NN I-NP gene NN I-NP . . O In IN B-PP nonerythroid JJ B-NP HL-60 NN I-NP cells NNS I-NP in IN B-PP which WDT B-NP the DT B-NP HS2 NN I-NP enhancer NN I-NP is VBZ B-VP inactive JJ B-ADJP COMMA COMMA O long JJ B-NP enhancer NN I-NP transcripts NNS I-NP are VBP B-VP not RB O detectable JJ B-ADJP . . O Splitting VBG B-VP the DT B-NP HS2 NN I-NP enhancer NN I-NP between IN B-PP two CD B-NP tandem JJ I-NP Ap1 NN I-NP sites NNS I-NP abolishes VBZ B-VP the DT B-NP synthesis NN I-NP of IN B-PP a DT B-NP group NN I-NP of IN B-PP long JJ B-NP enhancer NN I-NP transcripts NNS I-NP and CC O results VBZ B-VP in IN B-PP loss NN B-NP of IN B-PP enhancer NN B-NP function NN I-NP and CC O transcriptional JJ B-NP silencing NN I-NP of IN B-PP the DT B-NP cis-linked JJ I-NP CAT NN I-NP gene NN I-NP . . O In IN B-PP directing VBG B-VP the DT B-NP synthesis NN I-NP of IN B-PP RNA NN B-NP through IN B-PP the DT B-NP intervening VBG I-NP DNA NN I-NP and CC O the DT B-NP gene NN I-NP by IN B-PP a DT O tracking NN B-NP and CC O transcription NN B-NP mechanism NN B-NP COMMA COMMA O the DT B-NP HS2 NN I-NP enhancer NN I-NP may MD O ( ( B-LST i LS I-LST ) ) O open VB B-VP up RP B-PRT the DT B-NP chromatin NN I-NP structure NN I-NP of IN B-PP a DT B-NP gene NN I-NP domain NN I-NP and CC O ( ( B-LST ii LS I-LST ) ) O deliver VB B-VP enhancer NN B-NP binding NN I-NP proteins NNS I-NP to TO B-PP the DT B-NP promoter NN I-NP sequence NN I-NP where WRB B-ADVP they PRP B-NP may MD B-VP stimulate VB I-VP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP gene NN I-NP at IN B-PP the DT B-NP cap NN I-NP site NN I-NP . . O Phorbol NN B-NP ester NN I-NP reduces VBZ B-VP constitutive JJ B-NP nuclear JJ I-NP NF NN I-NP kappa NN I-NP B NN I-NP and CC O inhibits VBZ B-VP HIV-1 NN B-NP production NN I-NP in IN B-PP mature JJ B-NP human JJ I-NP monocytic JJ I-NP cells NNS I-NP . . O NF NN B-NP kappa NN I-NP B NN I-NP is VBZ B-VP a DT B-NP potent JJ I-NP mediator NN I-NP of IN B-PP specific JJ B-NP gene NN I-NP expression NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP and CC O has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP transcription NN B-NP of IN B-PP the DT B-NP HIV-1 NN I-NP genome NN I-NP in IN B-PP promonocytic JJ B-NP leukemias NNS I-NP . . O There EX B-NP is VBZ B-VP little JJ B-NP information NN I-NP available JJ B-ADJP on IN B-PP the DT B-NP response NN I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP to TO B-PP cytokines NNS B-NP in IN B-PP normal JJ B-NP human JJ I-NP monocytes NNS I-NP . . O We PRP B-NP have VBP B-VP used VBN I-VP a DT B-NP 32P-labeled JJ I-NP oligonucleotide NN I-NP derived VBN B-VP from IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV-1 NN B-NP ) ) O long JJ B-NP terminal JJ I-NP repeat NN I-NP COMMA COMMA O which WDT B-NP contains VBZ B-VP a DT B-NP tandem JJ I-NP repeat NN I-NP of IN B-PP the DT B-NP NF NN I-NP kappa NN I-NP B NN I-NP binding NN I-NP sequence NN I-NP COMMA COMMA O as IN B-PP a DT B-NP probe NN I-NP in IN B-PP a DT B-NP gel NN I-NP retardation NN I-NP assay NN I-NP to TO B-VP study VB I-VP this DT B-NP transcription NN I-NP factor NN I-NP . . O Using VBG B-VP this DT B-NP assay NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP detected VBN I-VP NF NN B-NP kappa NN I-NP B NN I-NP in IN B-PP extracts NNS B-NP of IN B-PP nuclei NNS B-NP from IN B-PP normal JJ B-NP human JJ I-NP monocytes NNS I-NP . . O Treatment NN B-NP of IN B-PP normal JJ B-NP monocytes NNS I-NP with IN B-PP 12-0-tetradecanoyl JJ B-NP phorbol-13-acetate NN I-NP ( ( O TPA NN B-NP ) ) O for IN B-PP 4-24 CD B-NP h NN I-NP caused VBD B-VP the DT B-NP complete JJ I-NP disappearance NN I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP from IN B-PP nuclear JJ B-NP extracts NNS I-NP of IN B-PP monocytes NNS B-NP . . O A DT B-NP similar JJ I-NP result NN I-NP was VBD B-VP obtained VBN I-VP with IN B-PP the DT B-NP mature JJ I-NP monocytic JJ I-NP leukemia NN I-NP cell NN I-NP line NN I-NP THP-1 NN I-NP . . O The DT B-NP constitutive JJ I-NP transcription NN I-NP factor NN I-NP SP1 NN I-NP was VBD B-VP unaffected JJ I-VP by IN B-PP addition NN B-NP of IN B-PP TPA NN B-NP . . O The DT B-NP disappearance NN I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP from IN B-PP the DT B-NP nucleus NN I-NP was VBD B-VP concentration NN B-NP dependent JJ B-ADJP between IN B-PP 10 CD B-NP and CC I-NP 50 CD I-NP ng\/ml NN I-NP of IN B-PP phorbol NN B-NP ester NN I-NP . . O In IN B-PP THP-1 NN B-NP cells NNS I-NP COMMA COMMA O TPA NN B-NP also RB B-ADVP induced VBD B-VP a DT B-NP new JJ I-NP COMMA COMMA I-NP faster-migrating JJ I-NP NF NN I-NP kappa NN I-NP B NN I-NP species NNS I-NP not RB B-VP induced VBN I-VP in IN B-PP monocytes NNS B-NP . . O Protein NN B-NP kinase NN I-NP C NN I-NP inhibitor NN I-NP staurosporine NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP cyclic JJ B-NP nucleotide-dependent JJ I-NP protein NN I-NP kinase NN I-NP inhibitor NN I-NP HA-1004 NN I-NP COMMA COMMA O also RB B-ADVP dramatically RB B-ADVP reduced VBD B-VP constitutive JJ B-NP levels NNS I-NP of IN B-PP nuclear JJ B-NP NF NN I-NP kappa NN I-NP B NN I-NP . . O Finally RB B-ADVP COMMA COMMA O TPA NN B-NP addition NN I-NP to TO B-PP monocytes NNS B-NP infected VBN B-VP with IN B-PP HIV-1 NN B-NP inhibited VBD B-VP HIV-1 NN B-NP replication NN I-NP COMMA COMMA O as IN B-SBAR determined VBN B-VP by IN B-PP reverse JJ B-NP transcriptase NN I-NP assays NNS I-NP COMMA COMMA O in IN B-PP a DT B-NP concentration-dependent JJ I-NP manner NN I-NP . . O These DT B-NP results NNS I-NP are VBP B-VP in IN B-PP striking JJ B-NP contrast NN I-NP to TO B-PP the DT B-NP increase NN I-NP in IN B-PP nuclear JJ B-NP NF NN I-NP kappa NN I-NP B NN I-NP and CC O HIV-1 NN B-NP replication NN I-NP induced VBN B-VP by IN B-PP phorbol NN B-NP esters NNS I-NP in IN B-PP promonocytic JJ B-NP leukemia NN I-NP cells NNS I-NP U937 NN B-NP and CC O HL-60 NN B-NP COMMA COMMA O and CC O emphasize VBP B-VP the DT B-NP importance NN I-NP of IN B-PP studying VBG B-VP cytokine NN B-NP regulation NN I-NP of IN B-PP HIV-1 NN B-NP in IN B-PP normal JJ B-NP monocytes NNS I-NP . . O Ablation NN B-NP of IN B-PP transplanted VBN B-NP HTLV-I NN I-NP Tax-transformed JJ I-NP tumors NNS I-NP in IN B-PP mice NNS B-NP by IN B-PP antisense JJ B-NP inhibition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP Science NNP B-NP 1993 CD I-NP Mar NNP I-NP 12 CD I-NP ; : I-NP 259 CD I-NP ( ( I-NP 5101 CD I-NP ) ) I-NP : : I-NP 1523 CD I-NP } ) O Mice NNS B-NP transgenic JJ B-ADJP for IN B-PP the DT O human JJ B-NP T NN I-NP cell NN I-NP leukemia NN I-NP virus NN I-NP ( ( O HTLV-I NN B-NP ) ) O Tax NN B-NP gene NN I-NP develop VBP B-VP fibroblastic JJ B-NP tumors NNS I-NP that WDT B-NP express VBP B-VP NF-kappa NN B-NP B-inducible JJ I-NP early JJ I-NP genes NNS I-NP . . O In FW B-NP vitro FW I-NP inhibition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP expression NN I-NP by IN B-PP antisense JJ B-NP oligodeoxynucleotides NNS B-NP ( ( O ODNs NNS B-NP ) ) O inhibited VBD B-VP growth NN B-NP of IN B-PP these DT B-NP culture-adapted JJ I-NP Tax-transformed JJ I-NP fibroblasts NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP an DT B-NP HTLV-I-transformed JJ I-NP human JJ I-NP lymphocyte NN I-NP line NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O antisense JJ B-NP inhibition NN I-NP of IN B-PP Tax NN B-NP itself PRP B-NP had VBD B-VP no DT B-NP apparent JJ I-NP effect NN I-NP on IN B-PP cell NN B-NP growth NN I-NP . . O Mice NNS B-NP treated VBN B-VP with IN B-PP antisense NN B-NP to TO B-PP NF-kappa NN B-NP B NN I-NP ODNs NNS I-NP showed VBD B-VP rapid JJ B-NP regression NN I-NP of IN B-PP transplanted VBN B-NP fibrosarcomas NNS I-NP . . O This DT B-NP suggests VBZ B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP expression NN I-NP may MD B-VP be VB I-VP necessary JJ B-ADJP for IN B-PP the DT B-NP maintenance NN I-NP of IN B-PP the DT B-NP malignant JJ I-NP phenotype NN I-NP and CC O provides VBZ B-VP a DT B-NP therapeutic JJ I-NP approach NN I-NP for IN B-PP HTLV-I-associated JJ B-NP disease NN I-NP . . O Inhibition NN B-NP of IN B-PP anti-CD3 JJ B-NP monoclonal JJ I-NP antibody-induced JJ I-NP T-cell NN I-NP proliferation NN I-NP by IN B-PP dexamethasone NN B-NP COMMA COMMA O isoproterenol NN B-NP COMMA COMMA O or CC O prostaglandin NN B-NP E2 NN I-NP either CC O alone RB B-ADVP or CC O in IN B-PP combination NN B-NP . . O 1 LS B-LST . . O The DT B-NP purpose NN I-NP of IN B-PP these DT B-NP studies NNS I-NP was VBD B-VP to TO B-VP investigate VB I-VP the DT B-NP modulation NN I-NP of IN B-PP the DT B-NP proliferation NN I-NP of IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP obtained VBN B-VP from IN B-PP peripheral JJ B-NP blood NN I-NP by IN B-PP dexamethasone NN B-NP ( ( O DEX NN B-NP ) ) O COMMA COMMA O isoproterenol NN B-NP ( ( O ISO NN B-NP ) ) O COMMA COMMA O and CC O prostaglandin NN B-NP E2 NN I-NP ( ( O PGE2 NN B-NP ) ) O . . O The DT B-NP former JJ I-NP two CD I-NP substances NNS I-NP interact VBP B-VP with IN B-PP T NN B-NP cells NNS I-NP via IN B-PP the DT O glucocorticoid NN B-NP and CC O beta-adrenergic JJ B-ADJP receptors NNS B-NP respectively RB B-ADVP . . O When WRB B-ADVP occupied VBN B-VP by IN B-PP their PRP$ B-NP natural JJ I-NP ligands NNS I-NP COMMA COMMA O glucocorticosteroids NNS B-NP and CC O catecholamines NNS B-NP COMMA COMMA O these DT B-NP receptors NNS I-NP have VBP B-VP a DT B-NP role NN I-NP in IN B-PP modulating VBG B-VP T-cell NN B-NP function NN I-NP during IN B-PP stress NN B-NP . . O During IN B-PP the DT B-NP inflammatory JJ I-NP response NN I-NP increased VBN B-NP levels NNS I-NP of IN B-PP PGE2 NN B-NP bind VBP B-VP to TO B-PP their PRP$ B-NP receptors NNS I-NP on IN B-PP T NN B-NP cells NNS I-NP and CC O thus RB O alter VBP B-VP responsiveness NN B-NP . . O Proliferation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP was VBD B-VP induced VBN I-VP by IN B-PP immobilized VBN B-NP anti-CD3 JJ I-NP monoclonal JJ B-NP antibody NN I-NP ( ( O mAb NN B-NP ) ) O in IN B-PP the DT B-NP presence NN B-NP or CC O absence NN B-NP of IN B-PP an DT B-NP additional JJ I-NP costimulatory JJ I-NP signal NN I-NP delivered VBN B-VP by IN B-PP anti-CD28 JJ B-NP mAb NN I-NP . . O 2 LS B-LST . . O Various JJ B-NP physiologic JJ I-NP concentrations NNS I-NP of IN B-PP DEX NN B-NP COMMA COMMA O ISO NN B-NP COMMA COMMA O or CC O PGE2 NN B-NP were VBD B-VP added VBN I-VP at IN B-PP the DT B-NP time NN I-NP of IN B-PP initiation NN B-NP of IN B-PP the DT B-NP cultures NNS I-NP and CC O subsequent JJ B-NP proliferation NN I-NP of IN B-PP the DT B-NP unstimulated JJ I-NP T NN I-NP cells NNS I-NP was VBD B-VP determined VBN I-VP . . O The DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR physiologic JJ B-NP concentrations NNS I-NP of IN B-PP all DT B-NP three CD I-NP of IN B-PP these DT B-NP agents NNS I-NP inhibit VBP B-VP the DT B-NP anti-CD3 JJ I-NP mAb-induced JJ I-NP proliferation NN I-NP of IN B-PP T NN B-NP cells NNS I-NP . . O 3 LS B-LST . . O Although IN B-SBAR DEX NN B-NP and CC O PGE2 NN B-NP were VBD B-VP equipotent JJ B-ADJP in IN B-PP suppressing JJ B-VP T-cell NN B-NP proliferation NN I-NP COMMA COMMA O ISO NN B-NP was VBD B-VP much RB B-ADJP less RBR I-ADJP effective JJ I-ADJP . . O 4 LS B-LST . . O Because IN B-SBAR concomitant JJ B-NP elevations NNS I-NP in IN B-PP the DT B-NP peripheral JJ I-NP levels NNS I-NP of IN B-PP these DT B-NP substances NNS I-NP may MD B-VP occur VB I-VP COMMA COMMA O experiments NNS B-NP were VBD B-VP performed VBN I-VP to TO B-VP determine VB I-VP the DT B-NP T-cell NN I-NP inhibitory JJ I-NP effects NNS I-NP of IN B-PP DEX NN B-NP together RB B-PP with IN I-PP either CC O PGE2 NN B-NP or CC O ISO NN B-NP . . O Synergistic JJ B-NP suppression NN I-NP of IN B-PP T-cell NN B-NP proliferation NN I-NP was VBD B-VP observed VBN I-VP when WRB B-ADVP various JJ B-NP concentrations NNS I-NP of IN B-PP DEX NN B-NP and CC O PGE2 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP DEX NN B-NP and CC O ISO NN B-NP COMMA COMMA O were VBD B-VP added VBN I-VP to TO B-PP cultures NNS B-NP . . O This DT B-NP synergistic JJ I-NP suppression NN I-NP could MD B-VP not RB I-VP be VB I-VP explained VBN I-VP by IN B-PP an DT B-NP increase NN I-NP in IN B-PP cAMP NN B-NP accumulation NN I-NP in IN B-PP T NN B-NP cells NNS I-NP stimulated VBN B-VP with IN B-PP DEX NN B-NP and CC O PGE2 NN B-NP . . O 5 LS B-LST . . O Finally RB B-ADVP COMMA COMMA O the DT B-NP addition NN I-NP of IN B-PP anti-CD28 JJ B-NP mAb NN I-NP to TO B-PP anti-CD3 JJ B-NP mAb-stimulated JJ I-NP T NN I-NP cells NNS I-NP overcame VBD B-VP much JJ B-NP of IN B-PP the DT B-NP suppression NN I-NP of IN B-PP proliferation NN B-NP induced VBN B-VP by IN B-PP PGE2 NN B-NP or CC O ISO NN B-NP but CC O less RBR B-ADVP so RB I-ADVP than IN B-PP that DT B-NP induced VBN B-VP by IN B-PP DEX NN B-NP . . O Targeted VBN B-NP degradation NN I-NP of IN B-PP c-Fos NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP v-Fos NN B-NP COMMA COMMA O by IN B-PP a DT B-NP phosphorylation-dependent JJ I-NP signal NN I-NP on IN B-PP c-Jun NN B-NP . . O The DT B-NP proto-oncogene NN I-NP products NNS I-NP c-Fos NN B-NP and CC O c-Jun NN B-NP heterodimerize VBP B-VP through IN B-PP their PRP$ B-NP leucine NN I-NP zippers NNS I-NP to TO B-VP form VB I-VP the DT B-NP AP-1 NN I-NP transcription NN I-NP factor NN I-NP . . O The DT B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP the DT B-NP heterodimer NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP signal-dependent JJ O phosphorylation NN B-NP and CC O dephosphorylation NN B-NP events NNS B-NP . . O The DT B-NP stability NN I-NP of IN B-PP c-Fos NN B-NP was VBD B-VP found VBN I-VP to TO I-VP also RB I-VP be VB I-VP controlled VBN I-VP by IN B-PP intracellular JJ B-NP signal NN I-NP transduction NN I-NP . . O In IN B-PP transient JJ B-NP expression NN I-NP and CC O in FW B-NP vitro FW I-NP degradation NN I-NP experiments NNS B-NP COMMA COMMA O the DT B-NP stability NN I-NP of IN B-PP c-Fos NN B-NP was VBD B-VP decreased VBN I-VP when WRB B-ADVP the DT B-NP protein NN I-NP was VBD B-VP dimerized JJ I-VP with IN B-PP phosphorylated VBN B-NP c-Jun NN I-NP . . O c-Jun NN B-NP protein NN I-NP isolated VBN B-VP from IN B-PP phorbol NN B-NP ester-induced JJ I-NP cells NNS I-NP did VBD B-VP not RB I-VP target VB I-VP c-Fos NN B-NP for IN B-PP degradation NN B-NP COMMA COMMA O which WDT B-NP suggests VBZ B-VP that IN B-SBAR c-Fos NN B-NP is VBZ B-VP transiently RB I-VP stabilized VBN I-VP after IN B-PP stimulation NN B-NP of IN B-PP cell NN B-NP growth NN I-NP . . O v-Fos NN B-NP protein NN I-NP COMMA COMMA O the DT B-NP retroviral JJ I-NP counterpart NN I-NP of IN B-PP c-Fos NN B-NP COMMA COMMA O was VBD B-VP not RB O susceptible JJ B-ADJP to TO B-PP degradation NN B-NP targeted VBN B-VP by IN B-PP c-Jun NN B-NP . . O Mutations NNS B-NP in IN B-PP the DT B-NP Pit-1 NN I-NP gene NN I-NP in IN B-PP children NNS B-NP with IN B-PP combined JJ B-NP pituitary JJ I-NP hormone NN I-NP deficiency NN I-NP . . O Pit-1 NN B-NP is VBZ B-VP a DT B-NP pituitary-specific JJ I-NP transcription NN I-NP factor NN I-NP that WDT B-NP binds VBZ B-VP to TO B-PP and CC O transactivates VBZ B-VP promoters NNS B-NP of IN B-PP growth NN B-NP hormone NN I-NP and CC O prolactin NN B-NP genes NNS I-NP . . O In IN B-PP three CD B-NP unrelated JJ I-NP Japanese JJ I-NP children NNS I-NP with IN B-PP combined JJ B-NP pituitary JJ I-NP hormone NN I-NP deficiency NN I-NP COMMA COMMA O we PRP B-NP identified VBD B-VP three CD B-NP point NN I-NP mutations NNS I-NP in IN B-PP the DT B-NP Pit-1 NN I-NP gene NN I-NP COMMA COMMA O Pro24Leu NN B-NP COMMA COMMA O Arg143Gln NN B-NP COMMA COMMA O and CC O Arg271Trp NN B-NP COMMA COMMA O located JJ O on IN B-PP the DT B-NP major JJ I-NP transactivation NN I-NP region NN I-NP COMMA COMMA O POU-specific JJ B-NP domain NN I-NP COMMA COMMA O and CC O POU-homeodomain NN B-NP COMMA COMMA O respectively RB B-ADJP . . O Calcitriol NN B-NP : : O a DT B-NP hematolymphopoietrope NN I-NP ? . O { ( O editorial NN B-NP } ) O A DT B-NP MEDLINE NN I-NP search NN I-NP of IN B-PP the DT B-NP English-language JJ I-NP literature NN I-NP was VBD B-VP conducted VBN I-VP using VBG B-VP the DT B-NP indexing NN I-NP terms NNS I-NP ' `` O immunology NN B-NP COMMA COMMA O calcitriol NN B-NP and CC O vitamin NN B-NP D NN I-NP ' '' O to TO B-VP identify VB I-VP studies NNS B-NP indicating VBG B-VP a DT B-NP role NN I-NP for IN B-PP calcitriol NN B-NP as IN B-PP a DT B-NP primary JJ I-NP immunomodulator NN I-NP . . O Sixty-six CD B-NP papers NNS I-NP published VBN B-VP between IN B-PP January NNP B-NP 1956 CD I-NP and CC O June NNP B-NP 1991 CD I-NP were VBD B-VP identified VBN I-VP . . O Forty-five CD B-NP of IN B-PP these DT B-NP reports NNS I-NP are VBP B-VP cited VBN I-VP in IN B-PP this DT B-NP review NN I-NP . . O The DT B-NP data NNS I-NP strongly RB B-ADVP suggest VBP B-VP an DT B-NP endocrine NN I-NP COMMA COMMA I-NP autocrine NN I-NP and\/or CC I-NP paracrine NN I-NP role NN I-NP for IN B-PP calcitriol NN B-NP in IN B-PP immune JJ B-NP regulation NN I-NP . . O No DT B-NP unifying JJ I-NP hypothesis NN I-NP has VBZ B-VP yet RB I-VP emerged VBN I-VP explaining VBG I-VP this DT B-NP collection NN I-NP of IN B-PP data NNS B-NP . . O This DT B-NP paper NN I-NP provides VBZ B-VP a DT B-NP brief JJ I-NP review NN I-NP of IN B-PP immune JJ B-NP properties NNS I-NP currently RB B-VP attributed VBN I-VP to TO B-PP calcitriol NN B-NP . . O Activation NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP and CC O elevation NN B-NP of IN B-PP cAMP NN B-NP interact VBP B-VP synergistically RB I-VP to TO I-VP raise VB I-VP c-Fos NN B-NP and CC O AP-1 NN B-NP activity NN B-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O We PRP B-NP have VBP B-VP earlier RBR I-VP found VBN I-VP that IN B-SBAR in IN B-PP Jurkat NN B-NP cells NNS I-NP activation NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O enhances VBZ B-VP the DT O cyclic JJ B-NP adenosine NN I-NP monophosphate NN I-NP ( ( O cAMP NN B-NP ) ) O accumulation NN B-NP induced VBN B-VP by IN B-PP adenosine NN B-NP receptor NN I-NP stimulation NN I-NP or CC O activation NN B-NP of IN B-PP Gs NN B-NP . . O Here RB B-ADVP we PRP B-NP have VBP B-VP therefore RB I-VP examined VBN I-VP the DT B-NP effect NN I-NP of IN B-PP the DT B-NP phorbol NN I-NP ester NN I-NP PMA NN B-NP ( ( O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ) ) O which WDT B-NP stimulates VBZ B-VP PKC NN B-NP and CC O a DT B-NP combination NN I-NP of IN B-PP the DT B-NP adenosine NN I-NP receptor NN I-NP agonist NN I-NP NECA NN B-NP ( ( O 5'-(N-ethyl)-carboxamido JJ B-NP adenosine NN I-NP ) ) O and CC O forskolin NN B-NP to TO B-VP raise VB I-VP cAMP NN B-NP COMMA COMMA O on IN B-PP the DT B-NP levels NNS I-NP of IN B-PP c-Fos NN B-NP and CC O Jun NN B-NP and CC B-PP on IN B-PP the DT B-NP binding VBG B-NP and CC O transcriptional JJ B-NP activity NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O activator NN B-NP protein-1 NN I-NP ( ( O AP-1 NN B-NP ) ) O . . O PMA NN B-NP treatment NN I-NP caused VBD B-VP a DT O concentration- NN B-NP and CC O time-dependent JJ B-ADJP increase NN B-NP in IN B-PP both CC O c-Fos NN B-NP and CC O Jun NN B-NP immunoreactivity NN B-NP in IN B-PP contrast NN I-PP to TO I-PP cAMP NN B-NP elevation NN I-NP that WDT B-NP had VBD B-VP only RB B-NP a DT I-NP slight JJ I-NP effect NN I-NP . . O Both CC O PMA NN B-NP and CC O the DT B-NP combination NN I-NP of IN B-PP NECA NN B-NP and CC O forskolin NN B-NP acted VBD B-VP together RB B-ADVP either CC O to TO B-VP increase VB I-VP ( ( O c-Fos NN B-NP ) ) O or CC O decrease VB B-VP ( ( O Jun NN B-NP ) ) O protein NN B-NP levels NNS I-NP as RB B-PP well RB I-PP as IN I-PP increasing VBG B-VP AP-1 NN B-NP binding NN I-NP COMMA COMMA O as IN B-SBAR judged VBN B-VP by IN B-PP gel-shift NN B-NP assay NN I-NP COMMA COMMA O and CC O AP-1 NN B-NP transcriptional JJ I-NP activity NN I-NP . . O Furthermore RB B-ADVP there EX B-NP was VBD B-VP a DT B-NP clear-cut JJ I-NP synergy NN I-NP between IN B-PP the DT B-NP PKC NN I-NP stimulator NN I-NP and CC O the DT B-NP cAMP NN I-NP elevating NN I-NP agents NNS I-NP . . O The DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP simultaneous JJ I-NP activation NN B-NP of IN B-PP PKC NN B-NP and CC O elevation NN B-NP of IN B-PP cAMP NN B-NP leads VBZ B-VP to TO B-PP an DT B-NP enhanced VBN I-NP AP-1 NN I-NP transcriptional JJ I-NP activity NN I-NP in IN B-PP a DT B-NP T-leukemia NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR the DT B-NP previously RB I-NP observed VBN I-NP interaction NN I-NP between IN B-PP the DT B-NP parallel JJ I-NP signal NN I-NP transduction NN I-NP pathways NNS I-NP may MD B-VP have VB I-VP functional JJ B-NP consequences NNS I-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP gene NN B-NP transcription NN I-NP . . O The DT B-NP use NN I-NP of IN B-PP interferon-gamma-treated JJ B-NP U937 NN I-NP cells NNS I-NP in IN B-PP chemiluminescence NN B-NP assays NNS I-NP to TO B-VP detect VB I-VP red JJ B-NP cell NN I-NP COMMA COMMA O platelet NN B-NP and CC O granulocyte NN B-NP antibodies NNS I-NP of IN B-PP potential JJ B-NP clinical JJ I-NP significance NN I-NP . . O The DT O chemiluminescent JJ O ( ( O CL JJ B-ADJP ) ) O response NN B-NP of IN B-PP interferon-gamma-treated JJ B-NP U937 NN I-NP ( ( O IFN-U937 NN B-NP ) ) O cells NNS B-NP to TO B-PP sensitized VBN B-NP target NN I-NP cells NNS I-NP has VBZ B-VP been VBN I-VP used VBN I-VP to TO B-VP detect VB I-VP red JJ B-NP cell NN I-NP COMMA COMMA O platelet NN B-NP and CC O granulocyte NN B-NP antibodies NNS I-NP . . O A DT B-NP clone NN I-NP of IN B-PP U937 NN B-NP cells NNS I-NP was VBD B-VP selected VBN I-VP which WDT B-NP expressed VBD B-VP Fc NN B-NP receptor NN I-NP I NN I-NP ( ( O Fc NN B-NP gamma NN I-NP RI NN I-NP ) ) O and CC O which WDT B-NP COMMA COMMA O after IN B-PP incubation NN B-NP with IN B-PP IFN-gamma NN B-NP for IN B-PP 72 CD B-NP h NN I-NP COMMA COMMA O was VBD B-VP capable JJ B-ADJP of IN B-PP generating VBG B-VP high JJ B-NP levels NNS I-NP of IN B-PP lucigenin-enhanced JJ B-NP CL NN I-NP . . O The DT B-NP CL NN I-NP responses NNS I-NP of IN B-PP IFN-U937 NN B-NP cells NNS I-NP and CC O peripheral JJ B-NP blood NN I-NP human JJ I-NP monocytes NNS I-NP to TO B-PP sensitized VBN B-NP red JJ B-NP cells NNS I-NP COMMA COMMA O platelets NNS B-NP or CC O granulocytes NNS B-NP were VBD B-VP then RB I-VP compared VBN I-VP . . O Assays NNS B-NP using VBG B-VP monocytes NNS B-NP or CC O IFN-U937 NN B-NP cells NNS I-NP were VBD B-VP of IN B-PP comparable JJ B-NP sensitivity NN I-NP for IN B-PP detection NN B-NP of IN B-PP antibodies NNS B-NP against IN B-PP all DT B-NP three CD I-NP types NNS I-NP of IN B-PP target NN B-NP cell NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O the DT B-NP use NN I-NP of IN B-PP IFN-U937 NN B-NP cells NNS I-NP reduced VBD B-VP interassay JJ B-NP variation NN I-NP and CC O simplified VBD B-VP assay NN B-NP performance NN I-NP . . O The DT B-NP potential JJ I-NP clinical JJ I-NP usefulness NN I-NP of IN B-PP these DT B-NP CL NN I-NP assays NNS I-NP was VBD B-VP suggested VBN I-VP by IN B-PP the DT B-NP ability NN I-NP of IN B-PP both CC O monocytes NNS B-NP and CC O IFN-U937 NN B-NP cells NNS I-NP to TO B-VP respond VB I-VP to TO B-PP red JJ B-NP cells NNS I-NP COMMA COMMA O platelets NNS B-NP or CC O granulocytes NNS B-NP sensitized VBN B-VP with IN B-PP sera NN B-NP from IN B-PP pregnant JJ B-NP women NNS I-NP whose WP$ B-NP babies NNS I-NP had VBD B-VP either CC O haemolytic JJ B-NP disease NN I-NP of IN I-NP the DT I-NP newborn JJ I-NP ( ( O HDN NN B-NP ) ) O COMMA COMMA O alloimmune JJ B-NP thrombocytopenia NN I-NP or CC O alloimmune JJ B-NP neutropenia NN I-NP respectively RB B-ADVP . . O In IN B-PP addition NN B-NP COMMA COMMA O monocytes NNS B-NP and CC O IFN-U937 NN B-NP cells NNS I-NP both DT B-NP responded VBD B-VP to TO B-PP red JJ B-NP cells NNS I-NP sensitized VBN B-VP with IN B-PP antibodies NNS B-NP against IN B-PP a DT B-NP variety NN I-NP of IN B-PP specificities NNS B-NP of IN B-PP assumed VBN B-NP ( ( I-NP although IN I-NP not RB I-NP documented VBN I-NP ) ) I-NP clinical JJ I-NP significance NN I-NP for IN B-PP blood NN B-NP transfusion NN I-NP recipients NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O monocytes NNS B-NP and CC O IFN-U937 NN B-NP cells NNS I-NP responded VBD B-VP only RB B-ADVP weakly RB I-ADVP to TO B-PP red JJ B-NP cells NNS I-NP sensitized VBN B-VP with IN B-PP either CC I-PP anti-D JJ B-NP in IN B-PP sera NN B-NP from IN B-PP mothers NNS B-NP of IN B-PP babies NNS B-NP unaffected JJ B-VP by IN B-PP HDN NN B-NP COMMA COMMA B-PP or CC I-PP with IN B-PP antisera NNS B-NP containing VBG B-VP high JJ B-NP titre NN I-NP antibodies NNS I-NP with IN B-PP specificities NNS B-NP not RB B-VP normally RB I-VP associated VBN I-VP with IN B-PP significantly RB B-NP reduced VBN I-NP red JJ I-NP cell NN I-NP survival NN I-NP . . O Photoaffinity NN B-NP labeling NN I-NP of IN B-PP plasma NN B-NP membrane NN I-NP receptors NNS I-NP for IN B-PP aldosterone NN B-NP from IN B-PP human JJ B-NP mononuclear JJ I-NP leukocytes NNS I-NP . . O Non-genomic JJ B-NP effects NNS I-NP of IN B-PP aldosterone NN B-NP on IN B-PP the DT B-NP sodium-proton-antiport NN I-NP have VBP B-VP been VBN I-VP shown VBN I-VP in IN B-PP human JJ B-NP mononuclear JJ I-NP leukocytes NNS I-NP which WDT B-NP could MD B-VP be VB I-VP related JJ B-ADJP to TO B-PP a DT B-NP new JJ I-NP aldosterone NN I-NP membrane NN I-NP receptor NN I-NP . . O In IN B-PP the DT B-NP present JJ I-NP paper NN I-NP plasma NN B-NP membranes NNS I-NP from IN B-PP human JJ B-NP mononuclear JJ I-NP leukocytes NNS I-NP were VBD B-VP covalently RB I-VP photolabeled VBN I-VP with IN B-PP a DT B-NP {125I}-aldosterone NN I-NP derivative NN I-NP . . O Sodium NN B-NP dodecyl NN I-NP sulfate-polyacrylamide JJ I-NP gel NN I-NP electrophoresis NN I-NP showed VBD B-VP significant JJ B-NP aldosterone NN I-NP binding NN I-NP at IN B-PP a DT B-NP molecular JJ I-NP weight NN I-NP of IN B-PP approximately RB B-NP 50000 CD I-NP Dalton NN I-NP which WDT B-NP was VBD B-VP absent JJ B-ADJP with IN B-PP 1 CD B-NP microM NN I-NP cold JJ B-NP aldosterone NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP cortisol NN B-NP in IN B-PP the DT B-NP binding VBG I-NP media NNS I-NP . . O The DT B-NP presence NN I-NP of IN B-PP the DT B-NP sulfhydryl NN I-NP agent NN I-NP dithiothreitol NN I-NP did VBD B-VP not RB I-VP affect VB I-VP results NNS B-NP suggesting VBG B-VP the DT B-NP absence NN I-NP of IN B-PP disulfide NN B-NP bridges NNS I-NP in IN B-PP the DT B-NP steroid NN I-NP binding NN I-NP domain NN I-NP of IN B-PP the DT B-NP receptor NN I-NP . . O These DT B-NP data NNS I-NP are VBP B-VP the DT B-NP first JJ I-NP to TO B-VP define VB I-VP the DT B-NP molecular JJ I-NP weight NN I-NP of IN B-PP the DT B-NP membrane NN I-NP receptor NN I-NP for IN B-PP aldosterone NN B-NP . . O Alpha-lipoic JJ B-NP acid NN I-NP is VBZ B-VP a DT B-NP potent JJ I-NP inhibitor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP . . O Acquired VBN B-NP immunodeficiency NN I-NP syndrome NN I-NP ( ( O AIDS NN B-NP ) ) O results VBZ B-VP from IN B-PP infection NN B-NP with IN B-PP a DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O . . O The DT O long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O region NN B-NP of IN B-PP HIV NN B-NP proviral JJ I-NP DNA NN I-NP contains VBZ B-VP binding VBG B-NP sites NNS I-NP for IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O COMMA COMMA O and CC O this DT B-NP transcriptional JJ I-NP activator NN I-NP appears VBZ B-VP to TO I-VP regulate VB I-VP HIV NN B-NP activation NN I-NP . . O Recent JJ B-NP findings NNS I-NP suggest VBP B-VP an DT B-NP involvement NN I-NP of IN B-PP reactive JJ B-NP oxygen NN I-NP species NNS I-NP ( ( O ROS NN B-NP ) ) O in IN B-PP signal NN B-NP transduction NN I-NP pathways NNS I-NP leading VBG B-VP to TO B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP . . O The DT B-NP present JJ I-NP study NN I-NP was VBD B-VP based VBN I-VP on IN B-PP reports NNS B-NP that IN B-SBAR antioxidants NNS B-NP which WDT B-NP eliminate VBP B-VP ROS NN B-NP should MD B-VP block VB I-VP the DT B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O subsequently RB B-ADVP HIV NN B-NP transcription NN I-NP COMMA COMMA O and CC O thus RB O antioxidants NNS B-NP can MD B-VP be VB I-VP used VBN I-VP as IN B-PP therapeutic JJ B-NP agents NNS I-NP for IN B-PP AIDS NN B-NP . . O Incubation NN B-NP of IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP ( ( O 1 CD B-NP x CC I-NP 10(6) CD I-NP cells\/ml NNS I-NP ) ) O with IN B-PP a DT B-NP natural JJ I-NP thiol NN I-NP antioxidant NN I-NP COMMA COMMA I-NP alpha-lipoic JJ I-NP acid NN I-NP COMMA COMMA O prior JJ B-PP to TO I-PP the DT B-NP stimulation NN I-NP of IN B-PP cells NNS B-NP was VBD B-VP found VBN I-VP to TO I-VP inhibit VB I-VP NF-kappa NN B-NP B NN I-NP activation NN I-NP induced VBN B-VP by IN B-PP tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O 25 CD B-NP ng\/ml NN I-NP ) ) O or CC B-PP by IN B-PP phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O 50 CD B-NP ng\/ml NN I-NP ) ) O . . O The DT B-NP inhibitory JJ I-NP action NN I-NP of IN B-PP alpha-lipoic JJ B-NP acid NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP very RB B-ADJP potent JJ I-ADJP as IN B-SBAR only RB B-NP 4 CD I-NP mM NN I-NP was VBD B-VP needed VBN I-VP for IN B-PP a DT B-NP complete JJ I-NP inhibition NN I-NP COMMA COMMA O whereas IN O 20 CD B-NP mM NN I-NP was VBD B-VP required VBN I-VP for IN B-PP N-acetylcysteine NN B-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR alpha-lipoic JJ B-NP acid NN I-NP may MD B-VP be VB I-VP effective JJ B-ADJP in IN B-PP AIDS NN B-NP therapeutics NNS I-NP . . O Activation NN B-NP of IN B-PP lymphokine NN B-NP genes NNS I-NP in IN B-PP T NN B-NP cells NNS I-NP : : O role NN B-NP of IN B-PP cis-acting JJ B-NP DNA NN I-NP elements NNS I-NP that WDT B-NP respond VBP B-VP to TO B-PP T NN B-NP cell NN I-NP activation NN I-NP signals NNS I-NP . . O Activation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP is VBZ B-VP initiated VBN I-VP by IN B-PP the DT B-NP recognition NN I-NP of IN B-PP antigen NN B-NP on IN B-PP antigen NN B-NP presenting NN I-NP cells NNS I-NP to TO B-VP exert VB I-VP the DT B-NP effector NN I-NP functions NNS I-NP in IN B-PP immune JJ B-NP and CC I-NP inflammatory JJ I-NP responses NNS I-NP . . O Two CD B-NP types NNS I-NP of IN B-PP helper NN B-NP T NN I-NP cell NN I-NP ( ( O Th NN B-NP ) ) O clones NNS B-NP ( ( O Th1 NN B-NP and CC O Th2 NN B-NP ) ) O are VBP B-VP defined VBN I-VP on IN B-PP the DT I-PP basis NN I-PP of IN I-PP different JJ B-NP patterns NNS I-NP of IN B-PP cytokine NN B-NP ( ( O lymphokine NN B-NP ) ) O secretion NN B-NP . . O They PRP B-NP determine VBP B-VP the DT B-NP outcome NN I-NP of IN B-PP an DT B-NP antigenic JJ I-NP response NN I-NP toward IN B-PP humoral JJ B-NP or CC I-NP cell-mediated JJ I-NP immunity NN I-NP . . O Although IN B-SBAR lymphokine NN B-NP genes NNS I-NP are VBP B-VP coordinately RB I-VP regulated VBN I-VP upon IN B-PP antigen NN B-NP stimulation NN I-NP COMMA COMMA O they PRP B-NP are VBP B-VP regulated VBN I-VP by IN B-PP the DT B-NP mechanisms NNS I-NP common JJ B-ADJP to TO B-PP all DT B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP those DT B-NP which WDT B-NP are VBP B-VP unique JJ B-ADJP to TO B-PP each DT B-NP gene NN I-NP . . O For IN B-PP most JJS B-NP lymphokine NN I-NP genes NNS I-NP COMMA COMMA O a DT B-NP combination NN I-NP of IN B-PP phorbol NN B-NP esters NNS I-NP ( ( O phorbol NN B-NP 12-myristate NN I-NP 13 CD I-NP acetate NN I-NP COMMA COMMA O PMA NN B-NP ) ) O and CC O calcium NN B-NP ionophores NNS I-NP ( ( O A23187 NN B-NP ) ) O is VBZ B-VP required VBN I-VP for IN B-PP their PRP$ B-NP maximal JJ I-NP induction NN I-NP . . O Yet RB O phorbol NN B-NP ester NN I-NP alone RB B-ADVP or CC O calcium NN B-NP ionophore NN I-NP alone RB B-ADVP produce VBP B-VP several JJ B-NP lymphokines NNS I-NP . . O The DT B-NP production NN I-NP of IN B-PP the DT B-NP granulocyte-macrophage JJ I-NP colony NN I-NP stimulating NN I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O is VBZ B-VP completely RB B-ADJP dependent JJ I-ADJP on IN B-PP the DT B-NP two CD I-NP signals NNS I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP found VBN I-VP a DT B-NP cis-acting JJ I-NP region NN I-NP spanning VBG B-VP the DT B-NP GM-CSF NN I-NP promoter NN I-NP region NN I-NP ( ( O positions NNS B-NP -95 CD B-NP to TO O +27 CD B-NP ) ) O that WDT B-NP confers VBZ B-VP inducibility NN B-NP to TO B-PP reporter NN B-NP genes NNS I-NP in IN B-PP transient JJ B-NP transfection NN I-NP assays NNS I-NP . . O Further JJ B-NP analysis NN I-NP identified VBD B-VP three CD B-NP elements NNS I-NP required VBN B-VP for IN B-PP efficient JJ B-NP induction NN I-NP COMMA COMMA O referred VBN B-VP to TO B-PP as IN B-PP GM2 NN B-NP COMMA COMMA O GC-box NN B-NP and CC O conserved VBN B-NP lymphokine NN I-NP element NN I-NP ( ( O CLE0 NN B-NP ) ) O . . O GM2 NN B-NP defines VBZ B-VP a DT B-NP binding VBG I-NP site NN I-NP for IN B-PP protein NN B-NP ( ( I-NP s NNS I-NP ) ) O whose WP$ B-NP binding NN I-NP is VBZ B-VP inducible JJ B-ADJP by IN B-PP PMA NN B-NP . . O One CD B-NP protein NN I-NP COMMA COMMA O NF-GM2 NN B-NP is VBZ B-VP similar JJ B-ADJP to TO B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kB NN I-NP . . O GC-box NN B-NP is VBZ B-VP a DT B-NP binding VBG I-NP site NN I-NP for IN B-PP constitutively RB B-NP bound VBN I-NP proteins NNS I-NP . . O CLEO NN B-NP defines VBZ B-VP a DT B-NP binding VBG I-NP site NN I-NP for IN B-PP protein NN B-NP ( ( I-NP s NNS I-NP ) ) O whose WP$ B-NP optimum NN I-NP binding NN I-NP is VBZ B-VP stimulated VBN I-VP by IN B-PP PMA NN B-NP and CC O A23187 NN B-NP . . O Viral JJ B-NP trans-activators NNS I-NP such JJ B-PP as IN I-PP Tax NN B-NP ( ( O human JJ B-NP T NN I-NP cell NN I-NP leukemia NN I-NP virus-1 NN I-NP COMMA COMMA O HTLV-1 NN B-NP ) ) O and CC O E2 NN B-NP ( ( O bovine JJ B-NP papilloma NN I-NP virus NN I-NP COMMA COMMA O BPV NN B-NP ) ) O proteins NNS B-NP are VBP B-VP other JJ B-NP agents NNS I-NP which WDT B-NP activate VBP B-VP lymphokine NN B-NP gene NN I-NP expression NN I-NP by IN B-PP bypassing VBG B-VP T NN B-NP cell NN I-NP receptor NN I-NP ( ( O TCR NN B-NP ) ) O mediated JJ B-NP signaling NN I-NP . . O The DT B-NP trans-activation NN I-NP domain NN I-NP of IN B-PP E2 NN B-NP and CC O Tax NN B-NP is VBZ B-VP interchangeable JJ B-ADJP although IN B-SBAR they PRP B-NP have VBP B-VP no DT B-NP obvious JJ I-NP sequence NN I-NP homology NN I-NP between IN B-PP them PRP B-NP . . O The DT B-NP viral JJ I-NP trans-activators NNS I-NP appear VBP B-VP to TO I-VP target VB I-VP specific JJ B-NP DNA NN I-NP binding NN I-NP protein NN I-NP such JJ B-PP as IN I-PP NF-kB NN B-NP and CC O Sp1 NN B-NP to TO B-PP cis-acting JJ B-NP DNA NN I-NP site NN I-NP and CC O promote VB B-VP lymphokine NN B-NP gene NN I-NP expression NN I-NP without IN B-PP TCR-mediated JJ B-NP stimulation NN I-NP . . O I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP masks VBZ B-VP the DT B-NP nuclear JJ I-NP localization NN I-NP signal NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP and CC O requires VBZ B-VP the DT B-NP transactivation NN I-NP domain NN I-NP to TO B-VP inhibit VB I-VP NF-kappa NN B-NP B NN I-NP p65 NN I-NP DNA NN I-NP binding NN I-NP . . O The DT B-NP active JJ I-NP nuclear JJ I-NP form NN I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP complex NN I-NP is VBZ B-VP composed VBN I-VP of IN B-PP two CD B-NP DNA NN I-NP binding NN I-NP subunits NNS I-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP p65 NN I-NP and CC O NF-kappa NN B-NP B NN I-NP p50 NN I-NP COMMA COMMA O both DT B-NP of IN B-PP which WDT B-NP share VBP B-VP extensive JJ B-NP N-terminal JJ I-NP sequence NN I-NP homology NN I-NP with IN B-PP the DT B-NP v-rel NN I-NP oncogene NN I-NP product NN I-NP . . O The DT B-NP NF-kappa NN I-NP B NN I-NP p65 NN I-NP subunit NN I-NP provides VBZ B-VP the DT B-NP transactivation NN I-NP activity NN I-NP in IN B-PP this DT B-NP complex JJ I-NP and CC O serves VBZ B-VP as IN B-PP an DT B-NP intracellular JJ I-NP receptor NN I-NP for IN B-PP a DT B-NP cytoplasmic JJ I-NP inhibitor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O termed VBN B-VP I NN B-NP kappa NN I-NP B NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP p50 NN I-NP alone RB B-ADVP fails VBZ B-VP to TO I-VP stimulate VB I-VP kappa NN B-NP B-directed JJ I-NP transcription NN I-NP COMMA COMMA O and CC O based VBN B-PP on IN B-PP prior JJ B-NP in FW I-NP vitro FW I-NP studies NNS I-NP COMMA COMMA O is VBZ B-VP not RB I-VP directly RB I-VP regulated VBN I-VP by IN B-PP I NN B-NP kappa NN I-NP B NN I-NP . . O To TO B-VP investigate VB I-VP the DT B-NP molecular JJ I-NP basis NN I-NP for IN B-PP the DT B-NP critical JJ I-NP regulatory JJ I-NP interaction NN I-NP between IN B-PP NF-kappa NN B-NP B NN I-NP and CC O I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP COMMA COMMA O a DT B-NP series NN I-NP of IN B-PP human JJ B-NP NF-kappa NN I-NP B NN I-NP p65 NN I-NP mutants NNS I-NP was VBD B-VP identified VBN I-VP that WDT B-NP functionally RB B-ADVP segregated VBD B-VP DNA NN B-NP binding NN I-NP COMMA COMMA O I NN B-NP kappa NN I-NP B-mediated JJ I-NP inhibition NN I-NP COMMA COMMA O and CC O I NN B-NP kappa NN I-NP B-induced JJ I-NP nuclear JJ I-NP exclusion NN I-NP of IN B-PP this DT B-NP transcription NN I-NP factor NN I-NP . . O Results NNS B-NP from IN B-PP in FW B-NP vivo FW I-NP expression NN I-NP studies NNS I-NP performed VBN B-VP with IN B-PP these DT B-NP NF-kappa NN I-NP B NN I-NP p65 NN I-NP mutants NNS I-NP revealed VBD B-VP the DT B-NP following NN I-NP : : O 1 LS B-LST ) ) O I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP completely RB B-ADVP inhibits VBZ B-VP NF-kappa NN B-NP B NN I-NP p65-dependent JJ I-NP transcriptional JJ I-NP activation NN I-NP mediated VBN B-VP through IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP kappa NN I-NP B NN I-NP enhancer NN I-NP in IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP COMMA COMMA O 2 LS B-LST ) ) O the DT B-NP binding NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP to TO B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP is VBZ B-VP sufficient JJ B-ADJP to TO B-VP retarget VB I-VP NF-kappa NN B-NP B NN I-NP p65 NN I-NP from IN B-PP the DT B-NP nucleus NN I-NP to TO B-PP the DT B-NP cytoplasm NN I-NP COMMA COMMA O 3 LS B-LST ) ) O selective JJ B-NP deletion NN I-NP of IN B-PP the DT B-NP functional JJ I-NP nuclear JJ I-NP localization NN I-NP signal NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP Rel NN I-NP homology NN I-NP domain NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP disrupts VBZ B-VP its PRP$ B-NP ability NN I-NP to TO B-VP engage VB I-VP I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP COMMA COMMA O and CC O 4 LS B-LST ) ) O the DT B-NP unique JJ I-NP C-terminus NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP attenuates VBZ B-VP its PRP$ B-NP own JJ I-NP nuclear JJ I-NP localization NN I-NP and CC O contains VBZ B-VP sequences NNS B-NP that WDT B-NP are VBP B-VP required VBN I-VP for IN B-PP I NN B-NP kappa NN I-NP B-mediated JJ I-NP inhibition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP DNA NN I-NP binding NN I-NP activity NN I-NP . . O Together RB B-ADVP COMMA COMMA O these DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP nuclear JJ B-NP localization NN I-NP signal NN I-NP and CC O transactivation NN B-NP domain NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP constitute VBP B-VP a DT B-NP bipartite JJ I-NP system NN I-NP that WDT B-NP is VBZ B-VP critically RB I-VP involved VBN I-VP in IN B-PP the DT B-NP inhibitory JJ I-NP function NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP . . O Unexpectedly RB B-ADVP COMMA COMMA O our PRP$ B-NP in FW I-NP vivo FW I-NP studies NNS I-NP also RB B-ADVP demonstrate VBP B-VP that IN B-SBAR I NN B-NP kappa NN I-NP B\/MAD-3 NN I-NP binds VBZ B-VP directly RB B-ADVP to TO B-PP NF-kappa NN B-NP B NN I-NP p50 NN I-NP . . O This DT B-NP interaction NN I-NP is VBZ B-VP functional JJ B-ADJP as IN B-SBAR it PRP B-NP leads VBZ B-VP to TO B-PP retargeting NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP p50 NN I-NP from IN B-PP the DT B-NP nucleus NN I-NP to TO B-PP the DT B-NP cytoplasm NN I-NP . . O However RB B-ADVP COMMA COMMA O no DT B-NP loss NN I-NP of IN B-PP DNA NN B-NP binding NN I-NP activity NN I-NP is VBZ B-VP observed VBN I-VP COMMA COMMA O presumably RB B-ADVP reflecting VBG B-VP the DT B-NP unique JJ I-NP C-terminal JJ I-NP domain NN I-NP that WDT B-NP is VBZ B-VP distinct JJ B-ADJP from IN B-PP that DT B-NP present JJ B-ADJP in IN B-PP NF-kappa NN B-NP B NN I-NP p65 NN I-NP . . O Surrogate NN B-NP thyroglobulin NN I-NP receptors NNS I-NP and CC O T NN B-NP cell NN I-NP proliferation NN I-NP in IN B-PP Hashimoto NN B-NP 's POS B-NP thyroiditis NN I-NP . . O Immunoglobulin NN B-NP molecules NNS I-NP on IN B-PP the DT B-NP surface NN I-NP of IN B-PP a DT B-NP B NN I-NP lymphocyte NN I-NP are VBP B-VP the DT B-NP endogenous JJ I-NP " `` I-NP receptors NNS I-NP " '' O to TO B-PP which WDT B-NP specific JJ B-NP antigens NNS I-NP bind VBP B-VP . . O Studies NNS B-NP in IN B-PP mice NNS B-NP have VBP B-VP shown VBN I-VP that IN B-SBAR a DT B-NP monoclonal JJ I-NP antibody NN I-NP COMMA COMMA O conjugated VBN B-VP with IN B-PP palmitate NN B-NP to TO B-VP provide VB I-VP a DT B-NP lipid NN I-NP tail NN I-NP COMMA COMMA O can MD B-VP be VB I-VP inserted VBN I-VP into IN B-PP the DT B-NP cell NN I-NP membrane NN I-NP to TO B-VP provide VB I-VP a DT B-NP " `` I-NP surrogate JJ I-NP " '' I-NP antigen NN I-NP receptor NN I-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP whether IN B-SBAR a DT B-NP palmitate JJ I-NP conjugate NN I-NP of IN B-PP a DT B-NP human JJ I-NP monoclonal JJ I-NP antibody NN I-NP specific JJ B-ADJP for IN B-PP thyroglobulin NN B-NP ( ( O TG NN B-NP ) ) O could MD B-VP function VB I-VP as IN B-PP a DT B-NP surrogate JJ I-NP TG NN I-NP receptor NN I-NP on IN B-PP blood NN B-NP mononuclear JJ I-NP cells NNS I-NP separated VBN B-VP into IN B-PP fractions NNS B-NP enriched VBN B-VP for IN B-PP T NN B-NP cells NNS I-NP or CC O depleted VBN B-VP of IN B-PP T NN B-NP cells NNS I-NP ( ( O non-T JJ B-NP cells NNS I-NP ) ) O . . O Using VBG B-VP flow NN B-NP cytometry NN I-NP COMMA COMMA O we PRP B-NP detected VBD B-VP surrogate JJ B-NP TG NN I-NP receptors NNS I-NP on IN B-PP non-T JJ B-NP ( ( B-PP but CC I-PP not RB B-PP on IN I-PP T NN B-NP ) ) O cells NNS B-NP from IN B-PP 11 CD B-NP of IN I-NP 11 CD I-NP individuals NNS I-NP studied VBN B-VP ( ( O 5 CD B-NP Hashimoto NN I-NP patients NNS I-NP and CC O 6 CD B-NP control NN I-NP donors NNS I-NP ) ) O . . O In IN B-PP contrast NN B-NP COMMA COMMA O endogenous JJ B-NP TG NN I-NP receptors NNS I-NP could MD B-VP only RB I-VP be VB I-VP detected VBN I-VP on IN B-PP non-T JJ B-NP cells NNS I-NP from IN B-PP 1 CD B-NP of IN I-NP 3 CD I-NP Hashimoto NN I-NP patients NNS I-NP and CC B-PP from IN B-PP 0 CD B-NP of IN I-NP 4 CD I-NP control NN I-NP donors NNS I-NP . . O Because IN B-PP of IN I-PP the DT B-NP efficient JJ I-NP binding NN I-NP of IN B-PP TG NN B-NP by IN B-PP surrogate JJ B-NP receptors NNS I-NP on IN B-PP non-T JJ B-NP cells NNS I-NP COMMA COMMA O we PRP B-NP assessed VBD B-VP the DT B-NP ability NN I-NP of IN B-PP such JJ B-NP cells NNS I-NP to TO B-VP present VB I-VP TG NN B-NP to TO B-PP T NN B-NP cells NNS I-NP . . O Proliferation NN B-NP in IN B-PP response NN I-PP to TO I-PP TG NN B-NP was VBD B-VP observed VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP from IN B-PP only RB B-NP 1 CD I-NP of IN I-NP 5 CD I-NP Hashimoto NN I-NP patients NNS I-NP . . O This DT B-NP low JJ I-NP frequency NN I-NP of IN B-PP response NN B-NP was VBD B-VP no RB B-ADJP different JJ I-ADJP from IN B-PP that DT B-NP previously RB B-VP detected VBN I-VP using VBG B-VP cultures NNS B-NP of IN B-PP T NN B-NP cells NNS I-NP and CC O autologous JJ B-NP dendritic JJ I-NP cells NNS I-NP . . O Therefore RB B-ADVP COMMA COMMA O the DT B-NP successful JJ I-NP generation NN I-NP of IN B-PP surrogate JJ B-NP receptors NNS I-NP on IN B-PP non-T JJ B-NP cells NNS I-NP is VBZ B-VP not RB I-VP associated VBN I-VP with IN B-PP more RBR B-NP efficient JJ I-NP TG NN I-NP presentation NN I-NP of IN B-PP T NN B-NP cells NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP significance NN I-NP of IN B-PP the DT B-NP present JJ I-NP study NN I-NP is VBZ B-VP that IN B-SBAR the DT B-NP T NN I-NP cells NNS I-NP COMMA COMMA B-NP not RB I-NP the DT B-NP antigen-presenting JJ I-NP cells NNS I-NP COMMA COMMA O are VBP B-VP likely JJ B-ADJP to TO B-VP be VB I-VP the DT B-NP limiting VBG I-NP element NN I-NP in IN B-PP the DT B-NP T NN I-NP cell NN I-NP proliferative JJ I-NP response NN I-NP to TO B-PP TG NN B-NP and CC O other JJ B-NP thyroid NN I-NP autoantigens NNS I-NP . . O Aldosterone-specific JJ B-NP membrane NN I-NP receptors NNS I-NP and CC O rapid JJ B-NP non-genomic JJ I-NP actions NNS I-NP of IN B-PP mineralocorticoids NNS B-NP . . O Functional JJ B-NP studies NNS I-NP in IN B-PP extrarenal JJ B-NP COMMA COMMA I-NP non-epithelial JJ I-NP cells NNS I-NP such JJ B-PP as IN I-PP smooth JJ B-NP muscle NN I-NP cells NNS I-NP and CC O more RBR B-ADVP recently RB I-ADVP circulating VBG B-NP human JJ I-NP lymphocytes NNS I-NP have VBP B-VP provided VBN I-VP increasing VBG B-NP evidence NN I-NP that IN B-SBAR aldosterone NN B-NP produces VBZ B-VP not RB B-CONJP only RB I-CONJP classical JJ B-NP genomic JJ I-NP effects NNS I-NP COMMA COMMA O but CC B-CONJP also RB I-CONJP rapid JJ B-NP COMMA COMMA I-NP non-genomic JJ I-NP effects NNS I-NP on IN B-PP transmembrane NN B-NP electrolyte NN I-NP movements NNS I-NP . . O These DT B-NP involve VBP B-VP activation NN B-NP of IN B-PP the DT B-NP sodium\/proton NN I-NP exchanger NN I-NP of IN B-PP the DT B-NP cell NN I-NP membrane NN I-NP at IN B-PP very RB B-NP low JJ I-NP COMMA COMMA I-NP physiological JJ I-NP concentrations NNS I-NP of IN B-PP aldosterone NN B-NP with IN B-PP an DT B-NP acute JJ I-NP onset NN I-NP within IN B-PP 1-2 CD B-NP min NN I-NP . . O A DT B-NP second JJ I-NP messenger NN I-NP cascade NN I-NP involved VBN B-VP is VBZ B-VP the DT B-NP inositol NN I-NP 1COMMA4COMMA5-trisphosphate\/calcium NN I-NP pathway NN I-NP which WDT B-NP responds VBZ B-VP over IN B-PP the DT B-NP same JJ I-NP rapid JJ I-NP time NN I-NP course NN I-NP . . O Such JJ B-NP changes NNS I-NP clearly RB B-ADVP can MD B-VP not RB I-VP be VB I-VP explained VBN I-VP by IN B-PP genomic JJ B-NP mechanisms NNS I-NP COMMA COMMA O which WDT B-NP are VBP B-VP responsible JJ B-ADJP for IN B-PP later JJ B-NP effects NNS I-NP than IN B-PP the DT O membrane NN B-NP related JJ B-NP rapid JJ I-NP responses NNS I-NP . . O The DT B-NP mechanisms NNS I-NP underlying VBG B-VP these DT B-NP rapid JJ I-NP effects NNS I-NP of IN B-PP aldosterone NN B-NP on IN B-PP electrolytes NNS B-NP have VBP B-VP been VBN I-VP extensively RB I-VP studied VBN I-VP in IN B-PP human JJ B-NP lymphocytes NNS I-NP COMMA COMMA O which WDT B-NP thus RB B-ADVP may MD B-VP represent VB I-VP valuable JJ B-NP tools NNS I-NP in IN B-PP the DT B-NP delineation NN I-NP of IN B-PP the DT B-NP receptor-effector JJ I-NP mechanisms NNS I-NP involved VBN B-VP . . O The DT B-NP unique JJ I-NP characteristics NNS I-NP of IN B-PP this DT B-NP new JJ I-NP pathway NN I-NP for IN B-PP steroid NN B-NP action NN I-NP include VBP B-VP its PRP$ B-NP rapid JJ I-NP time NN I-NP course NN I-NP COMMA COMMA O 10COMMA000-fold JJ B-NP selectivity NN I-NP for IN B-PP aldosterone NN B-NP over IN B-PP cortisol NN B-NP and CC O the DT B-NP ineffectiveness NN I-NP of IN B-PP spironolactones NNS B-NP COMMA COMMA O classical JJ B-NP mineralocorticoid NN I-NP antagonists NNS I-NP COMMA COMMA O as IN B-PP antagonists NNS B-NP of IN B-PP the DT B-NP response NN I-NP . . O Cellular JJ O immune JJ O and CC O cytokine NN B-NP pathways NNS B-NP resulting VBG B-VP in IN B-PP tissue NN B-NP factor NN I-NP expression NN I-NP and CC O relevance NN B-NP to TO B-PP septic JJ B-NP shock NN I-NP . . O Cells NNS B-NP of IN B-PP monocyte NN B-NP lineage NN I-NP serve VBP B-VP as IN B-PP effector NN B-NP cells NNS I-NP in IN B-PP the DT B-NP cellular JJ I-NP immune JJ I-NP response NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O they PRP B-NP respond VBP B-VP to TO B-PP LPS NN B-NP and CC O cytokines NNS B-NP with IN B-PP activation NN B-NP and CC O expression NN B-NP of IN B-PP inflammatory JJ B-NP effector NN I-NP gene NN I-NP products NNS I-NP similar JJ B-ADJP to TO B-PP those DT B-NP elicited VBN B-VP by IN B-PP the DT O antigen NN B-NP driven JJ B-NP response NN I-NP . . O The DT B-NP response NN I-NP to TO B-PP antigen NN B-NP proceeds VBZ B-VP at IN B-PP the DT B-NP T NN I-NP helper NN I-NP cell NN I-NP level NN I-NP through IN B-PP two CD B-NP independent JJ I-NP forms NNS I-NP of IN B-PP cellular JJ B-NP collaboration NN I-NP COMMA COMMA O contact NN B-NP and CC O lymphokine NN B-NP . . O We PRP B-NP review VBP B-VP the DT B-NP control NN I-NP of IN B-PP expression NN B-NP of IN B-PP the DT O Tissue NN B-NP Factor NN I-NP ( ( O TF NN B-NP ) ) O gene NN B-NP and CC O the DT B-NP function NN I-NP of IN B-PP the DT B-NP TF NN I-NP protein NN I-NP . . O The DT B-NP enhanced VBN I-NP initiation NN I-NP of IN B-PP transcription NN B-NP of IN B-PP the DT B-NP TF NN I-NP gene NN I-NP appears VBZ B-VP to TO I-VP require VB I-VP engagement NN B-NP of IN B-PP a DT B-NP 56 CD I-NP bp NN I-NP LPS NN I-NP Response NN I-NP Element NN I-NP COMMA COMMA O an DT B-NP enhancer NN I-NP that WDT B-NP is VBZ B-VP engaged VBN I-VP by IN B-PP both DT B-NP AP-1 NN B-NP type NN I-NP heterodimeric JJ I-NP complexes NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP NF NN B-NP kappa NN I-NP B NN I-NP like IN B-NP heterodimeric JJ I-NP complexes NNS I-NP . . O Dissociation NN B-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP from IN B-PP Ig NN B-NP kappa NN I-NP B NN I-NP by IN B-PP cytokine NN B-NP and CC O LPS NN B-NP stimulation NN B-NP COMMA COMMA O and CC O possibly RB B-ADVP activated VBN B-NP T NN I-NP cells NNS I-NP COMMA COMMA O may MD B-VP represent VB I-VP a DT B-NP common JJ I-NP pathway NN I-NP to TO B-PP induction NN B-NP of IN B-PP the DT B-NP TF NN B-NP and CC O other JJ B-NP inflammatory JJ I-NP genes NNS B-NP . . O Enhancement NN B-NP of IN B-PP expression NN B-NP of IN B-PP TF NN B-NP is VBZ B-VP observed VBN I-VP upon IN B-PP adhesion NN B-NP of IN B-PP Mo NN B-NP to TO B-PP endothelial JJ B-NP cells NNS I-NP and CC O extracellular JJ B-NP matrix JJ I-NP proteins NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP upon IN B-PP engagement NN B-NP of IN B-PP leukocyte NN B-NP integrins NNS I-NP . . O The DT B-NP biological JJ I-NP effects NNS I-NP that WDT B-NP follow VBP B-VP from IN B-PP expression NN B-NP of IN B-PP TF NN B-NP by IN B-PP vascular JJ B-NP cells NNS I-NP have VBP B-VP been VBN I-VP resolved VBN I-VP by IN B-PP analysis NN B-NP of IN B-PP function NN B-NP aided VBN B-VP by IN B-PP the DT B-NP use NN I-NP of IN B-PP recombinant JJ B-NP full JJ I-NP length NN I-NP TF NN I-NP and CC O truncated VBN B-NP surface NN I-NP domain NN I-NP of IN B-PP TF NN B-NP . . O The DT B-NP rules NNS I-NP of IN B-PP assembly NN B-NP of IN B-PP the DT B-NP cognate JJ I-NP ligands NNS I-NP of IN B-PP TF NN B-NP COMMA COMMA B-NP namely RB I-NP the DT B-NP zymogen NN I-NP plasma NN I-NP factors NNS I-NP VII NN I-NP and CC O the DT B-NP serine NN I-NP protease NN I-NP factor NN I-NP VIIa NN I-NP COMMA COMMA O with IN B-PP the DT B-NP soluble JJ I-NP surface NN I-NP domain NN I-NP of IN B-PP TF NN B-NP in IN B-PP free JJ B-NP solution NN I-NP COMMA COMMA O in IN B-PP the DT B-NP presence NN I-NP of IN B-PP phospholipid JJ B-NP surfaces NNS I-NP and CC O cell NN B-NP surface NN I-NP and CC B-PP of IN B-PP the DT B-NP anchored VBN I-NP TF NN I-NP molecule NN I-NP have VBP B-VP been VBN I-VP described VBN I-VP . . O It PRP B-NP is VBZ B-VP evident JJ B-ADJP that IN B-SBAR assembly NN B-NP of IN B-PP the DT B-NP surface NN I-NP domain NN I-NP of IN B-PP TF NN B-NP with IN B-PP VIIa NN B-NP to TO B-VP form VB I-VP the DT B-NP binary JJ I-NP TF.VIIa NN I-NP complex NN I-NP induces VBZ B-VP a DT B-NP significant JJ I-NP increase NN I-NP in IN B-PP the DT B-NP Kcat NN I-NP of IN B-PP the DT B-NP catalytic JJ I-NP domain NN I-NP of IN B-PP VIIa NN B-NP for IN B-PP small JJ B-NP peptidyl JJ I-NP substrates NNS I-NP and CC B-PP more JJR B-ADVP profoundly RB I-ADVP for IN B-PP protein NN B-NP substrate NN I-NP . . O This DT B-NP provides VBZ B-VP substantial JJ B-NP evidence NN I-NP for IN B-PP an DT B-NP allosteric JJ I-NP effect NN I-NP on IN B-PP the DT B-NP catalytic JJ I-NP cleft NN I-NP of IN B-PP VIIa NN B-NP that WDT B-NP is VBZ B-VP imparted VBN I-VP by IN B-PP binding VBG B-VP to TO B-PP TF NN B-NP COMMA COMMA O its PRP$ B-NP cognate JJ I-NP catalytic JJ I-NP cofactor NN I-NP . . O It PRP B-NP is VBZ B-VP also RB B-ADJP evident JJ I-ADJP that IN B-SBAR the DT B-NP TF.VIIa NN I-NP complex NN I-NP is VBZ B-VP proteolytically RB B-ADJP active JJ I-ADJP and CC O can MD B-VP activate VB I-VP the DT B-NP zymogen NN I-NP plasma NN I-NP factor NN I-NP X NN I-NP to TO B-PP the DT B-NP serine NN I-NP protease NN I-NP Xa NN I-NP in IN B-PP free JJ B-NP solution NN I-NP COMMA COMMA O inferring VBG B-VP that IN B-SBAR extended VBN B-NP substrate NN I-NP recognition NN I-NP by IN B-PP induced VBN B-NP structural JJ I-NP loci NNS I-NP of IN B-PP the DT B-NP TF.VIIa NN I-NP complex NN I-NP are VBP B-VP created VBN I-VP from IN B-PP either DT B-NP or CC O both DT B-NP proteins NNS B-NP to TO B-VP constitute VB I-VP a DT B-NP new JJ I-NP recognition NN I-NP structure NN I-NP . . O It PRP B-NP is VBZ B-VP also RB B-ADJP evident JJ I-ADJP that IN B-SBAR association NN B-NP of IN B-PP X NN B-NP with IN B-PP charged JJ B-NP phospholipid JJ I-NP surfaces NNS I-NP enhances VBZ B-VP the DT B-NP proteolytic JJ I-NP activation NN I-NP of IN B-PP this DT B-NP zymogen NN I-NP by IN B-PP increasing VBG B-VP recognition NN B-NP and CC O susceptibility NN B-NP of IN B-PP the DT B-NP sessile NN I-NP peptide NN I-NP bond NN I-NP deduced VBN B-VP from IN B-PP the DT B-NP markedly RB B-ADVP decreased VBN B-NP Km NN I-NP and CC O increased VBN B-NP Kcat NN I-NP . . O Involvement NN B-NP of IN B-PP Alu NN B-NP sequences NNS I-NP in IN B-PP the DT B-NP cell-specific JJ I-NP regulation NN I-NP of IN B-PP transcription NN B-NP of IN B-PP the DT B-NP gamma NN I-NP chain NN I-NP of IN B-PP Fc NN B-NP and CC O T NN B-NP cell NN I-NP receptors NNS B-NP . . O The DT B-NP Fc NN I-NP epsilon NN I-NP RI-gamma NN I-NP chains NNS I-NP are VBP B-VP expressed VBN I-VP in IN B-PP a DT B-NP variety NN I-NP of IN B-PP hematopoietic JJ B-NP cells NNS I-NP where WRB B-ADVP they PRP B-NP play VBP B-VP a DT B-NP critical JJ I-NP role NN I-NP in IN B-PP signal NN B-NP transduction NN I-NP . . O They PRP B-NP are VBP B-VP part NN B-NP of IN B-PP the DT B-NP high JJ I-NP affinity NN I-NP IgE NN I-NP receptor NN I-NP in IN B-PP mast NN B-NP cells NNS I-NP COMMA COMMA O basophils NNS B-NP COMMA COMMA O Langerhans NN B-NP cells NNS I-NP COMMA COMMA O and CC O possibly RB B-NP other JJ I-NP cells NNS I-NP ; : O a DT B-NP component NN I-NP of IN B-PP the DT B-NP low JJ I-NP affinity NN I-NP receptor NN I-NP for IN B-PP IgG NN B-NP ( ( O Fc NN B-NP gamma NN I-NP RIIIA NN I-NP or CC O CD16 NN B-NP ) ) O in IN B-PP natural JJ B-NP killer NN I-NP cells NNS I-NP and CC O macrophages NNS B-NP ; : O and CC O part NN B-NP of IN B-PP the DT B-NP T NN I-NP cell NN I-NP antigen NN I-NP receptor NN I-NP in IN B-PP subsets NNS B-NP of IN B-PP T NN B-NP cells NNS I-NP . . O Here RB B-ADVP we PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP transcriptional JJ I-NP regulation NN I-NP of IN B-PP the DT B-NP gamma NN I-NP chain NN I-NP gene NN I-NP by IN B-PP analyzing VBG B-VP the DT B-NP 2.5-kilobase JJ I-NP sequence NN I-NP upstream JJ B-ADVP of IN B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP . . O This DT B-NP sequence NN I-NP contains VBZ B-VP a DT B-NP promoter NN I-NP specific JJ B-ADJP to TO B-PP cells NNS B-NP of IN B-PP hematopoietic JJ B-NP lineage NN I-NP . . O We PRP B-NP have VBP B-VP identified VBN I-VP two CD B-NP adjacent JJ I-NP cis-acting JJ I-NP regulatory JJ I-NP elements NNS I-NP COMMA COMMA O both DT B-NP of IN B-PP which WDT B-NP are VBP B-VP part NN B-NP of IN B-PP an DT B-NP Alu NN I-NP repeat NN I-NP . . O The DT B-NP first JJ I-NP ( ( O -445\/-366 CD B-NP ) ) O is VBZ B-VP a DT B-NP positive JJ I-NP element NN I-NP active JJ B-ADJP in IN B-PP both CC O basophils NNS B-NP and CC O T NN B-NP cells NNS I-NP . . O The DT B-NP second JJ I-NP ( ( O -365\/-264 CD B-NP ) ) O binds VBZ B-VP to TO B-PP nuclear JJ B-NP factors NNS I-NP COMMA COMMA O which WDT B-NP appear VBP B-VP to TO I-VP be VB I-VP different JJ B-ADJP in IN B-PP basophils NNS B-NP and CC O T NN B-NP cells NNS I-NP COMMA COMMA O and CC O acts VBZ B-VP as IN B-PP a DT B-NP negative JJ I-NP element NN I-NP in IN B-PP basophils NNS B-NP and CC O as IN B-PP a DT B-NP positive JJ I-NP one NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O this DT B-NP Alu NN I-NP repeat NN I-NP ( ( O 90 CD B-NP % NN B-ADJP identical JJ B-PP to TO B-NP Alu NN I-NP consensus NN I-NP sequences NNS B-NP ) ) O has VBZ B-VP evolved VBN I-VP to TO I-VP become VB B-NP both CC I-NP a DT I-NP positive JJ I-NP and CC I-NP negative JJ I-NP regulator NN O Human JJ B-NP immunodeficiency NN I-NP viruses NNS I-NP containing VBG B-VP heterologous JJ B-NP enhancer\/promoters NNS I-NP are VBP B-VP replication NN B-ADJP competent JJ I-ADJP and CC O exhibit VBP B-VP different JJ B-NP lymphocyte NN I-NP tropisms NNS I-NP . . O The DT O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O type NN B-NP 1 CD I-NP long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O contains VBZ B-VP binding VBG B-NP sites NNS I-NP for IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O and CC O the DT B-NP constitutively RB I-NP expressed VBN I-NP transcription NN I-NP factor NN I-NP Sp1 NN I-NP COMMA COMMA O both DT B-NP of IN B-PP which WDT B-NP are VBP B-VP highly RB I-VP conserved VBN I-VP in IN B-PP HIV NN B-NP and CC O simian JJ B-NP immunodeficiency NN I-NP virus NN I-NP isolates NNS B-NP . . O To TO B-VP delineate VB I-VP the DT B-NP effects NNS I-NP of IN B-PP these DT B-NP motifs NNS I-NP on IN B-PP the DT B-NP replicative JJ I-NP capacity NN I-NP of IN B-PP HIV NN B-NP and CC O to TO B-VP explore VB I-VP the DT B-NP possibility NN I-NP of IN B-PP extending VBG B-VP the DT B-NP virus NN I-NP host NN I-NP range NN I-NP COMMA COMMA O known VBN B-NP heterologous JJ I-NP enhancer\/promoters NNS I-NP were VBD B-VP inserted VBN I-VP into IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP in IN B-PP place NN I-PP of IN I-PP the DT O NF-kappa NN B-NP B NN I-NP and CC O Sp1 NN B-NP binding NN B-NP sites NNS I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP these DT B-NP substitutions NNS I-NP on IN B-PP viral JJ B-NP replication NN I-NP in IN B-PP transfected VBN B-NP HeLa NN I-NP cells NNS I-NP and CC B-PP on IN B-PP HIV NN B-NP infection NN I-NP of IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP lymphocytes NNS I-NP or CC O continuous JJ B-NP T-leukemia NN I-NP cell NN I-NP lines NNS I-NP were VBD B-VP evaluated VBN I-VP . . O HIVs NN B-NP in IN B-PP which WDT B-NP the DT B-NP NF- NN I-NP kappa NN I-NP B\/Sp1 NN I-NP enhancer NN I-NP plus CC O the DT B-NP downstream JJ I-NP TATA NN I-NP element NN I-NP were VBD B-VP replaced VBN I-VP with IN B-PP heterologous JJ B-NP enhancer\/promoters NNS I-NP were VBD B-VP also RB I-VP constructed VBN I-VP . . O Viruses NNS B-NP containing VBG B-VP the DT B-NP human JJ I-NP cytomegalovirus NN I-NP immediate-early JJ I-NP enhancer NN I-NP exhibited VBD B-VP infectious JJ B-NP kinetics NNS I-NP similar JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP wild-type JJ B-NP HIV NN I-NP in IN B-PP activated VBN B-NP human JJ I-NP peripheral JJ I-NP blood NN I-NP lymphocytes NNS I-NP and CC O AA2 NN B-NP cells NNS I-NP but CC O replicated VBD B-VP less RBR B-ADVP efficiently RB I-ADVP in IN B-PP H9 NN B-NP and CC O CEM NN B-NP cells NNS B-NP . . O These DT B-NP studies NNS I-NP indicate VBP B-VP that IN B-SBAR heterologous JJ B-NP enhancer NN I-NP elements NNS I-NP are VBP B-VP capable JJ B-ADJP of IN B-PP restoring VBG B-VP Tat NN B-NP responsiveness NN I-NP to TO B-PP the DT B-NP HIV NN I-NP LTR NN I-NP in IN B-PP the DT I-PP context NN I-PP of IN I-PP directing VBG B-VP reporter NN B-NP gene NN I-NP expression NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP the DT B-NP production NN I-NP of IN B-PP infectious JJ B-NP progeny NN I-NP virions NNS I-NP . . O Tyrosine NN B-NP phosphorylation NN I-NP is VBZ B-VP a DT B-NP mandatory JJ I-NP proximal JJ I-NP step NN I-NP in IN B-PP radiation-induced JJ B-NP activation NN I-NP of IN B-PP the DT B-NP protein NN I-NP kinase NN I-NP C NN I-NP signaling NN I-NP pathway NN I-NP in IN B-PP human JJ B-NP B- NN I-NP lymphocyte NN I-NP precursors NNS I-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP Proc NNP B-NP Natl NNP I-NP Acad NNP I-NP Sci NNP I-NP U NNP I-NP S NNP I-NP A NNP I-NP 1993 CD B-NP Apr NNP I-NP 15 CD I-NP ; : O 90 CD B-NP ( ( I-NP 8 CD I-NP ) ) I-NP : : I-NP 3775 CD I-NP } ) O Ionizing VBG B-NP radiation NN I-NP triggers VBZ B-VP a DT B-NP signal NN I-NP in IN B-PP human JJ B-NP B-lymphocyte NN I-NP precursors NNS I-NP that WDT B-NP is VBZ B-VP intimately RB I-VP linked VBN I-VP to TO B-PP an DT B-NP active JJ I-NP protein-tyrosine NN I-NP kinase NN I-NP regulatory JJ I-NP pathway NN I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR in IN B-PP B-lymphocyte NN B-NP precursors NNS I-NP COMMA COMMA O irradiation NN B-NP with IN B-PP gamma-rays NNS B-NP leads VBZ B-VP to TO B-PP ( ( B-LST i LS I-LST ) ) O stimulation NN B-NP of IN B-PP phosphatidylinositol NN B-NP turnover NN I-NP ; : O ( ( B-LST ii LS I-LST ) ) O downstream JJ B-NP activation NN I-NP by IN B-PP covalent JJ B-NP modification NN I-NP of IN B-PP multiple JJ B-NP serine-specific JJ I-NP protein NN I-NP kinases NNS I-NP COMMA COMMA O including VBG B-PP protein NN B-NP kinase NN I-NP C NN I-NP ; : O and CC O ( ( B-LST iii LS I-LST ) ) O activation NN B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP . . O All DT B-NP of IN B-PP the DT B-NP radiation-induced JJ I-NP signals NNS I-NP were VBD B-VP effectively RB I-VP prevented VBN I-VP by IN B-PP the DT B-NP protein-tyrosine NN I-NP kinase NN I-NP inhibitors NNS I-NP genistein NN B-NP and CC O herbimycin NN B-NP A NN I-NP . . O Thus RB B-ADVP COMMA COMMA O tyrosine NN B-NP phosphorylation NN I-NP is VBZ B-VP an DT O important JJ O and CC O perhaps RB B-ADVP mandatory JJ B-NP proximal JJ I-NP step NN I-NP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP protein NN I-NP kinase NN I-NP C NN I-NP signaling NN I-NP cascade NN I-NP in IN B-PP human JJ B-NP B-lymphocyte NN I-NP precursors NNS I-NP . . O Our PRP$ B-NP report VBP I-NP expands NNS B-VP current JJ B-NP knowledge NN I-NP of IN B-PP the DT B-NP radiation-induced JJ I-NP signaling NN I-NP cascade NN I-NP by IN B-PP clarifying VBG B-VP the DT B-NP chronological JJ I-NP sequence NN I-NP of IN B-PP biochemical JJ B-NP events NNS I-NP that WDT B-NP follow VBP B-VP irradiation NN B-NP . . O A DT B-NP human JJ I-NP putative JJ I-NP lymphocyte NN I-NP G0\/G1 NN I-NP switch VBP I-NP gene NN I-NP homologous JJ B-ADJP to TO B-PP a DT B-NP rodent JJ I-NP gene NN I-NP encoding VBG B-VP a DT B-NP zinc-binding JJ I-NP potential JJ I-NP transcription NN I-NP factor NN I-NP . . O G0S24 NN B-NP is VBZ B-VP a DT B-NP member NN I-NP of IN B-PP a DT B-NP set NN I-NP of IN B-PP genes NNS B-NP ( ( O putative JJ B-NP G0\/G1 NN I-NP switch NN I-NP regulatory JJ I-NP genes NNS I-NP ) ) O that WDT B-NP are VBP B-VP expressed VBN I-VP transiently RB B-ADVP within IN B-PP 1-2 CD B-NP hr NN I-NP of IN B-PP the DT B-NP addition NN I-NP of IN B-PP lectin NN B-NP or CC O cycloheximide NN B-NP to TO B-PP human JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP . . O Comparison NN B-NP of IN B-PP a DT B-NP full-length JJ I-NP cDNA NN I-NP sequence NN I-NP with IN B-PP the DT B-NP corresponding JJ I-NP genomic JJ I-NP sequence NN I-NP reveals VBZ B-VP an DT B-NP open JJ I-NP reading NN I-NP frame NN I-NP of IN B-PP 326 CD B-NP amino NN I-NP acids NNS I-NP COMMA COMMA O distributed VBN B-VP across IN B-PP two CD B-NP exons NNS I-NP . . O Potential JJ B-NP phosphorylation NN I-NP sites NNS I-NP include VBP B-VP the DT B-NP sequence NN I-NP PSPTSPT NN I-NP COMMA COMMA O which WDT B-NP resembles VBZ B-VP an DT B-NP RNA NN I-NP polymerase NN I-NP II CD I-NP repeat NN I-NP reported VBN B-VP to TO I-VP be VB I-VP a DT B-NP target NN I-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP control NN I-NP kinase NN I-NP cdc2 NN I-NP . . O Comparison NN B-NP of IN B-PP the DT B-NP derived VBN I-NP protein NN I-NP sequence NN I-NP with IN B-PP those DT B-NP of IN B-PP rodent JJ B-NP homologs NNS I-NP allows VBZ B-VP classification NN B-NP into IN B-PP three CD B-NP groups NNS I-NP . . O Group NN B-NP 1 CD I-NP contains VBZ B-VP G0S24 NN B-NP and CC O the DT O rat NN B-NP and CC O mouse NN B-NP TIS11 NN B-NP genes NNS I-NP ( ( O also RB B-VP known VBN I-VP as IN B-PP TTP NN B-NP COMMA COMMA O Nup475 NN B-NP COMMA COMMA O and CC O Zfp36 NN B-NP ) ) O . . O Members NNS B-NP of IN B-PP this DT B-NP group NN I-NP have VBP B-VP three CD B-NP tetraproline JJ I-NP repeats NNS I-NP . . O Groups NNS B-NP 1 CD B-NP and CC O 2 CD B-NP have VBP B-VP a DT B-NP serine-rich JJ I-NP region NN I-NP and CC O an DT B-NP " `` I-NP arginine NN I-NP element NN I-NP " '' O ( ( O RRLPIF NN B-NP ) ) O at IN B-PP the DT B-NP carboxyl NN I-NP terminus NN I-NP . . O All DT B-NP groups NNS I-NP contain VBP B-VP cysteine- NN B-NP and CC O histidine-rich JJ B-ADJP putative JJ B-NP zinc NN I-NP finger NN I-NP domains NNS I-NP and CC O a DT B-NP serine-phenylalanine JJ I-NP " `` I-NP SFS NNS I-NP " '' I-NP domain NN I-NP similar JJ B-ADJP to TO B-PP part NN B-NP of IN B-PP the DT B-NP large JJ I-NP subunit NN I-NP of IN B-PP eukaryotic JJ B-NP RNA NN I-NP polymerase NN I-NP II CD I-NP . . O Comparison NN B-NP of IN B-PP group NN O 1 CD O human JJ O and CC O mouse NN B-NP genomic JJ B-NP sequences NNS I-NP shows VBZ B-VP high JJ B-NP conservation NN I-NP in IN B-PP the DT B-NP 5' JJ I-NP flank NN I-NP and CC O exons NNS B-NP . . O A DT B-NP CpG NN I-NP island NN I-NP suggests VBZ B-VP expression NN B-NP in IN B-PP the DT B-NP germ NN I-NP line NN I-NP . . O G0S24 NN B-NP has VBZ B-VP potential JJ B-NP sites NNS I-NP for IN B-PP transcription NN B-NP factors NNS I-NP in IN B-PP the DT B-NP 5' JJ I-NP flank NN I-NP and CC O intron NN B-NP ; : O these DT B-NP include VBP B-VP a DT B-NP serum NN I-NP response NN I-NP element NN I-NP . . O Protein NN B-NP and CC O genomic JJ B-ADJP sequences NNS B-NP show VBP B-VP similarities NNS B-NP with IN B-PP those DT B-NP of IN B-PP a DT B-NP variety NN I-NP of IN B-PP proteins NNS B-NP involved VBN B-VP in IN B-PP transcription NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR the DT B-NP G0S24 NN I-NP product NN I-NP has VBZ B-VP a DT B-NP similar JJ I-NP role NN I-NP . . O Interleukin-4 NN B-NP inhibits VBZ B-VP the DT B-NP lipopolysaccharide-induced JJ B-NP expression NN I-NP of IN B-PP c-jun NN B-NP and CC O c-fos NN B-NP messenger NN B-NP RNA NN I-NP and CC O activator NN B-NP protein-1 NN I-NP binding NN I-NP activity NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP . . O We PRP B-NP studied VBD B-VP the DT B-NP effect NN I-NP of IN B-PP interleukin-4 NN B-NP ( ( O IL-4 NN B-NP ) ) O on IN B-PP the DT O lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O induction NN B-NP of IN B-PP two CD B-NP immediate JJ I-NP early JJ I-NP genes NNS I-NP c-fos NN B-NP and CC O c-jun NN B-NP . . O These DT B-NP genes NNS I-NP encode VBP B-VP proteins NNS B-NP that WDT B-NP form VBP B-VP the DT B-NP dimeric JJ I-NP complex NN I-NP activator NN I-NP protein-1 NN I-NP ( ( O AP-1 NN B-NP ) ) O COMMA COMMA O which WDT B-NP is VBZ B-VP active JJ B-ADJP as IN B-PP a DT B-NP transcriptional JJ I-NP factor NN I-NP . . O Maximal JJ B-NP accumulation NN I-NP of IN B-PP either CC O c-fos NN B-NP and CC O c-jun NN B-NP messenger NN B-NP RNA NN I-NP ( ( O mRNA NN B-NP ) ) O occurred VBD B-VP 30 CD B-NP minutes NNS I-NP after IN B-PP LPS NN B-NP addition NN I-NP . . O When WRB B-ADVP cells NNS B-NP were VBD B-VP treated VBN I-VP with IN B-PP IL-4 NN B-NP for IN B-PP 5 CD B-NP hours NNS I-NP before IN B-PP LPS NN B-NP activation NN I-NP COMMA COMMA O both CC O the DT B-NP c-fos NN I-NP and CC O the DT B-NP c-jun NN I-NP mRNA NN B-NP expression NN I-NP was VBD B-VP decreased VBN I-VP . . O The DT B-NP inhibition NN I-NP of IN B-PP c-fos NN B-NP and CC O c-jun NN B-NP expression NN B-NP by IN B-PP IL-4 NN B-NP in IN B-PP LPS-treated JJ B-NP cells NNS I-NP was VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP due JJ B-PP to TO I-PP a DT B-NP lower JJR I-NP transcription NN I-NP rate NN I-NP of IN B-PP the DT O c-fos NN B-NP and CC O c-jun NN B-NP genes NNS B-NP . . O IL-4 NN B-NP did VBD B-VP not RB I-VP affect VB I-VP the DT B-NP stability NN I-NP of IN B-PP the DT O c-fos NN B-NP and CC O c-jun NN B-NP transcripts NNS B-NP . . O Finally RB B-ADVP COMMA COMMA O using VBG B-VP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP COMMA COMMA O evidence NN B-NP was VBD B-VP obtained VBN I-VP that IN B-SBAR IL-4 NN B-NP inhibits VBZ B-VP LPS-induced JJ B-NP expression NN I-NP of IN B-PP AP-1 NN B-NP protein NN I-NP . . O These DT B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR IL-4 NN B-NP suppresses VBZ B-VP the DT B-NP induction NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP in IN B-PP human JJ B-NP activated VBN I-NP monocytes NNS I-NP . . O Ras NN B-NP oncogene NN I-NP transformation NN I-NP of IN B-PP human JJ B-NP B NN I-NP lymphoblasts NNS I-NP is VBZ B-VP associated VBN I-VP with IN B-PP lymphocyte NN B-NP activation NN I-NP and CC B-PP with IN B-PP a DT B-NP block NN I-NP of IN B-PP differentiation NN B-NP . . O The DT B-NP p21ras NN I-NP small JJ I-NP GTP NN I-NP binding NN I-NP proteins NNS I-NP participate VBP B-VP in IN B-PP signal JJ B-NP transduction NN I-NP from IN B-PP cell NN B-NP surface NN I-NP receptors NNS I-NP and CC O affect VB B-VP neoplastic JJ B-NP transformation NN B-NP and CC O development NN B-NP in IN B-PP many JJ B-NP different JJ I-NP cell NN I-NP types NNS I-NP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP COMMA COMMA O we PRP B-NP examined VBD B-VP the DT B-NP relationship NN I-NP between IN B-PP ras NN B-NP transformation NN B-NP and CC O differentiation NN B-NP of IN B-PP human JJ B-NP B NN I-NP lymphocytes NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP constitutive JJ I-NP expression NN I-NP of IN B-PP the DT B-NP T24 NN I-NP Ha-ras NN I-NP oncogene NN I-NP in IN B-PP EBV-immortalized JJ B-NP B NN I-NP lymphoblasts NNS I-NP was VBD B-VP associated VBN I-VP with IN B-PP the DT B-NP induction NN I-NP of IN B-PP the DT B-NP interleukin NN I-NP 2 CD I-NP receptor NN I-NP alpha NN I-NP subunit NN I-NP COMMA COMMA O with IN B-PP an DT B-NP impaired JJ I-NP immunoglobulin NN I-NP gene NN I-NP expression NN I-NP COMMA COMMA O altered JJ B-NP adhesion NN I-NP properties NNS I-NP and CC O increased VBN B-NP survival NN I-NP in IN B-PP serum-free JJ B-NP medium NN I-NP . . O Since IN B-SBAR induction NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP receptor NN I-NP alpha NN I-NP subunit NN I-NP is VBZ B-VP a DT B-NP hallmark NN I-NP of IN B-PP lymphocyte NN B-NP activation NN I-NP COMMA COMMA O we PRP B-NP suggest VBP B-VP that IN B-SBAR p21ras NN B-NP naturally RB B-ADVP triggers VBZ B-VP B NN B-NP cell NN I-NP activation NN I-NP . . O The DT B-NP ras-transformed JJ I-NP lymphocytes NNS I-NP displayed VBD B-VP a DT B-NP fully RB I-NP functional JJ I-NP IL-2r NN I-NP COMMA COMMA O as IN B-SBAR assessed VBN B-VP by IN B-PP c-fos NN B-NP induction NN I-NP following VBG B-PP treatment NN B-NP with IN B-PP IL-2 NN B-NP ; : O nevertheless RB B-ADVP COMMA COMMA O they PRP B-NP were VBD B-VP not RB O growth NN B-NP stimulated VBN B-VP by IN B-PP this DT B-NP lymphokine NN I-NP . . O The DT B-NP decreased VBN I-NP expression NN I-NP of IN B-PP immunoglobulin NN B-NP genes NNS I-NP indicates VBZ B-VP that IN B-SBAR the DT B-NP ras NN I-NP oncogene NN I-NP blocks VBZ B-VP terminal JJ B-NP differentiation NN I-NP to TO B-PP plasma NN B-NP cells NNS I-NP COMMA COMMA O possibly RB B-ADVP by IN B-PP inhibiting VBG B-VP the DT B-NP activity NN I-NP of IN B-PP lymphocyte-specific JJ B-NP transcription NN I-NP factors NNS I-NP . . O Somewhat RB B-ADVP unexpectedly RB I-ADVP COMMA COMMA O the DT B-NP constitutive JJ I-NP p21ras NN I-NP activity NN I-NP did VBD B-VP not RB I-VP cause VB I-VP an DT B-NP increased VBN I-NP DNA NN I-NP binding NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP PEA1 NN B-NP ( ( O AP1 NN B-NP ) ) O COMMA COMMA O PEA3 NN B-NP COMMA COMMA O Oct-2 NN B-NP or CC O NF-kB NN B-NP . . O Transcription NN B-NP factor NN I-NP GATA-1 NN I-NP and CC O erythroid JJ B-NP development NN I-NP . . O In IN B-PP summary NN B-NP COMMA COMMA O we PRP B-NP derived VBD B-VP an DT B-NP experimental JJ I-NP system NN I-NP that WDT B-NP allows VBZ B-VP us PRP B-NP to TO B-VP dissect VB I-VP the DT B-NP function NN I-NP of IN B-PP GATA-1 NN B-NP in IN B-PP red JJ B-NP cell NN I-NP development NN I-NP at IN B-PP a DT B-NP genetic JJ I-NP level NN I-NP . . O We PRP B-NP have VBP B-VP established VBN I-VP the DT B-NP essential JJ I-NP nature NN I-NP of IN B-PP GATA-1 NN B-NP during IN B-PP both CC B-NP primitive JJ I-NP and CC I-NP definitive JJ I-NP erythropoiesis NN I-NP . . O By IN B-PP ablating VBG B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP endogenous JJ I-NP GATA-1 NN I-NP gene NN I-NP COMMA COMMA O we PRP B-NP are VBP B-VP in IN B-PP a DT B-NP position NN I-NP to TO B-VP introduce VB I-VP a DT B-NP variety NN I-NP of IN B-PP constructs NNS B-NP that WDT B-NP harbor VBP B-VP subtle JJ B-NP modifications NNS I-NP in IN B-PP flanking JJ B-NP or CC I-NP protein-coding JJ I-NP sequences NNS I-NP . . O We PRP B-NP can MD B-VP now RB I-VP study VB I-VP regulatory JJ B-NP regions NNS I-NP and CC O functional JJ B-NP domains NNS I-NP of IN B-PP the DT B-NP protein NN I-NP in IN B-PP the DT B-NP context NN I-NP of IN B-PP a DT B-NP true JJ I-NP erythroid JJ I-NP environment NN I-NP COMMA COMMA O experiments NNS B-NP that WDT B-NP have VBP B-VP not RB I-VP been VBN I-VP possible JJ B-ADJP heretofore RB B-ADVP . . O Although IN B-SBAR the DT B-NP assay NN I-NP involves VBZ B-VP the DT B-NP dramatic JJ I-NP loss NN I-NP of IN B-PP red JJ B-NP cell NN I-NP production NN I-NP COMMA COMMA O it PRP B-NP should MD B-VP be VB I-VP possible JJ B-ADJP to TO B-VP define VB I-VP important JJ B-NP regulatory JJ I-NP domains NNS I-NP that WDT B-NP can MD B-VP then RB I-VP be VB I-VP assayed VBN I-VP using VBG B-VP less RBR B-NP stringent JJ I-NP systems NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP cell-free JJ B-NP extracts NNS I-NP for IN B-PP in FW B-NP vitro FW I-NP transcription NN I-NP . . O The DT B-NP ideal JJ I-NP situation NN I-NP would MD B-VP be VB I-VP analyses NNS B-NP conducted VBN B-VP in IN B-PP GATA-1- JJ B-NP erythroid NN I-NP cells NNS I-NP . . O However RB B-ADVP COMMA COMMA O these DT B-NP cells NNS I-NP have VBP B-VP been VBN I-VP impossible JJ B-ADJP to TO B-VP generate VB I-VP given VBN B-PP the DT B-NP requirement NN I-NP of IN B-PP GATA-1 NN B-NP for IN B-PP Epo NN B-NP receptor NN I-NP expression NN I-NP and CC O red JJ B-NP cell NN I-NP viability NN I-NP ( ( O C. NNP B-NP Simon NNP I-NP and CC O S. NNP B-NP Orkin NNP I-NP COMMA COMMA O unpublished JJ B-NP observations NNS I-NP ) ) O . . O It PRP B-NP may MD B-VP be VB I-VP possible JJ B-ADJP to TO B-VP produce VB I-VP such JJ B-NP cells NNS I-NP by IN B-PP first RB B-VP expressing VBG I-VP the DT B-NP Epo NN I-NP receptor NN I-NP under IN B-PP the DT B-NP influence NN I-NP of IN B-PP a DT B-NP constitutive JJ I-NP promoter NN I-NP and CC O then RB B-VP targeting VBG I-VP the DT B-NP GATA-1 NN I-NP gene NN I-NP . . O If IN B-SBAR GATA-1- JJ B-NP -red JJ I-NP cells NNS I-NP were VBD B-VP available JJ B-ADJP COMMA COMMA O the DT B-NP analyses NNS I-NP would MD B-VP involve VB I-VP the DT B-NP actual JJ B-NP transcription NN I-NP of IN B-PP or CC O chromatin NN B-NP structure NN I-NP surrounding VBG B-VP the DT B-NP globin NN I-NP genes NNS I-NP . . O Structure-function JJ B-NP studies NNS I-NP of IN B-PP the DT B-NP GATA-1 NN I-NP protein NN I-NP could MD B-VP be VB I-VP greatly RB I-VP simplified VBN I-VP and CC O a DT B-NP larger JJR I-NP number NN I-NP of IN B-PP mutants NNS B-NP studied VBN B-VP . . O However RB B-ADVP COMMA COMMA O the DT B-NP ES NN I-NP cell NN I-NP system NN I-NP can MD B-VP be VB I-VP used VBN I-VP as IN B-PP an DT B-NP alternative NN I-NP until IN B-SBAR targeted VBN B-NP erythroleukemia NN I-NP cells NNS I-NP become VBP B-VP available JJ B-ADJP . . O Other JJ B-NP applications NNS I-NP involve VBP B-VP the DT B-NP introduction NN I-NP of IN B-PP other JJ B-NP GATA-binding JJ I-NP protein NN I-NP family NN I-NP members NNS I-NP to TO B-VP determine VB I-VP whether IN B-SBAR they PRP B-NP rescue VBP B-VP the DT B-NP mutation NN I-NP . . O If IN B-SBAR they PRP B-NP can MD B-VP not RB O COMMA COMMA O chimeric JJ B-NP proteins NNS I-NP can MD B-VP be VB I-VP tested VBN I-VP to TO B-VP identify VB I-VP which WDT B-NP amino NN I-NP acids NNS I-NP distinguish VBP B-VP the DT B-NP different JJ I-NP family NN I-NP members NNS I-NP . . O We PRP B-NP feel VBP B-VP that IN B-SBAR these DT B-NP experiments NNS I-NP are VBP B-VP vital JJ B-ADJP to TO B-PP understanding VBG B-VP the DT B-NP function NN I-NP of IN B-PP GATA-1 NN B-NP during IN B-PP erythroid JJ B-NP ontogeny NN I-NP . . O How WRB B-ADVP does VBZ O GATA-1 NN B-NP regulate VB B-VP red JJ B-NP cell NN I-NP genes NNS I-NP like IN B-PP globin NN B-NP or CC O the DT B-NP Epo NN I-NP receptor NN I-NP ? . O Once IN B-SBAR we PRP B-NP identify VB B-VP the DT B-NP functional JJ I-NP domains NNS I-NP of IN B-PP the DT B-NP GATA-binding JJ I-NP proteins NNS I-NP COMMA COMMA O we PRP B-NP hope VBP B-VP to TO I-VP learn VB I-VP what WP B-NP proteins NNS I-NP GATA-1 NN B-NP binds VBZ B-VP to TO B-PP in IN B-PP the DT B-NP basic JJ I-NP transcription NN I-NP machinery NN I-NP or CC B-PP in IN B-PP chromatin NN B-NP . . O Is VBZ O GATA-1 NN B-NP necessary JJ B-ADJP for IN B-PP globin NN B-NP gene NN I-NP switching NN I-NP ? . O GATA-1 NN B-NP may MD B-VP be VB I-VP modified VBN I-VP differently RB B-ADVP during IN B-PP development NN B-NP so IN B-SBAR that IN I-SBAR the DT B-NP locus NN I-NP control NN I-NP region NN I-NP can MD B-VP interact VB I-VP with IN B-PP different JJ B-NP globin NN I-NP promoters NNS I-NP . . O We PRP B-NP may MD B-VP find VB I-VP that IN B-SBAR one CD B-NP region NN I-NP of IN B-PP the DT B-NP protein NN I-NP is VBZ B-VP required VBN I-VP for IN B-PP embryonic JJ B-NP expression NN I-NP and CC O another DT B-NP for IN B-PP adult JJ B-NP globin NN I-NP gene NN I-NP expression NN I-NP . . O The DT B-NP zinc NN I-NP finger NN I-NP transcription NN I-NP factor NN I-NP Egr-1 NN I-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP and CC O restricts VBZ B-VP differentiation NN B-NP along IN B-PP the DT B-NP macrophage NN I-NP lineage NN I-NP . . O We PRP B-NP have VBP B-VP isolated VBN I-VP cDNA NN B-NP clones NNS I-NP of IN B-PP myeloid JJ B-NP differentiation NN I-NP primary JJ I-NP response NN I-NP ( ( O MyD NN B-NP ) ) O genes NNS B-NP COMMA COMMA O activated VBN B-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP de FW B-NP novo FW I-NP protein NN I-NP synthesis NN I-NP following VBG B-PP induction NN B-NP for IN B-PP differentiation NN B-NP along IN B-PP either CC O the DT O macrophage NN B-NP or CC O granulocyte NN B-NP lineage NN B-NP in IN B-PP human JJ B-NP myeloblastic JJ I-NP leukemia NN I-NP HL-60 NN I-NP cells NNS I-NP . . O One CD B-NP cDNA NN I-NP clone NN I-NP of IN B-PP a DT B-NP primary JJ I-NP response NN I-NP gene NN I-NP COMMA COMMA O expressed VBN B-VP upon IN B-PP macrophage NN B-NP differentiation NN I-NP COMMA COMMA O encoded VBD B-VP for IN B-PP Egr-1 NN B-NP COMMA COMMA O a DT B-NP zinc NN I-NP finger NN I-NP transcription NN I-NP factor NN I-NP . . O The DT B-NP Egr-1 NN I-NP gene NN I-NP was VBD B-VP observed VBN I-VP to TO I-VP be VB I-VP transcriptionally RB B-ADVP silent JJ B-ADJP in IN B-PP HL-60 NN B-NP cells NNS I-NP COMMA COMMA O but CC O active JJ B-ADJP in IN B-PP U-937 NN B-NP and CC O M1 NN B-NP cells NNS B-NP COMMA COMMA O the DT B-NP latter JJ I-NP two CD I-NP being VBG B-VP predetermined VBN B-ADJP for IN B-PP macrophage NN B-NP differentiation NN I-NP . . O Egr-1 NN B-NP antisense JJ I-NP oligomers NNS I-NP in IN B-PP the DT B-NP culture NN I-NP media NNS I-NP blocked VBD B-VP macrophage NN B-NP differentiation NN I-NP in IN B-PP both DT B-NP myeloid JJ B-NP leukemia NN I-NP cell NN I-NP lines NNS I-NP and CC O normal JJ B-NP myeloblasts NNS I-NP . . O HL-60 NN B-NP cells NNS I-NP constitutively RB B-VP expressing VBG I-VP an DT B-NP Egr-1 NN I-NP transgene NN I-NP ( ( O HL-60Egr-1 NN B-NP ) ) O could MD B-VP be VB I-VP induced VBN I-VP for IN B-PP macrophage NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP granulocyte NN B-NP COMMA COMMA O differentiation NN B-NP . . O These DT B-NP observations NNS I-NP indicate VBP B-VP that IN B-SBAR expression NN B-NP of IN B-PP Egr-1 NN B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP and CC O restricts VBZ B-VP differentiation NN B-NP of IN B-PP myeloblasts NNS B-NP along IN B-PP the DT B-NP macrophage NN I-NP lineage NN I-NP . . O Expression NN B-NP of IN B-PP tal-1 NN B-NP and CC O GATA-binding JJ B-ADJP proteins NNS B-NP during IN B-PP human JJ B-NP hematopoiesis NN I-NP . . O Tal-1 NN B-NP rearrangements NNS I-NP are VBP B-VP associated VBN I-VP with IN B-PP nearly RB B-NP 30 CD I-NP % NN I-NP of IN B-PP human JJ B-NP T NN I-NP acute JJ I-NP lymphoblastic JJ I-NP leukemia NN I-NP . . O Tal-1 NN B-NP gene NN I-NP encodes VBZ B-VP a DT B-NP putative JJ I-NP transcription NN I-NP factor NN I-NP with IN B-PP a DT B-NP basic JJ I-NP helix-loop-helix JJ I-NP domain NN I-NP and CC O is VBZ B-VP known VBN I-VP to TO I-VP be VB I-VP predominantly RB I-VP expressed VBN I-VP in IN B-PP hematopoietic JJ B-NP cells NNS I-NP . . O We PRP B-NP investigated VBD B-VP the DT B-NP pattern NN I-NP of IN B-PP tal-1 NN B-NP expression NN I-NP in IN B-PP purified VBN B-NP human JJ I-NP hematopoietic JJ I-NP cells NNS I-NP by IN B-PP in FW B-NP situ FW I-NP hybridization NN I-NP and CC O reverse JJ B-NP transcriptase NN I-NP polymerase NN I-NP chain NN I-NP reaction NN I-NP analysis NN I-NP . . O Both DT B-NP methods NNS I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP tal-1 NN I-NP gene NN I-NP is VBZ B-VP expressed VBN I-VP in IN B-PP megakaryocytes NNS B-NP and CC O erythroblasts NNS B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP basophilic JJ B-NP granulocytes NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O our PRP$ B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP tal-1 NN I-NP 1A NN I-NP promoter NN I-NP COMMA COMMA O which WDT B-NP contains VBZ B-VP two CD B-NP consensus NN I-NP GATA-binding JJ I-NP sites NNS I-NP COMMA COMMA O is VBZ B-VP active JJ B-ADJP mainly RB B-PP in IN I-PP these DT B-NP lineages NNS I-NP . . O Because IN B-SBAR the DT B-NP GATA-1 NN I-NP gene NN I-NP is VBZ B-VP known VBN I-VP to TO I-VP transactivate VB I-VP several JJ B-NP genes NNS I-NP specific JJ B-ADJP for IN B-PP the DT B-NP erythroid JJ I-NP COMMA COMMA I-NP megakaryocytic JJ I-NP COMMA COMMA I-NP and CC I-NP mastocytic\/basophilic JJ I-NP lineages NNS I-NP COMMA COMMA O we PRP B-NP studied VBD B-VP GATA-1 NN B-NP expression NN I-NP in IN B-PP these DT B-NP purified VBN I-NP hematopoietic JJ I-NP cells NNS I-NP . . O We PRP B-NP found VBD B-VP that IN B-SBAR GATA-1 NN B-NP and CC O tal-1 NN B-NP genes NNS B-NP are VBP B-VP coexpressed VBN I-VP in IN B-PP these DT B-NP three CD I-NP lineages NNS I-NP . . O Remarkably RB B-ADVP COMMA COMMA O the DT B-NP expression NN I-NP of IN B-PP both DT B-NP genes NNS I-NP is VBZ B-VP downmodulated VBN I-VP during IN B-PP erythroid JJ B-NP and CC I-NP megakaryocytic JJ I-NP terminal JJ I-NP maturation NN I-NP . . O In IN B-PP immature JJ B-NP hematopoietic JJ I-NP cells NNS I-NP COMMA COMMA O tal-1 NN B-NP and CC O GATA-1 NN B-NP genes NNS B-NP are VBP B-VP coexpressed VBN I-VP in IN B-PP committed VBN B-NP progenitors NNS I-NP cells NNS I-NP ( ( O CD34+\/CD38(2+) JJ B-NP ) ) O COMMA COMMA O whereas IN B-SBAR they PRP B-NP are VBP B-VP not RB O detectable JJ B-ADJP in IN B-PP the DT B-NP most RBS I-NP primitive JJ I-NP cells NNS I-NP ( ( O CD34(2+)\/CD38- JJ B-NP ) ) O . . O In IN B-PP contrast NN B-NP COMMA COMMA O GATA-2 NN B-NP is VBZ B-VP strongly RB I-VP expressed VBN I-VP in IN B-PP both CC O most RBS B-NP primitive JJ I-NP and CC O committed VBN B-NP progenitors NNS I-NP cells NNS B-NP COMMA COMMA O whereas IN O GATA-3 NN B-NP is VBZ B-VP mostly RB I-VP detected VBN I-VP in IN B-PP most RBS B-NP primitive JJ I-NP ones NNS I-NP . . O Altogether RB B-ADVP our PRP$ B-NP results NNS I-NP strongly RB B-ADVP suggest VBP B-VP that IN B-SBAR GATA-1 NN B-NP modulates VBZ B-VP the DT B-NP transcription NN I-NP of IN B-PP tal-1 NN B-NP during IN B-PP the DT B-NP differentiation NN I-NP of IN B-PP the DT B-NP erythroid JJ I-NP COMMA COMMA I-NP megakaryocytic JJ I-NP COMMA COMMA I-NP and CC I-NP basosophilic JJ I-NP lineages NNS I-NP . . O Cell-type-specific JJ B-NP transactivation NN I-NP of IN B-PP the DT B-NP parathyroid JJ I-NP hormone-related JJ I-NP protein NN I-NP gene NN I-NP promoter NN I-NP by IN B-PP the DT O human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP ( ( O HTLV-I NN B-NP ) ) O tax NN B-NP and CC O HTLV-II NN B-NP tax NN I-NP proteins NNS B-NP . . O The DT O human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP ( ( O HTLV-I NN B-NP ) ) O and CC O HTLV-II NN B-NP Tax NN B-NP proteins NNS I-NP are VBP B-VP potent JJ B-NP transactivators NNS I-NP of IN B-PP viral JJ B-NP and CC I-NP cellular JJ I-NP gene NN I-NP expression NN I-NP . . O Using VBG B-VP deletion NN B-NP mutants NNS I-NP COMMA COMMA O the DT O downstream JJ O parathyroid JJ B-NP hormone-related JJ I-NP protein NN I-NP ( ( O PTHrP NN B-NP ) ) O promoter NN B-NP is VBZ B-VP shown VBN I-VP to TO I-VP be VB I-VP responsive JJ B-ADJP to TO B-PP both CC O HTLV-I NN B-NP and CC O HTLV-II NN B-NP Tax NN B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP the DT B-NP AP1\/c-jun NN I-NP proto-oncogene NN I-NP . . O Transactivation NN B-NP of IN B-PP PTHrP NN B-NP by IN B-PP Tax NN B-NP was VBD B-VP seen VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP B-cell NN B-NP lines NNS I-NP or CC O fibroblasts NNS B-NP . . O A DT B-NP carboxy NN I-NP terminal JJ I-NP Tax NN I-NP deletion NN I-NP mutant NN I-NP was VBD B-VP deficient JJ B-ADJP in IN B-PP transactivation NN B-NP of IN B-PP both CC O the DT O PTHrP NN B-NP and CC O IL2R NN B-NP alpha NN I-NP promoters NNS B-NP but CC B-CONJP not RB I-CONJP the DT B-NP HTLV-I NN I-NP long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O . . O Exogenous JJ B-NP provision NN I-NP of IN B-PP NFkB NN B-NP rescued VBD B-VP IL2R NN B-NP alpha NN I-NP expression NN I-NP but CC B-CONJP not RB I-CONJP the DT B-NP PTHrP NN I-NP promoter NN I-NP . . O Thus RB B-ADVP COMMA COMMA O HTLV-I NN B-NP Tax NN I-NP COMMA COMMA O HTLV-II NN B-NP Tax NN I-NP COMMA COMMA O and CC O c-jun NN B-NP transactivate VBP B-VP PTHrP NN B-NP and CC O may MD B-VP contribute VB I-VP to TO B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP hypercalcemia NN B-NP in IN B-PP adult JJ B-NP T-cell NN I-NP leukemia NN I-NP . . O Interleukin-3 NN B-NP expression NN I-NP by IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP involves VBZ B-VP an DT B-NP inducible JJ I-NP COMMA COMMA I-NP T-cell-specific JJ I-NP factor NN I-NP and CC O an DT B-NP octamer NN I-NP binding NN I-NP protein NN I-NP . . O Interleukin-3 NN B-NP ( ( O IL-3 NN B-NP ) ) O is VBZ B-VP exclusively RB I-VP expressed VBN I-VP by IN B-PP activated VBN B-NP T NN I-NP and CC O natural JJ B-NP killer NN I-NP cells NNS B-NP COMMA COMMA O a DT B-NP function NN I-NP that WDT B-NP is VBZ B-VP tightly RB I-VP controlled VBN I-VP both CC O in IN B-PP a DT B-NP lineage-specific JJ I-NP and CC B-PP in IN B-PP a DT B-NP stimulation-dependent JJ I-NP manner NN B-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP protein NN B-NP binding NN I-NP characteristics NNS I-NP and CC O functional JJ B-NP importance NN I-NP of IN B-PP the DT B-NP ACT-1-activating JJ I-NP region NN I-NP of IN B-PP the DT B-NP IL-3 NN I-NP promoter NN I-NP . . O This DT B-NP region NN I-NP binds VBZ B-VP an DT B-NP inducible JJ I-NP COMMA COMMA I-NP T-cell-specific JJ I-NP factor NN I-NP over IN B-PP its PRP$ B-NP 5' JJ I-NP end NN I-NP COMMA COMMA O a DT B-NP site NN I-NP that WDT B-NP is VBZ B-VP necessary JJ B-ADJP for IN B-PP the DT B-NP expression NN I-NP of IN B-PP IL-3 NN B-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP other JJ B-NP upstream JJ I-NP elements NNS I-NP . . O Over IN B-PP its PRP$ B-NP 3' JJ I-NP end NN I-NP COMMA COMMA O it PRP B-NP binds VBZ B-VP a DT B-NP factor NN I-NP that WDT B-NP is VBZ O ubiquitously RB B-ADVP and CC O constitutively RB B-ADVP expressed VBN B-VP . . O This DT B-NP factor NN I-NP is VBZ B-VP Oct-1 NN B-NP or CC O an DT B-NP immunologically RB I-NP related JJ I-NP octamer-binding JJ I-NP protein NN I-NP COMMA COMMA O and CC O it PRP B-NP plays VBZ B-VP a DT B-NP role NN I-NP in IN B-PP coordinating VBG B-VP the DT B-NP activity NN I-NP of IN B-PP several JJ B-NP regulatory JJ I-NP elements NNS I-NP . . O These DT B-NP characteristics NNS I-NP make VBP B-VP the DT B-NP ACT-1 NN I-NP site NN I-NP analogous JJ B-ADJP to TO B-PP the DT B-NP activating VBG I-NP ARRE-1 NN I-NP site NN I-NP in IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O and CC O despite IN B-PP a DT B-NP lack NN I-NP of IN B-PP sequence NN B-NP homology NN I-NP COMMA COMMA O the DT B-NP promoters NNS I-NP of IN B-PP IL-3 NN B-NP and CC O IL-2 NN B-NP share VBP B-VP an DT B-NP organizational JJ I-NP pattern NN I-NP of IN B-PP regulatory JJ B-NP elements NNS I-NP that WDT B-NP is VBZ B-VP likely JJ B-ADJP to TO B-VP be VB I-VP important JJ B-ADJP for IN B-PP the DT B-NP T-cell-specific JJ I-NP expression NN I-NP of IN B-PP these DT B-NP genes NNS I-NP . . O The DT B-NP Epstein-Barr JJ I-NP virus NN I-NP nuclear JJ I-NP antigen NN I-NP 2 CD I-NP interacts VBZ B-VP with IN B-PP an DT B-NP EBNA2 NN I-NP responsive JJ I-NP cis-element NN I-NP of IN B-PP the DT B-NP terminal JJ I-NP protein NN I-NP 1 CD I-NP gene NN I-NP promoter NN I-NP . . O The DT B-NP Epstein-Barr JJ I-NP virus NN I-NP protein NN I-NP EBNA2 NN I-NP acts VBZ B-VP as IN B-PP a DT B-NP transcriptional JJ I-NP activator NN I-NP of IN B-PP cellular JJ B-NP and CC I-NP viral JJ I-NP genes NNS I-NP and CC O plays VBZ B-VP a DT B-NP crucial JJ I-NP role NN I-NP in IN B-PP the DT B-NP immortalization NN I-NP of IN B-PP human JJ B-NP primary JJ I-NP B-cells NNS I-NP by IN B-PP EBV NN B-NP . . O We PRP B-NP have VBP B-VP shown VBN I-VP previously RB B-ADVP that IN B-SBAR EBNA2 NN B-NP transactivates VBZ B-VP the DT B-NP promoters NNS I-NP of IN B-PP the DT B-NP latent JJ I-NP membrane NN I-NP antigens NNS I-NP LMP NN B-NP COMMA COMMA O TP1 NN B-NP and CC O TP2 NN B-NP . . O The DT B-NP promoter NN I-NP of IN B-PP the DT B-NP TP1 NN I-NP gene NN I-NP was VBD B-VP chosen VBN I-VP as IN B-PP a DT B-NP model JJ I-NP system NN I-NP to TO B-VP study VB I-VP the DT B-NP molecular JJ I-NP mechanism NN I-NP of IN B-PP EBNA2 NN B-NP mediated JJ I-NP transactivation NN I-NP . . O To TO B-VP identify VB I-VP an DT B-NP EBNA2 NN I-NP dependent JJ I-NP cis-acting JJ I-NP element NN I-NP COMMA COMMA O various JJ B-NP TP1 NN I-NP promoter-reporter NN I-NP gene NN I-NP constructs NNS I-NP were VBD B-VP transfected VBN I-VP in IN B-PP the DT B-NP absence NN B-NP and CC O presence NN B-NP of IN B-PP an DT B-NP EBNA2 NN I-NP expression NN I-NP vector NN I-NP into IN B-PP the DT B-NP established JJ I-NP B-cell NN I-NP line NN I-NP BL41-P3HR1 NN I-NP . . O We PRP B-NP were VBD B-VP able JJ B-ADJP to TO B-VP delineate VB I-VP an DT B-NP 81 CD I-NP bp NN I-NP EBNA2 NN I-NP responsive JJ I-NP region NN I-NP between IN B-PP -258 CD B-NP and CC O -177 CD B-NP relative JJ B-PP to TO I-PP the DT B-NP TP1 NN I-NP RNA NN I-NP start NN I-NP site NN I-NP . . O The DT B-NP element NN I-NP worked VBD B-VP in IN B-PP either DT B-NP orientation NN I-NP and CC O could MD B-VP mediate VB I-VP EBNA2 NN B-NP dependent JJ I-NP transactivation NN I-NP on IN B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP revealed VBD B-VP three CD B-NP specific JJ I-NP protein-DNA NN I-NP complexes NNS I-NP formed VBN B-VP with IN B-PP sequences NNS B-NP of IN B-PP the DT B-NP EBNA2 NN I-NP responsive JJ I-NP element NN I-NP . . O Two CD B-NP of IN B-PP these DT B-NP were VBD B-VP not RB O cell NN B-NP type NN I-NP specific JJ B-ADJP COMMA COMMA O but CC O the DT B-NP third JJ I-NP was VBD B-VP detected VBN I-VP only RB B-PP in IN I-PP EBNA2 NN B-NP positive JJ I-NP cell NN I-NP extracts NNS I-NP . . O Gel-shift JJ B-NP analysis NN I-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP EBNA2 NN B-NP specific JJ I-NP monoclonal JJ I-NP antibodies NNS I-NP revealed VBD B-VP that IN B-SBAR EBNA2 NN B-NP is VBZ B-VP a DT B-NP component NN I-NP of IN B-PP the DT B-NP third JJ I-NP complex NN I-NP . . O Thus RB B-ADVP COMMA COMMA O these DT B-NP experiments NNS I-NP demonstrate VBP B-VP that IN B-SBAR EBNA2 NN B-NP interacts VBZ B-VP with IN B-PP an DT B-NP EBNA2 NN I-NP responsive JJ I-NP cis-element NN I-NP of IN B-PP the DT B-NP TP1 NN I-NP promoter NN I-NP . . O ras NN B-NP protein NN I-NP activity NN I-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP T-cell NN B-NP antigen NN I-NP receptor NN I-NP signal NN I-NP transduction NN I-NP . . O In IN B-PP a DT B-NP Jurkat NN I-NP cell NN I-NP model NN I-NP of IN B-PP T-cell NN B-NP activation NN I-NP an DT B-NP interleukin-2 NN I-NP promoter\/reporter NN I-NP gene NN I-NP construct NN I-NP was VBD B-VP activated VBN I-VP by IN B-PP antigen NN B-NP receptor NN I-NP agonism NN I-NP in IN B-PP combination NN B-NP with IN B-PP the DT B-NP lymphokine NN I-NP interleukin-1 NN I-NP . . O Antigen NN B-NP receptor NN I-NP signals NNS I-NP could MD B-VP be VB I-VP mimicked VBN I-VP by IN B-PP suboptimal JJ B-NP activation NN I-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O with IN B-PP phorbol NN B-NP esters NNS I-NP in IN B-PP combination NN B-NP with IN B-PP calcium NN B-NP mobilization NN I-NP by IN B-PP an DT B-NP ionophore NN I-NP . . O In IN B-PP cotransfection NN B-NP experiments NNS I-NP COMMA COMMA O oncogenic JJ B-NP rats NNS I-NP obviated VBD B-VP the DT B-NP need NN I-NP for IN B-PP PKC NN B-NP stimulation NN I-NP but CC O did VBD B-VP not RB I-VP replace VB I-VP either CC O the DT B-NP calcium NN I-NP signal NN I-NP or CC O interleukin-1 NN B-NP . . O Activated VBN B-NP ras NN I-NP expression NN I-NP also RB B-ADVP replaced VBD B-VP the DT B-NP requirement NN I-NP for IN B-PP PKC NN B-NP stimulation NN I-NP in IN B-PP activation NN B-NP of IN B-PP the DT B-NP T-cell NN I-NP transcription NN I-NP factor NN I-NP NF-AT NN I-NP . . O A DT B-NP dominant JJ I-NP inhibitory JJ I-NP ras NN I-NP mutant NN I-NP specifically RB B-ADVP blocked VBD B-VP antigen NN B-NP receptor NN I-NP agonism NN I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR ras NN B-NP activity NN I-NP is VBZ B-VP required VBN I-VP for IN B-PP antigen NN B-NP receptor NN I-NP signaling NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP PKC NN B-NP blocked VBD B-VP both CC O activated VBD B-NP ras NN I-NP and CC O phorbol NN B-NP ester NN I-NP stimulation NN I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP role NN I-NP for IN B-PP ras NN B-NP upstream JJ B-ADVP of IN B-PP PKC NN B-NP . . O Characterization NN B-NP of IN B-PP the DT B-NP nuclear JJ I-NP and CC I-NP cytoplasmic JJ I-NP components NNS I-NP of IN B-PP the DT O lymphoid-specific JJ O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O complex NN B-NP . . O The DT B-NP lymphoid-specific JJ I-NP transcription NN I-NP complex NN I-NP COMMA COMMA O NF-AT NN B-NP COMMA COMMA O is VBZ B-VP involved VBN I-VP in IN B-PP early JJ B-NP gene NN I-NP activation NN I-NP in IN B-PP T NN B-NP cells NNS I-NP and CC O is VBZ B-VP assembled VBN I-VP from IN B-PP a DT O pre-existing JJ O COMMA COMMA O T NN B-NP cell NN I-NP restricted JJ B-NP cytoplasmic JJ I-NP factor NN I-NP and CC O an DT B-NP inducible JJ I-NP ubiquitous JJ I-NP nuclear JJ I-NP component NN I-NP within IN B-NP 30 CD I-NP min NN I-NP after IN B-PP activation NN B-NP through IN B-PP the DT B-NP antigen NN I-NP receptor NN I-NP . . O Recent JJ B-NP studies NNS I-NP have VBP B-VP implicated VBN I-VP the DT B-NP family NN I-NP of IN B-PP AP1 NN B-NP factors NNS I-NP as IN B-PP components NNS B-NP of IN B-PP the DT B-NP murine JJ I-NP NF-AT NN I-NP complex NN I-NP . . O Evidence NN B-NP is VBZ B-VP provided VBN I-VP here RB B-ADVP that IN B-SBAR the DT B-NP nuclear JJ I-NP component NN I-NP of IN B-PP human JJ B-NP NF-AT NN I-NP contains VBZ B-VP the DT B-NP phorbol NN I-NP ester-inducible JJ I-NP transcription NN I-NP factor NN I-NP AP1 NN I-NP ( ( O Jun\/Fos NN B-NP ) ) O . . O We PRP B-NP further RB B-ADVP characterize VBP B-VP which WDT B-NP AP1 NN I-NP family NN I-NP members NNS I-NP can MD B-VP assume VB I-VP this DT B-NP role NN I-NP . . O Antisera NN B-NP to TO B-PP Fos NN B-NP inhibits VBZ B-VP NF-AT NN B-NP DNA NN I-NP binding NN I-NP as IN B-SBAR does VBZ O an DT B-NP oligonucleotide NN I-NP containing VBG B-VP a DT B-NP binding VBG I-NP site NN I-NP for IN B-PP AP1 NN B-NP . . O Constitutive JJ B-NP expression NN I-NP in FW B-ADVP vivo FW I-ADVP of IN B-PP Fos NN B-NP COMMA COMMA O and CC O to TO B-PP a DT B-NP lesser JJR I-NP extent NN I-NP Fra-1 NN B-NP COMMA COMMA O eliminates VBZ B-VP the DT B-NP requirement NN I-NP for IN B-PP phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O stimulation NN B-NP COMMA COMMA O leaving VBG B-VP NF-AT-directed JJ B-NP transcription NN I-NP responsive JJ B-ADJP to TO B-PP calcium NN B-NP ionophore NN I-NP alone RB B-ADVP . . O Overexpression NN B-NP of IN B-PP cJun NN B-NP or CC O JunD NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP JunB NN B-NP COMMA COMMA O also RB B-ADVP eliminates VBZ B-VP the DT B-NP requirement NN I-NP for IN B-PP PMA NN B-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR many JJ O but CC O not RB O all DT O Jun- NN B-NP and CC O Fos-related JJ B-ADJP proteins NNS B-NP functionally RB B-ADVP activate VBP B-VP NF-AT-dependent JJ B-NP transcription NN I-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP the DT B-NP cytoplasmic JJ I-NP component NN I-NP . . O NF-AT NN B-NP DNA NN I-NP binding NN I-NP can MD B-VP be VB I-VP reconstituted VBN I-VP in FW B-ADVP vitro FW I-ADVP using VBG B-VP semi-purified JJ B-NP AP1 NN I-NP proteins NNS I-NP mixed VBN B-VP with IN B-PP cytosol NN B-NP from IN B-PP T NN B-NP lymphocytes NNS I-NP . . O Fos NN B-NP proteins NNS I-NP are VBP B-VP not RB I-VP needed VBN I-VP for IN B-PP this DT B-NP reconstitution NN I-NP COMMA COMMA O and CC O although IN B-SBAR JunB NN B-NP is VBZ B-VP not RB O functional JJ B-ADJP COMMA COMMA O it PRP B-NP can MD B-VP participate VB I-VP in IN B-PP the DT B-NP NF-AT NN I-NP DNA NN I-NP binding NN I-NP complex NN I-NP . . O Finally RB B-ADVP COMMA COMMA O we PRP B-NP have VBP B-VP partially RB I-VP purified VBN I-VP the DT B-NP cytoplasmic JJ I-NP component NN I-NP of IN B-PP NF-AT NN B-NP and CC O show VBP B-VP by IN B-PP elution NN B-NP and CC O renaturation NN B-NP from IN B-PP SDS-polyacrylamide NN B-NP gel NN I-NP electrophoresis NN I-NP gels NNS I-NP that IN B-SBAR it PRP B-NP has VBZ B-VP a DT B-NP molecular JJ I-NP mass NN I-NP between IN B-NP 94 CD I-NP and CC I-NP 116 CD I-NP kDa NN I-NP and CC O may MD B-VP have VB I-VP multiple JJ B-NP differentially RB I-NP modified JJ I-NP forms NNS I-NP . . O The DT B-NP c-rel NN I-NP protooncogene NN I-NP product NN I-NP represses VBZ B-VP NF-kappa NN B-NP B NN I-NP p65-mediated JJ I-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP of IN B-PP type NN B-NP 1 CD I-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP . . O The DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O of IN B-PP the DT B-NP type NN I-NP 1 CD I-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV-1 NN B-NP ) ) O and CC O the DT B-NP 5' JJ I-NP regulatory JJ I-NP region NN I-NP of IN B-PP the DT B-NP gene NN I-NP encoding VBG B-VP the DT B-NP interleukin NN I-NP 2 CD I-NP receptor NN I-NP alpha NN I-NP subunit NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O share NN B-VP functional JJ B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP elements NNS I-NP involved VBN B-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP these DT B-NP inducible JJ I-NP transcription NN I-NP units NNS I-NP during IN B-PP T-cell NN B-NP activation NN I-NP . . O These DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP elements NNS I-NP are VBP B-VP recognized VBN I-VP by IN B-PP a DT B-NP structurally RB I-NP related JJ I-NP family NN I-NP of IN B-PP interactive JJ B-NP proteins NNS I-NP that WDT B-NP includes VBZ B-VP p50 NN B-NP COMMA COMMA O p65 NN B-NP COMMA COMMA O and CC O the DT B-NP product NN I-NP of IN B-PP the DT B-NP c-rel NN I-NP protooncogene NN I-NP ( ( O c-Rel NN B-NP ) ) O . . O Recent JJ B-NP biochemical JJ I-NP studies NNS I-NP have VBP B-VP shown VBN I-VP that IN B-SBAR p65 NN B-NP and CC O p50 NN B-NP form VBP B-VP the DT B-NP prototypical JJ I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP rapidly RB I-VP translocated VBN I-VP from IN B-PP the DT B-NP cytoplasm NN I-NP to TO B-PP the DT B-NP nucleus NN I-NP during IN B-PP T-cell NN B-NP activation NN I-NP . . O This DT B-NP intracellular JJ I-NP signaling NN I-NP complex NN I-NP potently RB B-ADVP stimulates VBZ B-VP kappa NN B-NP B-directed JJ I-NP transcription NN I-NP from IN B-PP either CC O the DT B-NP HIV-1 NN I-NP LTR NN I-NP or CC O the DT B-NP IL-2R NN I-NP alpha NN I-NP promoter NN I-NP via IN B-PP the DT B-NP strong JJ I-NP transactivation NN I-NP domain NN I-NP present JJ B-ADJP in IN B-PP p65 NN B-NP . . O We PRP B-NP now RB B-ADVP demonstrate VBP B-VP that IN B-SBAR nuclear JJ B-NP expression NN I-NP of IN B-PP human JJ B-NP c-Rel NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP induced VBN I-VP by IN B-PP either DT B-NP phorbol NN B-NP ester NN I-NP or CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP with IN B-PP delayed VBN B-NP kinetics NNS I-NP relative JJ B-ADJP to TO B-PP p65 NN B-NP COMMA COMMA O markedly RB B-ADVP represses VBZ B-VP p65-mediated JJ B-NP activation NN I-NP of IN B-PP these DT B-NP transcription NN I-NP units NNS I-NP . . O These DT B-NP inhibitory JJ I-NP effects NNS I-NP of IN B-PP c-Rel NN B-NP correlate VBP B-VP with IN B-PP its PRP$ B-NP DNA-binding JJ I-NP activity NN I-NP but CC B-PP not RB B-PP with IN I-PP its PRP$ B-NP ability NN I-NP to TO B-VP heterodimerize VB I-VP with IN B-PP p50 NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR c-Rel NN B-NP inhibition NN I-NP involves VBZ B-VP competition NN B-NP with IN B-PP p50\/p65 NN B-NP for IN B-PP occupancy NN B-NP of IN B-PP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP element NN I-NP . . O Together RB B-ADVP COMMA COMMA O these DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR one CD B-NP function NN I-NP of IN B-PP c-Rel NN B-NP is VBZ B-VP as IN B-PP a DT B-NP physiologic JJ I-NP repressor NN I-NP of IN B-PP the DT O HIV-1 NN B-NP LTR NN I-NP and CC O IL-2R NN B-NP alpha NN I-NP promoters NNS B-NP COMMA COMMA O serving VBG B-VP to TO I-VP efficiently RB I-VP counter VB I-VP the DT B-NP strong JJ I-NP transcriptional JJ I-NP activating JJ I-NP effects NNS I-NP of IN B-PP p65 NN B-NP . . O Protease NN B-NP treatment NN I-NP of IN B-PP nuclear JJ B-NP extracts NNS I-NP distinguishes VBZ B-VP between IN B-PP class NN B-NP II CD I-NP MHC NN I-NP X1 NN I-NP box NN I-NP DNA-binding JJ I-NP proteins NNS I-NP in IN B-PP wild-type JJ B-NP and CC I-NP class NN I-NP II-deficient JJ I-NP B NN I-NP cells NNS I-NP . . O The DT B-NP X NN I-NP box NN I-NP region NN I-NP is VBZ B-VP critical JJ B-ADJP for IN B-PP directing VBG B-VP the DT B-NP expression NN I-NP of IN B-PP class NN B-NP II CD I-NP major JJ I-NP histocompatibility NN I-NP complex NN I-NP genes NNS I-NP in IN B-PP B NN B-NP lymphocytes NNS I-NP . . O Although IN B-SBAR several JJ B-NP class NN I-NP II CD I-NP promoter-specific JJ I-NP DNA NN I-NP binding NN I-NP factors NNS I-NP have VBP B-VP been VBN I-VP described VBN I-VP COMMA COMMA O only RB B-NP the DT I-NP X NN I-NP box NN I-NP region NN I-NP factor NN I-NP COMMA COMMA O RFX NN B-NP COMMA COMMA O shows VBZ B-VP a DT B-NP genetic JJ I-NP correlation NN I-NP with IN B-PP class NN B-NP II CD I-NP expression NN I-NP COMMA COMMA O being VBG B-VP deficient JJ B-ADJP in IN B-PP some DT B-NP B NN I-NP cell NN I-NP lines NNS I-NP derived VBN B-VP from IN B-PP patients NNS B-NP with IN B-PP class NN B-NP II-deficient JJ I-NP congenital JJ I-NP immunodeficiency NN I-NP . . O To TO B-VP further RB I-VP evaluate VB I-VP the DT B-NP role NN I-NP of IN B-PP X NN B-NP box NN I-NP DNA-binding JJ I-NP proteins NNS I-NP in IN B-PP class NN B-NP II CD I-NP gene NN I-NP expression NN I-NP COMMA COMMA O the DT B-NP role NN I-NP of IN B-PP the DT B-NP X NN I-NP box NN I-NP region NN I-NP was VBD B-VP examined VBN I-VP in IN B-PP both DT B-NP class NN I-NP II-positive JJ I-NP and CC I-NP -negative JJ I-NP lymphoid JJ I-NP cells NNS I-NP . . O In IN B-PP addition NN I-PP to TO I-PP the DT B-NP wild-type JJ I-NP B NN I-NP cell NN I-NP line NN I-NP Raji NN I-NP COMMA COMMA O two CD B-NP class NN I-NP II CD I-NP transcriptional JJ I-NP mutant JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O SJO NN B-NP and CC O RJ2.2.5 NN B-NP COMMA COMMA O and CC O Jurkat NN B-NP COMMA COMMA O a DT B-NP class NN I-NP II CD I-NP negative JJ I-NP T NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O were VBD B-VP examined VBN I-VP . . O In IN B-PP contrast NN I-PP to TO I-PP wild-type JJ B-NP B NN I-NP cells NNS I-NP COMMA COMMA O neither DT B-NP of IN B-PP the DT B-NP class NN I-NP II CD I-NP mutant JJ I-NP cell NN I-NP lines NNS I-NP could MD B-VP use VB I-VP the DT B-NP X NN I-NP box NN I-NP region NN I-NP to TO B-VP direct VB I-VP the DT B-NP expression NN I-NP of IN B-PP a DT B-NP transiently RB I-NP transfected VBN I-NP reporter NN I-NP gene NN I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP X NN I-NP box-dependent JJ I-NP transcriptional JJ I-NP pathway NN I-NP is VBZ B-VP defective JJ B-ADJP in IN B-PP these DT B-NP cells NNS I-NP . . O The DT B-NP binding NN I-NP activity NN I-NP of IN B-PP the DT B-NP X1 NN I-NP box NN I-NP DNA-binding JJ I-NP protein NN I-NP RFX NN I-NP was VBD B-VP examined VBN I-VP and CC O found VBN B-VP to TO I-VP be VB I-VP present JJ B-ADJP in IN B-PP wild-type JJ B-NP B NN I-NP cells NNS I-NP and CC O the DT B-NP mutant JJ I-NP RJ2.2.5 NN I-NP but CC O was VBD B-VP absent JJ B-ADJP in IN B-PP SJO NN B-NP and CC O Jurkat NN B-NP . . O However RB B-ADVP COMMA COMMA O other JJ B-NP X1 NN I-NP box-specific JJ I-NP activities NNS I-NP were VBD B-VP detected VBN I-VP in IN B-PP all DT B-NP these DT I-NP cell NN I-NP lines NNS I-NP . . O To TO B-VP determine VB I-VP whether IN B-SBAR these DT B-NP different JJ I-NP X1 NN I-NP box NN I-NP activities NNS I-NP represented VBD B-VP distinct JJ B-NP DNA NN I-NP binding NN I-NP proteins NNS I-NP or CC O multimeric JJ B-NP forms NNS I-NP of IN B-PP the DT B-NP same JJ I-NP factor NN I-NP ( ( I-NP s NNS I-NP ) ) O COMMA COMMA O protease NN B-NP treatment NN I-NP of IN B-PP the DT B-NP crude JJ I-NP nuclear JJ I-NP extracts NNS I-NP followed VBN B-VP by IN B-PP DNA-binding JJ B-NP assays NNS I-NP were VBD B-VP carried VBN I-VP out RP B-PRT and CC O demonstrated VBD B-VP that IN B-SBAR B NN B-NP cell NN I-NP extracts NNS I-NP contain VBP B-VP at IN B-NP least JJS I-NP two CD I-NP X1-specific JJ I-NP factors NNS I-NP . . O One CD B-NP of IN B-PP these DT B-NP cleaved VBN I-NP products NNS I-NP ( ( O band NN B-NP 1 CD I-NP pk NN I-NP ) ) O correlates VBZ B-VP with IN B-PP RFX NN B-NP activity NN I-NP . . O A DT B-NP similar JJ I-NP comparison NN I-NP with IN B-PP protease-treated JJ B-NP extracts NNS I-NP prepared VBN B-VP from IN B-PP Jurkat NN B-NP cells NNS I-NP demonstrated VBD B-VP the DT B-NP presence NN I-NP of IN B-PP the DT B-NP band NN I-NP 1pk NN I-NP activity NN I-NP despite IN B-PP an DT B-NP absence NN I-NP of IN B-PP the DT B-NP native JJ I-NP RFX NN I-NP activity NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O protease NN B-NP treatment NN B-NP and CC O analysis NN B-NP of IN B-PP SJO NN B-NP extracts NNS I-NP showed VBD B-VP no DT B-NP detectable JJ I-NP levels NNS I-NP of IN B-PP the DT B-NP band NN I-NP 1pk NN I-NP activity NN I-NP . . O These DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR multiple JJ B-NP X1 NN I-NP box-specific JJ I-NP DNA-binding JJ I-NP activities NNS I-NP exist VBP B-VP in IN B-PP all DT B-NP lymphoid JJ I-NP cells NNS I-NP COMMA COMMA O but CC O the DT B-NP presence NN I-NP of IN B-PP an DT B-NP actively RB I-NP binding NN I-NP RFX NN I-NP species NNS I-NP correlates VBZ B-VP with IN B-PP class NN B-NP II CD I-NP transcription NN I-NP . . O Replication NN B-NP of IN B-PP type NN B-NP 1 CD I-NP human JJ I-NP immunodeficiency NN I-NP viruses NNS I-NP containing VBG B-VP linker NN B-NP substitution NN I-NP mutations NNS I-NP in IN B-PP the DT B-NP -201 CD B-NP to TO O -130 CD B-NP region NN B-NP of IN B-PP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O In IN B-PP previous JJ B-NP transfection NN I-NP analyses NNS I-NP using VBG B-VP the DT B-NP chloramphenicol JJ I-NP acetyltransferase NN I-NP reporter NN I-NP gene NN I-NP system NN I-NP COMMA COMMA O we PRP B-NP determined VBD B-VP that IN B-SBAR linker NN B-NP substitution NN I-NP ( ( O LS NN B-NP ) ) O mutations NNS B-NP between IN B-PP -201 CD B-NP and CC O -130 CD B-NP ( ( O relative JJ B-ADJP to TO B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP ) ) O of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O caused VBD B-VP moderate JJ B-NP decreases NNS I-NP in IN B-PP LTR NN B-NP transcriptional JJ I-NP activity NN I-NP in IN B-PP a DT B-NP T-cell NN I-NP line NN I-NP ( ( O S.L.Zeichner NNP B-NP COMMA COMMA O J.Y.H. NNP B-NP Kim NNP I-NP COMMA COMMA O and CC O J.C.Alwine NNP B-NP COMMA COMMA O J.Virol.65 NNP B-NP : : O 2436-2444 CD B-NP COMMA COMMA O 1991 CD B-NP ) ) O . . O In IN B-PP addition NN B-NP COMMA COMMA O two CD B-NP mutations NNS I-NP between IN B-PP -93 CD B-NP and CC O -76 CD B-NP and CC B-PP between IN B-PP -75 CD B-NP and CC O -58 CD B-NP were VBD B-VP utilized VBN I-VP COMMA COMMA O since IN B-SBAR they PRP B-NP affect VBP B-VP the DT O nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O - : O and CC O Sp1-binding JJ B-ADJP sites NNS B-NP and CC O were VBD B-VP expected VBN I-VP to TO I-VP diminish VB I-VP viral JJ B-NP replication NN I-NP . . O Our PRP$ B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR while IN B-SBAR transfection NN B-NP analyses NNS I-NP offer VBP B-VP an DT B-NP adequate JJ I-NP approximation NN I-NP of IN B-PP the DT B-NP effects NNS I-NP of IN B-PP the DT B-NP LS NN I-NP mutations NNS I-NP COMMA COMMA O the DT B-NP analysis NN I-NP of IN B-PP viral JJ B-NP replication NN I-NP using VBG B-VP a DT B-NP mutant JJ I-NP viral JJ I-NP stock NN I-NP presents VBZ B-VP a DT B-NP more RBR I-NP accurate JJ I-NP picture NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP sometimes RB B-ADVP at IN B-PP variance NN I-PP with IN I-PP the DT B-NP transfection NN I-NP results NNS I-NP . . O Three CD B-NP mutants NNS I-NP ( ( O -201\/-184 CD B-NP NXS NN I-NP COMMA COMMA O -165\/-148 CD B-NP NXS NN I-NP COMMA COMMA O and CC O -147\/-130 CD B-NP NXS NN I-NP ) ) O had VBD B-VP effects NNS B-NP on IN B-PP viral JJ B-NP replication NN I-NP that WDT B-NP were VBD B-VP much RB B-ADJP more RBR I-ADJP severe JJ I-ADJP than IN B-PP the DT B-NP effects NNS I-NP predicted VBN B-VP from IN B-PP their PRP$ B-NP performance NN I-NP in IN B-PP transfection NN B-NP analyses NNS I-NP COMMA COMMA O and CC O the DT B-NP effects NNS I-NP of IN B-PP two CD B-NP LS NN I-NP mutations NNS I-NP ( ( O -201\/-184 CD B-NP NXS NN I-NP and CC O -183\/-166 CD B-NP NXS NN I-NP ) ) O were VBD B-VP not RB I-VP predicted VBN I-VP by IN B-PP their PRP$ B-NP effects NNS I-NP in IN B-PP transfection NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O we PRP B-NP observed VBD B-VP cell NN B-NP type-specific JJ I-NP permissiveness NN I-NP to TO B-PP replication NN B-NP of IN B-PP some DT B-NP mutant JJ I-NP viruses NNS I-NP . . O In IN B-PP the DT B-NP cell NN I-NP types NNS I-NP tested VBN B-VP COMMA COMMA O the DT B-NP LS NN I-NP mutations NNS I-NP indicated VBD B-VP an DT B-NP apparent JJ I-NP requirement NN I-NP not RB B-CONJP only RB I-CONJP for IN B-PP the DT O intact JJ O NF-kappa NN B-NP B NN I-NP and CC O SP1-binding JJ B-ADJP sites NNS B-NP but CC B-CONJP also RB I-CONJP for IN B-PP several JJ B-NP regions NNS I-NP between IN B-PP -201 CD B-NP and CC O -130 CD B-NP not RB B-VP previously RB I-VP associated VBN I-VP with IN B-PP viral JJ B-NP infectivity NN I-NP . . O Dimerization NN B-NP of IN B-PP NF-KB2 NN B-NP with IN B-PP RelA(p65) NN B-NP regulates VBZ B-VP DNA NN B-NP binding NN I-NP COMMA COMMA O transcriptional JJ B-NP activation NN I-NP COMMA COMMA O and CC O inhibition NN B-NP by IN B-PP an DT B-NP I NN I-NP kappa NN I-NP B-alpha NN I-NP ( ( O MAD-3 NN B-NP ) ) O . . O Inducible JJ B-NP expression NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O is VBZ B-VP regulated VBN I-VP by IN B-PP a DT B-NP cellular JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O . . O NF-kappa NN B-NP B NN I-NP is VBZ B-VP composed VBN I-VP of IN B-PP distinct JJ B-NP subunits NNS I-NP ; : O five CD B-NP independent JJ I-NP genes NNS I-NP COMMA COMMA O NFKB1(p105) NN B-NP COMMA COMMA O NFKB2(p100) NN B-NP COMMA COMMA O RelA(p65) NN B-NP COMMA COMMA O c-rel NN B-NP and CC O relB NN B-NP COMMA COMMA O that WDT B-NP encode VBP B-VP related JJ B-NP proteins NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP kappa NN B-NP B NN I-NP DNA NN I-NP elements NNS I-NP have VBP B-VP been VBN I-VP isolated VBN I-VP . . O We PRP B-NP have VBP B-VP previously RB I-VP found VBN I-VP that IN B-SBAR NFKB2(p49\/p52) NN B-NP acts VBZ B-VP in IN B-PP concert NN I-PP with IN I-PP RelA(p65) NN B-NP to TO B-VP stimulate VB I-VP the DT B-NP HIV NN I-NP enhancer NN I-NP in IN B-PP Jurkat NN B-NP T-leukemia NN I-NP cells NNS I-NP . . O Here RB B-ADVP we PRP B-NP examine VBP B-VP the DT B-NP biochemical JJ I-NP basis NN I-NP for IN B-PP the DT B-NP transcriptional JJ I-NP regulation NN I-NP of IN B-PP HIV NN B-NP by IN B-PP NFKB2 NN B-NP . . O Using VBG B-VP Scatchard NN B-NP analysis NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP determined VBN I-VP the DT B-NP dissociation NN I-NP constants NNS I-NP of IN B-PP homodimeric JJ B-NP p49 NN I-NP and CC O heterodimeric JJ B-NP p49\/p65 NN I-NP for IN B-PP binding NN B-VP to TO B-PP the DT B-NP HIV NN I-NP kappa NN I-NP B NN I-NP site NN I-NP . . O p49 NN B-NP has VBZ B-VP a DT B-NP approximately RB I-NP 18-fold-lower JJ I-NP affinity NN I-NP for IN B-PP the DT B-NP HIV NN I-NP kappa NN I-NP B NN I-NP site NN I-NP ( ( O KD NN B-NP = JJ B-VP 69.1 CD B-NP pM NN I-NP ) ) O than IN B-SBAR does VBZ O the DT B-NP approximately RB I-NP 50-kDa JJ I-NP protein NN I-NP NFKB1(p50) NN B-NP derived VBN B-VP from IN B-PP p105 NN B-NP ( ( O KD NN B-NP = JJ B-VP 3.9 CD B-NP pM NN I-NP ) ) O . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP affinity NN I-NP of IN B-PP heterodimeric JJ B-NP NFKB2(p49)\/RelA(p65) NN I-NP for IN B-PP this DT B-NP site NN I-NP is VBZ B-VP approximately RB B-ADJP 6-fold RB I-ADJP higher JJR I-ADJP ( ( O KD NN B-NP = JJ B-VP 11.8 CD B-NP pM NN I-NP ) ) O than IN B-PP that DT B-NP of IN B-PP p49 NN B-NP alone RB B-ADVP . . O Consistent JJ B-ADJP with IN B-PP these DT B-NP findings NNS I-NP COMMA COMMA O in FW B-NP vitro FW I-NP transcription NN I-NP was VBD B-VP stimulated VBN I-VP 18-fold RB B-ADVP by IN B-PP the DT B-NP addition NN I-NP of IN B-PP preformed JJ B-NP COMMA COMMA I-NP heterodimeric JJ I-NP NFKB2(p49)\/RelA(p65) NN I-NP protein NN I-NP . . O Transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT B-NP HIV NN I-NP enhancer NN I-NP was VBD B-VP also RB B-ADVP subject JJ B-ADJP to TO B-PP regulation NN B-NP by IN B-PP recently RB B-NP cloned VBN I-NP I NN B-NP kappa NN I-NP B-alpha NN I-NP ( ( O MAD-3 NN B-NP ) ) O . . O Recombinant JJ B-NP I NN B-NP kappa NN I-NP B-alpha NN I-NP ( ( O MAD-3 NN B-NP ) ) O inhibited VBD B-VP the DT B-NP DNA NN I-NP binding NN I-NP activity NN I-NP of IN B-PP p65 NN B-NP COMMA COMMA O p49\/p65 NN B-NP COMMA COMMA O and CC O p50\/p65 NN B-NP but CC O stimulated VBD B-VP the DT B-NP binding NN I-NP of IN B-PP NFKB2(p49) NN B-NP or CC O NFKB1(p50) NN B-NP . . O Functional JJ B-NP activation NN I-NP of IN B-PP an DT B-NP HIV NN I-NP reporter NN I-NP plasmid NN I-NP by IN B-PP p49\/p65 NN B-NP in IN B-PP transiently RB B-NP transfected VBN I-NP Jurkat NN I-NP T-leukemia JJ I-NP cells NNS I-NP was VBD B-VP also RB I-VP inhibited VBN I-VP by IN B-PP coexpression NN B-NP of IN B-PP MAD-3 NN B-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O The DT B-NP human JJ I-NP prointerleukin NN I-NP 1 CD I-NP beta NN I-NP gene NN I-NP requires VBZ B-VP DNA NN B-NP sequences NNS I-NP both CC O proximal JJ B-ADJP and CC O distal JJ B-ADJP to TO B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP for IN B-PP tissue-specific JJ B-NP induction NN I-NP . . O In IN B-PP these DT B-NP studies NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP identified VBN I-VP DNA NN B-NP sequences NNS I-NP and CC O specific JJ B-NP protein NN I-NP interactions NNS I-NP necessary JJ B-ADJP for IN B-PP transcriptional JJ B-NP regulation NN I-NP of IN B-PP the DT O human JJ O prointerleukin NN B-NP 1 CD I-NP beta NN I-NP ( ( O proIL-1 NN B-NP beta NN I-NP ) ) O gene NN B-NP . . O A DT B-NP cell-type-independent JJ I-NP lipopolysaccharide NN I-NP ( ( I-NP LPS NN I-NP ) ) I-NP -responsive JJ I-NP enhancer NN I-NP element NN I-NP located JJ O between IN B-PP -3757 CD B-NP and CC O -2729 CD B-NP bp NN B-NP upstream RB B-ADJP from IN B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP ( ( O cap NN B-NP site NN I-NP ) ) O consisted VBD B-VP of IN B-PP at IN B-NP least JJS I-NP six CD I-NP discrete JJ I-NP subregions NNS I-NP which WDT B-NP were VBD B-VP essential JJ B-ADJP to TO B-PP the DT B-NP maximal JJ I-NP induction NN I-NP by IN B-PP LPS NN B-NP in IN B-PP transfected VBN B-NP monocytes NNS I-NP . . O The DT B-NP enhancer NN I-NP also RB B-ADVP appeared VBD B-VP to TO I-VP mediate VB I-VP phorbol NN B-NP myristate NN I-NP acetate NN I-NP induction NN I-NP in IN B-PP monocytes NNS B-NP and CC O IL-1 NN B-NP responsiveness NN I-NP in IN B-PP fibroblasts NNS B-NP . . O Deletion NN B-NP and CC O base NN B-NP substitution NN I-NP mutations NNS I-NP along IN B-CONJP with IN I-CONJP DNA NN B-NP binding NN I-NP studies NNS I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP enhancer NN I-NP contained VBD B-VP a DT B-NP minimum NN I-NP of IN B-PP three CD B-NP functional JJ I-NP protein NN I-NP binding NN I-NP sequences NNS I-NP COMMA COMMA O two CD B-NP of IN B-PP which WDT B-NP appeared VBD B-VP to TO I-VP be VB I-VP important JJ B-ADJP for IN B-PP gene NN B-NP induction NN I-NP . . O One CD B-NP of IN B-PP the DT B-NP essential JJ I-NP proteins NNS I-NP which WDT B-NP bound VBD B-VP to TO B-PP the DT B-NP enhancer NN I-NP was VBD B-VP similar JJ B-ADJP or CC O identical JJ B-ADJP to TO B-PP members NNS B-NP of IN B-PP the DT B-NP C\/EBP NN I-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP required VBN B-VP for IN B-PP both CC O IL-1- NN B-NP and CC O LPS-specific JJ B-ADJP induction NN B-NP of IN B-PP the DT B-NP IL-6 NN I-NP gene NN I-NP ( ( O i.e. FW B-ADVP COMMA COMMA B-NP the DT I-NP NF-IL6 NN I-NP proteins NNS I-NP ) ) O . . O When WRB B-ADVP ligated VBN B-VP to TO B-PP the DT B-NP proIL-1 NN I-NP beta NN I-NP cap NN I-NP site-proximal JJ I-NP region NN I-NP ( ( O located JJ B-ADJP between IN B-PP -131 CD B-NP to TO O +12 CD B-NP ) ) O COMMA COMMA O both CC O the DT B-NP proIL-1 NN I-NP beta NN I-NP and CC O the DT B-NP simian JJ I-NP virus NN I-NP 40 CD I-NP enhancer NN I-NP elements NNS I-NP functioned VBD B-VP more RBR B-ADVP efficiently RB I-ADVP in IN B-PP monocytes NNS B-NP than IN B-PP in IN B-PP HeLa NN B-NP cells NNS I-NP COMMA COMMA O which WDT B-NP are VBP B-VP not RB O normally RB B-ADVP competent JJ B-ADJP for IN B-PP IL-1 NN B-NP beta NN I-NP expression NN I-NP . . O When WRB B-ADVP ligated VBN B-VP to TO B-PP the DT B-NP murine JJ I-NP c-fos NN I-NP promoter NN I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O the DT B-NP proIL-1 NN I-NP beta NN I-NP enhancer NN I-NP was VBD B-VP inducible JJ B-ADJP in IN B-PP phorbol NN B-NP myristate NN I-NP acetate-stimulated JJ I-NP HeLa NN I-NP cells NNS I-NP COMMA COMMA O suggesting VBG B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP proIL-1 NN I-NP beta NN I-NP promoter-proximal JJ I-NP requirement NN I-NP for IN B-PP tissue NN B-NP specificity NN I-NP . . O Expression NN B-NP of IN B-PP PILOT NN B-NP COMMA COMMA O a DT B-NP putative JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O requires VBZ B-VP two CD B-NP signals NNS I-NP and CC O is VBZ B-VP cyclosporin NN B-NP A NN I-NP sensitive JJ B-ADJP in IN B-PP T NN B-NP cells NNS I-NP . . O Few JJ B-NP known JJ I-NP genes NNS I-NP ( ( O IL-2 NN B-NP COMMA COMMA O members NNS B-NP of IN B-PP the DT B-NP IL-8 NN I-NP family NN I-NP COMMA COMMA O interferon-gamma NN B-NP ) ) O are VBP B-VP induced VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP only RB B-PP through IN I-PP the DT B-NP combined JJ I-NP effect NN I-NP of IN B-PP phorbol NN B-NP myristic JJ I-NP acetate NN I-NP ( ( O PMA NN B-NP ) ) O and CC O a DT B-NP Ca(2+)-ionophore NN I-NP COMMA COMMA O and CC O expression NN B-NP of IN B-PP only RB B-NP these DT I-NP genes NNS I-NP can MD B-VP be VB I-VP fully RB I-VP suppressed VBN I-VP by IN B-PP Cyclosporin NN B-NP A NN I-NP ( ( O CyA NN B-NP ) ) O . . O We PRP B-NP have VBP B-VP identified VBN I-VP a DT B-NP putative JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O designated VBN B-VP PILOT NN B-NP COMMA COMMA O with IN B-PP an DT B-NP identical JJ I-NP dual JJ I-NP signal NN I-NP requirement NN I-NP for IN B-PP expression NN B-NP . . O Induction NN B-NP of IN B-PP the DT B-NP PILOT NN I-NP gene NN I-NP is VBZ B-VP detectable JJ B-ADJP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP 20 CD B-NP min NN I-NP following VBG B-PP activation NN B-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP cycloheximide NN B-NP and CC O is VBZ B-VP fully RB I-VP suppressed VBN I-VP by IN B-PP CyA NN B-NP . . O The DT B-NP PILOT NN I-NP protein NN I-NP has VBZ B-VP a DT B-NP calculated VBN I-NP M(r) NN I-NP of IN B-PP 42.6 CD B-NP kDa NN I-NP and CC O contains VBZ B-VP three CD B-NP zinc NN I-NP fingers NNS I-NP of IN B-PP the DT B-NP C2H2-type NN I-NP at IN B-PP the DT B-NP carboxyl-terminus NN I-NP which WDT B-NP are VBP B-VP highly RB B-ADJP homologous JJ I-ADJP to TO B-PP the DT B-NP zinc NN I-NP finger NN I-NP regions NNS I-NP of IN B-PP the DT B-NP transcription NN I-NP factors NNS I-NP EGR1 NNS B-NP COMMA COMMA O EGR2 NNS B-NP COMMA COMMA O and CC O pAT NN B-NP 133 CD I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP T NN B-NP cells NNS I-NP COMMA COMMA O in IN B-PP fibroblasts NNS B-NP PILOT NN B-NP gene NN I-NP expression NN I-NP requires VBZ B-VP only RB B-NP one CD I-NP signal NN I-NP ( ( O PMA NN B-NP ) ) O and CC O is VBZ B-VP not RB I-VP affected VBN I-VP by IN B-PP CyA NN B-NP . . O This DT B-NP observation NN I-NP directly RB B-ADVP demonstrates VBZ B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP Ca2+ NN I-NP signal-dependent JJ I-NP regulatory JJ I-NP element NN I-NP obligatory JJ B-ADJP for IN B-PP expression NN B-NP of IN B-PP some DT B-NP genes NNS I-NP in IN B-PP T NN B-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP fibroblasts NNS B-NP . . O This DT B-NP differential JJ I-NP expression NN I-NP model NN I-NP will MD B-VP be VB I-VP valuable JJ B-ADJP in IN B-PP the DT B-NP dissection NN I-NP of IN B-PP the DT B-NP dual JJ I-NP signal NN I-NP pathway NN I-NP in IN B-PP T NN B-NP cells NNS I-NP and CC O the DT B-NP effects NNS I-NP of IN B-PP CyA NN B-NP upon IN B-PP it PRP B-NP . . O Human JJ B-NP CD4 NN I-NP lymphocytes NNS I-NP specifically RB B-ADVP recognize VBP B-VP a DT B-NP peptide NN I-NP representing VBG B-VP the DT B-NP fusion NN I-NP region NN I-NP of IN B-PP the DT B-NP hybrid NN I-NP protein NN I-NP pml\/RAR NN I-NP alpha NN I-NP present JJ B-ADJP in IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP cells NNS I-NP . . O Fusion NN B-NP proteins NNS I-NP present JJ B-ADJP in IN B-PP leukemic JJ B-NP cells NNS I-NP frequently RB B-ADVP contain VBP B-VP a DT B-NP new JJ I-NP amino NN I-NP acid NN I-NP at IN B-PP the DT B-NP fusion NN I-NP point NN I-NP . . O We PRP B-NP tested VBD B-VP whether IN B-SBAR a DT B-NP peptide NN I-NP ( ( O BCR1\/25 NN B-NP ) ) O encompassing VBG B-VP the DT B-NP fusion NN I-NP region NN I-NP of IN B-PP the DT B-NP hybrid NN I-NP molecule NN I-NP pml\/RAR NN I-NP alpha NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP selectively RB I-VP expressed VBN I-VP by IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP ( ( O APL NN B-NP ) ) O cells NNS B-NP COMMA COMMA O can MD B-VP be VB I-VP recognized VBN I-VP by IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP in FW B-ADVP vitro FW I-ADVP . . O CD4+ JJ B-NP lymphocytes NNS I-NP COMMA COMMA O at IN B-PP both CC B-NP polyclonal JJ I-NP and CC I-NP clonal JJ I-NP level NN I-NP COMMA COMMA O recognized VBD B-VP peptide NN B-NP BCR1\/25 NN I-NP in IN B-PP an DT B-NP HLA-DR--restricted JJ I-NP fashion NN I-NP on IN B-PP presentation NN B-NP by IN B-PP autologous JJ B-NP antigen-presenting JJ B-NP cell NN I-NP ( ( O APC NN B-NP ) ) O or CC B-PP by IN B-PP APC NN B-NP expressing VBG B-VP the DT B-NP HLA-DR11 NN I-NP restricting NN I-NP molecule NN I-NP . . O Control NN B-NP peptides NNS I-NP corresponding VBG B-VP to TO B-PP the DT O normal JJ B-NP pml NN I-NP and CC O RAR NN B-NP alpha NN I-NP proteins NNS B-NP were VBD B-VP not RB I-VP recognized VBN I-VP . . O One CD B-NP clone NN I-NP ( ( O DEG5 NN B-NP ) ) O also RB B-ADVP exerted VBD B-VP a DT B-NP high JJ I-NP and CC I-NP specific JJ I-NP cytotoxicity NN I-NP against IN B-PP autologous JJ B-NP cells NNS I-NP pulsed VBN B-VP with IN B-PP BCR1\/25 NN B-NP . . O The DT B-NP autologous JJ I-NP DE NN I-NP LCL NN I-NP containing VBG B-VP a DT B-NP transduced VBN I-NP pml\/RAR NN I-NP alpha NN I-NP fusion NN I-NP gene NN I-NP and CC O expressing VBG B-VP a DT B-NP bcr1 NN I-NP type NN I-NP of IN B-PP the DT B-NP pml\/RAR NN I-NP alpha NN I-NP hybrid NN I-NP protein NN I-NP induced VBD B-VP the DT B-NP proliferation NN I-NP of IN B-PP DE NN B-NP anti-BCR1\/25 CD I-NP T NN I-NP cell NN I-NP clones NNS I-NP . . O It PRP B-NP is VBZ B-VP concluded VBN I-VP that IN B-SBAR the DT B-NP bcr1 NN I-NP type-pml\/RAR NN I-NP alpha NN I-NP fusion NN I-NP protein NN I-NP of IN B-PP APL NN B-NP contains VBZ B-VP an DT B-NP antigenic JJ I-NP site NN I-NP COMMA COMMA O absent JJ B-ADJP from IN B-PP the DT B-NP normal JJ I-NP parent NN I-NP molecules NNS I-NP and CC O recognized VBN B-VP by IN B-PP human JJ B-NP CD4+ JJ I-NP lymphocytes NNS I-NP . . O A DT B-NP serum NN I-NP response NN I-NP element NN I-NP and CC O a DT B-NP binding VBG I-NP site NN I-NP for IN B-PP NF-Y NN B-NP mediate VB B-VP the DT B-NP serum NN I-NP response NN I-NP of IN B-PP the DT B-NP human JJ I-NP thrombospondin NN I-NP 1 CD I-NP gene NN I-NP . . O The DT B-NP expression NN I-NP of IN B-PP thrombospondin NN B-NP 1 CD I-NP ( ( O TSP NN B-NP 1 CD I-NP ) ) O COMMA COMMA O a DT B-NP member NN I-NP of IN B-PP the DT B-NP TSP NN I-NP gene NN I-NP family NN I-NP COMMA COMMA O is VBZ B-VP rapidly RB I-VP induced VBN I-VP by IN B-PP growth NN B-NP factors NNS I-NP . . O We PRP B-NP tested VBD B-VP the DT B-NP ability NN I-NP of IN B-PP human JJ B-NP TSP NN I-NP 1-chloramphenicol JJ I-NP acetyltransferase NN I-NP constructs NNS I-NP to TO B-VP respond VB I-VP to TO B-PP serum NN B-NP in IN B-PP stably RB B-NP transfected VBN I-NP NIH-3T3 NN I-NP cells NNS I-NP . . O Two CD B-NP transcriptional JJ I-NP elements NNS I-NP in IN B-PP the DT B-NP TSP NN I-NP 1 CD I-NP promoter NN I-NP COMMA COMMA O a DT B-NP distal JJ I-NP element NN I-NP at IN B-PP -1280 CD B-NP and CC O a DT B-NP proximal JJ I-NP element NN I-NP at IN B-PP -65 CD B-NP COMMA COMMA O were VBD B-VP required VBN I-VP for IN B-PP the DT B-NP response NN I-NP of IN B-PP the DT B-NP human JJ I-NP TSP NN I-NP 1 CD I-NP gene NN I-NP to TO B-PP serum NN B-NP . . O Deletions NNS B-NP or CC O mutations NNS B-NP in IN B-PP this DT B-NP element NN I-NP reduced VBD B-VP the DT B-NP serum NN I-NP response NN I-NP of IN B-PP the DT B-NP TSP NN I-NP 1 CD I-NP gene NN I-NP by IN B-PP 80-90 CD B-NP % NN I-NP . . O In IN B-PP gel-shift JJ B-NP assays NNS I-NP COMMA COMMA O the DT B-NP -1280 CD I-NP element NN I-NP and CC O the DT B-NP c-fos NN I-NP SRE NN I-NP cross-competed VBD B-VP COMMA COMMA O whereas IN O their PRP$ B-NP functional JJ I-NP and CC I-NP binding VBG I-NP mutants NNS I-NP did VBD B-VP not RB O . . O The DT B-NP proximal JJ I-NP element NN I-NP contains VBZ B-VP the DT B-NP sequence NN I-NP 5'-GGCCAATGGG-3' NN I-NP COMMA COMMA O which WDT B-NP closely RB B-VP resembles VBZ I-VP the DT B-NP consensus NN I-NP binding NN I-NP motif NN I-NP for IN B-PP the DT B-NP CCAAT-binding JJ I-NP factor NN I-NP NF-Y NN I-NP ( ( O CBF NN B-NP COMMA COMMA O CP1 NN B-NP COMMA COMMA O alpha NN B-NP CP1 NN I-NP ) ) O . . O Deletions NNS B-NP or CC O mutations NNS B-NP in IN B-PP this DT B-NP element NN I-NP also RB B-ADVP reduced VBD B-VP the DT B-NP serum NN I-NP response NN I-NP by IN B-PP 80-90 CD B-NP % NN I-NP . . O Methylation NN B-NP interference NN I-NP analysis NN I-NP of IN B-PP the DT B-NP -65 CD I-NP region NN I-NP identified VBD B-VP a DT B-NP pattern NN I-NP of IN B-PP contacts NNS B-NP with IN B-PP nuclear JJ B-NP factors NNS I-NP resembling VBG B-VP that DT B-NP for IN B-PP NF-Y NN B-NP COMMA COMMA O and CC O an DT B-NP NF-Y-binding JJ I-NP site NN I-NP and CC O the DT B-NP proximal JJ I-NP TSP NN I-NP 1 CD I-NP element NN I-NP cross-competed VBD B-VP in IN B-PP gel-shift JJ B-NP assays NNS I-NP COMMA COMMA O whereas IN O their PRP$ B-NP binding VBG I-NP mutants NNS I-NP did VBD B-VP not RB O . . O Finally RB B-ADVP COMMA COMMA O an DT B-NP abbreviated VBN I-NP TSP NN I-NP 1 CD I-NP promoter\/5'-flank NN I-NP COMMA COMMA O containing VBG B-VP the DT O SRE- NN B-NP and CC O NF-Y-binding JJ B-ADJP sites NNS B-NP COMMA COMMA O mediated VBD B-VP a DT B-NP serum NN I-NP response NN I-NP that WDT B-NP was VBD B-VP close JJ B-ADJP in IN B-PP magnitude NN B-NP to TO B-PP that DT B-NP of IN B-PP the DT B-NP parent NN I-NP promoter NN I-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR the DT B-NP serum NN I-NP response NN I-NP of IN B-PP the DT B-NP human JJ I-NP TSP NN I-NP 1 CD I-NP gene NN I-NP requires VBZ B-VP the DT B-NP coordinated VBN I-NP function NN I-NP of IN B-PP an DT O SRE- NN B-NP and CC O NF-Y-binding JJ B-ADJP site NN B-NP . . O Suppression NN B-NP of IN B-PP a DT B-NP cellular JJ I-NP differentiation NN I-NP program NN I-NP by IN B-PP phorbol NN B-NP esters NNS I-NP coincides VBZ B-VP with IN B-PP inhibition NN B-NP of IN B-PP binding NN B-NP of IN B-PP a DT B-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP ( ( O NF-E2 NN B-NP ) ) O to TO B-PP an DT B-NP enhancer NN I-NP element NN I-NP required VBN B-VP for IN B-PP expression NN B-NP of IN B-PP an DT B-NP erythroid-specific JJ I-NP gene NN I-NP . . O Induction NN B-NP by IN B-PP hemin NN B-NP increases VBZ B-VP COMMA COMMA O while IN B-SBAR induction NN B-NP with IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( O TPA NN B-NP ) ) O represses VBZ B-VP COMMA COMMA O erythroid-specific JJ B-NP gene NN I-NP expression NN I-NP in IN B-PP the DT B-NP human JJ I-NP cell NN I-NP line NN I-NP K562 NN I-NP . . O We PRP B-NP analyzed VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP hemin NN B-NP or CC O TPA NN B-NP induction NN B-NP on IN B-PP the DT B-NP binding NN B-NP and CC O activity NN B-NP of IN B-PP transcription NN B-NP factors NNS I-NP at IN B-PP a DT B-NP regulatory JJ I-NP element NN I-NP found VBN B-VP within IN B-PP the DT B-NP transcriptional JJ I-NP regulatory JJ I-NP sequences NNS I-NP of IN B-PP many JJ B-NP erythroid-specific JJ I-NP genes NNS I-NP . . O TPA NN B-NP induction NN I-NP increases VBZ B-VP the DT B-NP binding NN I-NP of IN B-PP ubiquitous JJ B-NP AP-1 NN I-NP factors NNS I-NP to TO B-PP this DT B-NP element NN I-NP . . O TPA NN B-NP induction NN I-NP inhibits VBZ B-VP the DT B-NP binding NN I-NP of IN B-PP the DT B-NP lineage NN I-NP limited JJ I-NP transcription NN I-NP factor NN I-NP NF-E2 NN I-NP to TO B-PP this DT B-NP transcriptional JJ I-NP control NN I-NP element NN I-NP . . O Hemin NN B-NP induction NN I-NP of IN B-PP K562 NN B-NP cells NNS I-NP does VBZ B-VP not RB I-VP facilitate VB I-VP the DT B-NP binding NN I-NP of IN B-PP NF-E2 NN B-NP to TO B-PP its PRP$ B-NP recognition NN I-NP site NN I-NP . . O Hemin NN B-NP induction NN I-NP appears VBZ B-VP to TO I-VP nonspecifically RB I-VP increase VB I-VP the DT B-NP expression NN I-NP of IN B-PP transiently RB B-NP transfected VBN I-NP genes NNS I-NP in IN B-PP K562 NN B-NP cells NNS I-NP . . O Beyond IN B-PP this DT B-NP nonspecific JJ I-NP increase NN I-NP in IN B-PP gene NN B-NP expression NN I-NP COMMA COMMA O hemin NN B-NP induction NN I-NP acts VBZ B-VP to TO I-VP increase VB I-VP the DT B-NP activity NN I-NP of IN B-PP the DT B-NP lineage NN I-NP limited JJ I-NP transcription NN I-NP factor NN I-NP NF-E2 NN I-NP . . O The DT B-NP divergent JJ I-NP effects NNS I-NP of IN B-PP hemin NN B-NP and CC O TPA NN B-NP on IN B-PP gene NN B-NP expression NN I-NP in IN B-PP K562 NN B-NP cells NNS I-NP are VBP B-VP mediated VBN I-VP COMMA COMMA O in IN B-PP part NN B-NP COMMA COMMA B-PP by IN I-PP their PRP$ B-NP contrasting JJ I-NP effects NNS I-NP on IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-E2 NN I-NP . . O The DT B-NP interleukin NN I-NP 2 CD I-NP CD28-responsive JJ I-NP complex NN I-NP contains VBZ B-VP at IN B-NP least JJS I-NP three CD I-NP members NNS I-NP of IN B-PP the DT B-NP NF NN I-NP kappa NN I-NP B NN I-NP family NN I-NP : : O c-Rel NN B-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O and CC O p65 NN B-NP . . O Optimal JJ B-NP activation NN I-NP of IN B-PP T NN B-NP cells NNS I-NP requires VBZ B-VP at IN B-NP least JJS I-NP two CD I-NP signals NNS I-NP . . O One CD B-NP signal NN I-NP can MD B-VP be VB I-VP delivered VBN I-VP by IN B-PP the DT B-NP antigen-specific JJ I-NP T-cell NN I-NP receptor NN I-NP COMMA COMMA O and CC O the DT B-NP second JJ I-NP signal NN I-NP is VBZ B-VP provided VBN I-VP by IN B-PP the DT B-NP costimulatory JJ I-NP molecule NN I-NP ( ( I-NP s NNS I-NP ) ) O delivered VBN B-VP by IN B-PP the DT B-NP antigen-presenting JJ I-NP cell NN I-NP . . O CD28 NN B-NP is VBZ B-VP a DT B-NP T-cell NN I-NP surface NN I-NP molecule NN I-NP and CC O stimulation NN B-NP through IN B-PP this DT B-NP protein NN I-NP plays VBZ B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP delivering VBG B-VP the DT B-NP second JJ I-NP activation NN I-NP signal NN I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR in IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP COMMA COMMA O CD28-mediated JJ B-NP signal NN I-NP transduction NN I-NP involves VBZ B-VP the DT B-NP rel NN I-NP family NN I-NP proteins NNS I-NP -- : O c-Rel NN B-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O and CC O p65 NN B-NP . . O Treatment NN B-NP of IN B-PP peripheral JJ B-NP blood NN I-NP T NN I-NP cells NNS I-NP with IN B-PP phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O and CC O anti-CD28 JJ B-NP monoclonal JJ I-NP antibody NN I-NP ( ( O mAb NN B-NP ) ) O results VBZ B-VP in IN B-PP augmentation NN B-NP of IN B-PP nuclear JJ B-NP c-Rel NN B-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O and CC O p65 NN B-NP COMMA COMMA O and CC O this DT B-NP augmentation NN I-NP can MD B-VP occur VB I-VP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP the DT B-NP immunosuppressant JJ I-NP cyclosporin NN I-NP A NN I-NP . . O It PRP B-NP is VBZ B-VP also RB I-VP shown VBN I-VP in IN B-PP this DT B-NP report NN I-NP that IN B-SBAR COMMA COMMA O in IN B-PP response NN I-PP to TO I-PP PMA\/anti-CD28 JJ B-NP mAb NN I-NP or CC O anti-CD3\/anti-CD28 JJ B-NP mAb NN I-NP COMMA COMMA O c-Rel NN B-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O and CC O p65 NN B-NP are VBP B-VP associated VBN I-VP with IN B-PP CD28-responsive JJ B-NP element NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP promoter NN I-NP of IN B-PP the DT B-NP human JJ I-NP interleukin NN I-NP 2 CD I-NP gene NN I-NP . . O The DT B-NP functional JJ I-NP significance NN I-NP of IN B-PP c-Rel NN B-NP involvement NN I-NP in IN B-PP the DT B-NP CD28-responsive JJ I-NP complex NN I-NP is VBZ B-VP demonstrated VBN I-VP by IN B-PP transient JJ B-NP transfection NN I-NP analysis NN I-NP COMMA COMMA O where WRB B-ADVP cotransfection NN B-NP of IN B-PP c-Rel NN B-NP augments VBZ B-VP the DT B-NP level NN I-NP of IN B-PP expression NN B-NP of IN B-PP a DT B-NP chloramphenicol JJ I-NP acetyltransferase NN I-NP reporter NN I-NP gene NN I-NP linked VBN B-VP to TO B-PP the DT B-NP CD28-responsive JJ I-NP element NN I-NP . . O Expression NN B-NP of IN B-PP the DT B-NP Tat NN I-NP protein NN I-NP of IN B-PP HIV1 NN B-NP in IN B-PP human JJ B-NP promonocytic JJ I-NP U937 NN I-NP cells NNS I-NP . . O Numerous JJ B-NP studies NNS I-NP have VBP B-VP shown VBN I-VP that IN B-SBAR COMMA COMMA O upon IN B-PP HIV1 NN B-NP infection NN I-NP COMMA COMMA O human JJ B-NP promonocytic JJ I-NP U937 NN I-NP cells NNS I-NP were VBD B-VP induced VBN I-VP to TO I-VP differentiate VB I-VP COMMA COMMA O as IN B-SBAR indicated VBN B-VP COMMA COMMA O for IN B-PP example NN B-NP COMMA COMMA O by IN B-PP increased VBN B-NP expression NN I-NP of IN B-PP adhesion NN B-NP molecules NNS I-NP . . O One CD B-NP of IN B-PP the DT B-NP viral JJ I-NP proteins NNS I-NP involved VBN B-VP in IN B-PP this DT B-NP process NN I-NP might MD B-VP be VB I-VP the DT B-NP Tat NN I-NP protein NN I-NP . . O Indeed RB B-ADVP COMMA COMMA O this DT B-NP viral JJ I-NP protein NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP productive JJ B-NP infection NN I-NP COMMA COMMA O has VBZ B-VP also RB I-VP been VBN I-VP shown VBN I-VP to TO I-VP display VB I-VP growth-stimulating JJ B-NP properties NNS I-NP and CC O immunomodulatory JJ B-NP activities NNS I-NP . . O In IN B-SBAR order NN O to TO O apprehend VB B-VP the DT B-NP role NN I-NP of IN B-PP the DT B-NP HIV1 NN I-NP tat NN I-NP gene NN I-NP in IN B-PP inducing VBG B-VP the DT B-NP differentiation NN I-NP of IN B-PP HIV1-infected JJ B-NP U937 NN I-NP cells NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP successfully RB I-VP introduced VBN I-VP this DT B-NP gene NN I-NP into IN B-PP U937 NN B-NP cells NNS I-NP by IN B-PP infecting VBG B-VP them PRP B-NP with IN B-PP retroviral JJ B-NP particles NNS I-NP transducing VBG I-NP tat NN I-NP . . O The DT B-NP effect NN I-NP of IN B-PP the DT B-NP Tat NN I-NP protein NN I-NP constitutively RB B-VP expressed VBN I-VP by IN B-PP these DT B-NP cells NNS I-NP upon IN B-PP their PRP$ B-NP differentiation NN I-NP was VBD B-VP then RB I-VP evaluated VBN I-VP by IN B-PP looking VBG B-VP for IN B-PP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP c-fos NN I-NP and CC B-PP of IN B-PP the DT B-NP c-fms NN I-NP proto-oncogenes NNS B-NP which WDT B-NP are VBP B-VP linked VBN I-VP to TO B-PP the DT B-NP differentiation NN I-NP of IN B-PP myelomonoblastic JJ B-NP cells NNS I-NP . . O Northern NN B-NP blot NN I-NP analysis NN I-NP revealed VBD B-VP in IN B-PP these DT B-NP cells NNS I-NP COMMA COMMA O an DT B-NP increase NN I-NP in IN B-PP the DT B-NP transcription NN I-NP of IN B-PP these DT B-NP two CD I-NP proto-oncogenes NNS I-NP COMMA COMMA O and CC O this DT B-NP increase NN I-NP was VBD B-VP amplified VBN I-VP after IN B-PP treatment NN B-NP with IN B-PP phorbol NN B-NP myristate NN I-NP acetate NN I-NP . . O No DT B-NP such JJ I-NP increase NN I-NP was VBD B-VP observed VBN I-VP in IN B-PP control NN B-NP U937 NN I-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR COMMA COMMA O among IN B-PP HIV1 NN B-NP gene NN I-NP products NNS I-NP COMMA COMMA O the DT B-NP Tat NN I-NP protein NN I-NP appears VBZ B-VP to TO I-VP trigger VB I-VP monocytic JJ B-NP differentiation NN I-NP COMMA COMMA O and CC O suggests VBZ B-VP that IN B-SBAR this DT B-NP viral JJ I-NP protein NN I-NP directs VBZ B-VP progenitors NNS B-NP of IN B-PP the DT B-NP monocyte\/macrophage NN I-NP lineage NN I-NP towards IN B-PP a DT B-NP differentiation NN I-NP stage NN I-NP in IN B-PP which WDT B-NP production NN B-NP of IN B-PP viral JJ B-NP antigens NNS I-NP and CC O virions NNS B-NP might MD B-VP be VB I-VP more RBR B-ADJP efficient JJ I-ADJP . . O Transcriptional JJ B-NP regulation NN I-NP of IN B-PP the DT B-NP pyruvate NN I-NP kinase NN I-NP erythroid-specific JJ I-NP promoter NN I-NP . . O Mammal JJ B-NP pyruvate NN I-NP kinases NNS I-NP are VBP B-VP encoded VBN I-VP by IN B-PP two CD B-NP genes NNS I-NP . . O The DT B-NP L NN I-NP gene NN I-NP produces VBZ B-VP the DT B-NP erythroid JJ I-NP ( ( O R-PK NN B-NP ) ) O or CC O the DT B-NP hepatic JJ I-NP ( ( O L-PK JJ B-NP ) ) O isozymes NNS B-NP by IN B-PP the DT B-NP alternative JJ I-NP use NN I-NP of IN B-PP two CD B-NP promoters NNS I-NP . . O We PRP B-NP report VBP B-VP the DT B-NP characterization NN I-NP of IN B-PP the DT O cis- JJ B-NP and CC O trans-acting JJ B-ADJP elements NNS B-NP involved VBN B-VP in IN B-PP the DT B-NP tissue-specific JJ I-NP activity NN I-NP of IN B-PP the DT B-NP L NN I-NP gene NN I-NP erythroid JJ I-NP promoter NN I-NP . . O A DT B-NP R-PK NN I-NP DNA NN I-NP fragment NN I-NP extending VBG B-VP from IN B-PP -870 CD B-NP to TO B-PP +54 CD B-NP relative JJ B-PP to TO I-PP the DT B-NP cap NN I-NP site NN I-NP confers VBZ B-VP erythroid JJ B-NP specificity NN I-NP to TO B-PP a DT B-NP reporter NN I-NP gene NN I-NP . . O Within IN B-PP this DT B-NP region NN I-NP COMMA COMMA O we PRP B-NP define VBP B-VP a DT B-NP minimal JJ I-NP promoter NN I-NP ( ( O -62 CD B-NP to TO O +54 CD B-NP ) ) O that WDT B-NP displays VBZ B-VP erythroid-specific JJ B-NP activity NN I-NP and CC O contains VBZ B-VP two CD B-NP DNA NN I-NP binding NN I-NP sites NNS I-NP . . O One CD B-NP COMMA COMMA O located JJ B-ADJP at IN B-PP -50 CD B-NP COMMA COMMA O binds VBZ B-VP members NNS B-NP of IN B-PP the DT B-NP CCACC\/Sp1 NN I-NP family NN I-NP and CC O the DT B-NP other JJ I-NP COMMA COMMA O located JJ B-ADJP at IN B-PP -20 CD B-NP COMMA COMMA O binds VBZ B-VP the DT B-NP erythroid JJ I-NP factor NN I-NP GATA-1 NN I-NP . . O Although IN B-SBAR the DT B-NP -20 CD I-NP GATA NN I-NP binding NN I-NP site NN I-NP ( ( O AGATAA NN B-NP ) ) O is VBZ B-VP also RB B-ADVP a DT B-NP potential JJ I-NP TFIID NN I-NP binding NN I-NP site NN I-NP COMMA COMMA O it PRP B-NP does VBZ B-VP not RB I-VP bind VB I-VP TFIID NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP substitution NN I-NP of IN B-PP this DT B-NP GATA NN I-NP binding NN I-NP site NN I-NP by IN B-PP a DT B-NP canonical JJ I-NP TFIID NN I-NP binding NN I-NP site NN I-NP suppresses VBZ B-VP the DT B-NP promoter NN I-NP activity NN I-NP . . O Mutations NNS B-NP and CC O deletions NNS B-NP of IN B-PP both DT B-NP sites NNS I-NP indicate VBP B-VP that IN B-SBAR only RB B-NP the DT I-NP association NN I-NP of IN B-PP CCACC\/Sp1 NN B-NP and CC O GATA NN B-NP binding NN B-NP sites NNS I-NP can MD B-VP drive VB I-VP efficient JJ B-NP and CC I-NP tissue-specific JJ I-NP expression NN I-NP of IN B-PP this DT B-NP R-PK NN I-NP minimal JJ I-NP promoter NN I-NP . . O Finally RB B-ADVP COMMA COMMA O by IN B-PP co-transfection NN B-NP experiments NNS I-NP COMMA COMMA O we PRP B-NP study VBD B-VP the DT B-NP elements NNS I-NP involved VBN B-VP in IN B-PP the DT B-NP hGATA-1 NN I-NP transactivation NN I-NP of IN B-PP the DT B-NP R-PK NN I-NP promoter NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP . . O Stimulation NN B-NP of IN B-PP interleukin-1 NN B-NP alpha NN I-NP and CC O interleukin-1 NN B-NP beta NN I-NP production NN B-NP in IN B-PP human JJ B-NP monocytes NNS I-NP by IN B-PP protein NN O phosphatase NN O 1 CD B-NP and CC O 2A NN B-NP inhibitors NNS B-NP . . O Protein NN B-NP phosphatases NNS I-NP 1 CD B-NP and CC O 2A NN B-NP are VBP B-VP important JJ B-ADJP in IN B-PP regulating VBG B-VP cellular JJ B-NP functions NNS I-NP by IN B-PP controlling VBG B-VP the DT B-NP phosphorylation NN I-NP state NN I-NP of IN B-PP their PRP$ B-NP substrates NNS I-NP . . O In IN B-PP human JJ B-NP monocytes NNS I-NP COMMA COMMA O the DT B-NP inhibitors NNS I-NP of IN B-PP these DT B-NP phosphatases NNS I-NP COMMA COMMA O okadaic JJ B-NP acid NN I-NP and CC O calyculin NN B-NP A NN I-NP COMMA COMMA O were VBD B-VP found VBN I-VP to TO I-VP increase VB I-VP the DT B-NP mRNA NN B-NP accumulation NN I-NP and CC O cytokine NN B-NP production NN I-NP of IN B-PP interleukin-1 NN B-NP beta NN I-NP and CC O interleukin-1 NN B-NP alpha NN I-NP . . O The DT B-NP increased VBN I-NP mRNA NN I-NP accumulation NN I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP primarily RB B-PP because IN I-PP of IN I-PP the DT B-NP increase NN I-NP in IN B-PP the DT B-NP transcription NN I-NP rate NN I-NP of IN B-PP the DT B-NP interleukin-1 NN I-NP genes NNS I-NP . . O Stimulation NN B-NP of IN B-PP interleukin-1 NN B-NP gene NN I-NP transcription NN I-NP may MD B-VP be VB I-VP caused VBN I-VP by IN B-PP the DT B-NP stimulation NN I-NP of IN B-PP transcription NN B-NP factor NN I-NP activities NNS I-NP COMMA COMMA O including VBG B-PP those DT B-NP of IN B-PP AP-1 NN B-NP COMMA COMMA O by IN B-PP these DT B-NP protein NN I-NP phosphatase NN I-NP inhibitors NNS I-NP . . O Okadaic JJ B-NP acid NN I-NP increased VBD B-VP the DT B-NP synthesis NN I-NP of IN B-PP the DT O interleukin-1 NN O beta NN O precursor NN B-NP and CC O mature JJ B-ADJP forms NNS B-NP and CC O their PRP$ B-NP secretion NN I-NP . . O This DT B-NP increased VBD I-NP processing NN B-NP and CC O secretion NN B-NP correlated VBN B-VP with IN B-PP the DT B-NP stimulation NN I-NP of IN B-PP IL-1 NN B-NP beta NN I-NP convertase NN I-NP mRNA NN I-NP accumulation NN I-NP . . O The DT B-NP stimulation NN I-NP of IN B-PP interleukin-1 NN B-NP alpha NN I-NP production NN I-NP by IN B-PP okadaic JJ B-NP acid NN I-NP was VBD B-VP more RBR B-ADJP modest JJ I-ADJP than IN B-PP that DT B-NP of IN B-PP interleukin-1 NN B-NP beta NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP phosphorylation NN I-NP of IN B-PP the DT B-NP precursor NN I-NP interleukin-1 NN I-NP alpha NN I-NP cytokine NN I-NP was VBD B-VP increased VBN I-VP . . O These DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR protein NN O phosphatase NN O 1 CD B-NP and CC O 2A NN B-NP inhibitors NNS B-NP exert VBP B-VP multiple JJ B-NP effects NNS I-NP on IN B-PP cytokine NN B-NP production NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP and CC O suggest VBP B-VP that IN B-SBAR these DT B-NP two CD I-NP phosphatases NNS I-NP play VBP B-VP important JJ B-NP roles NNS I-NP in IN B-PP regulating VBG B-VP interleukin-1 NN B-NP production NN I-NP . . O Cell NN B-NP type- NN I-NP and CC O stage-specific JJ B-ADJP expression NN B-NP of IN B-PP the DT B-NP CD20\/B1 NN I-NP antigen NN I-NP correlates VBZ B-VP with IN B-PP the DT B-NP activity NN I-NP of IN B-PP a DT B-NP diverged JJ I-NP octamer NN I-NP DNA NN I-NP motif NN I-NP present JJ B-ADJP in IN B-PP its PRP$ B-NP promoter NN I-NP . . O The DT B-NP CD20 NN I-NP ( ( I-NP B1 NN I-NP ) ) I-NP gene NN I-NP encodes VBZ B-VP a DT B-NP B NN I-NP cell-specific JJ I-NP protein NN I-NP involved VBN B-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP human JJ B-NP B NN I-NP cell NN I-NP proliferation NN B-NP and CC O differentiation NN B-NP . . O Studies NNS B-NP with IN B-PP 5' JJ B-NP deletion NN I-NP CD20 NN I-NP promoter-CAT NN I-NP constructs NNS I-NP have VBP B-VP previously RB I-VP revealed VBN I-VP two CD B-NP regions NNS I-NP of IN B-PP the DT B-NP promoter NN I-NP between IN B-PP bases NNS B-NP -186 CD B-NP and CC O -280 CD B-NP and CC B-PP between IN B-PP bases NNS B-NP -280 CD B-NP and CC O -454 CD B-NP which WDT B-NP contained VBD B-VP positive JJ B-NP regulatory JJ I-NP elements NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP identified VBD B-VP a DT B-NP sequence NN I-NP element NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP most RBS I-NP proximal JJ I-NP region NN I-NP located JJ B-ADJP between IN B-PP bases NNS B-NP -214 CD B-NP and CC O -201 CD B-NP COMMA COMMA O TTCTTCTAATTAA NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP important JJ B-ADJP in IN B-PP the DT B-NP high JJ I-NP constitutive JJ I-NP expression NN I-NP of IN B-PP CD20 NN B-NP in IN B-PP mature JJ B-NP B NN I-NP cells NNS I-NP and CC O the DT B-NP induction NN I-NP of IN B-PP CD20 NN B-NP in IN B-PP pre-B JJ B-NP cells NNS I-NP . . O This DT B-NP sequence NN I-NP element NN I-NP was VBD B-VP referred VBN I-VP to TO B-PP as IN B-PP the DT B-NP BAT NN I-NP box NN I-NP and CC O its PRP$ B-NP deletion NN I-NP significantly RB B-ADVP reduced VBD B-VP the DT B-NP activity NN I-NP of IN B-PP a DT B-NP CD20 NN I-NP promoter-CAT JJ I-NP construct NN I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Mobility NN B-NP shift NN I-NP assays NNS I-NP with IN B-PP various JJ B-NP mutant JJ I-NP probes NNS I-NP and CC O B NN B-NP cell NN I-NP nuclear JJ I-NP extracts NNS I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP core NN I-NP sequence NN I-NP TAAT NN I-NP was VBD B-VP essential JJ B-ADJP for IN B-PP binding VBG B-VP to TO B-PP this DT B-NP site NN I-NP . . O Cross NN B-NP competition NN I-NP experiments NNS I-NP with IN B-PP an DT B-NP octamer NN I-NP sequence NN I-NP from IN B-PP the DT B-NP Ig NN I-NP heavy JJ I-NP chain NN I-NP promoter NN I-NP COMMA COMMA O the DT B-NP BAT NN I-NP box NN I-NP COMMA COMMA O and CC O a DT B-NP TA-rich JJ I-NP sequence NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP CD21 NN I-NP promoter NN I-NP revealed VBD B-VP that IN B-SBAR all DT B-NP three CD I-NP sequences NNS I-NP bound VBD B-VP the DT B-NP same JJ I-NP nuclear JJ I-NP proteins NNS I-NP suggesting VBG B-VP that IN B-SBAR the DT B-NP BAT NN I-NP box NN I-NP binding NN I-NP proteins NNS I-NP were VBD B-VP Oct-1 NN B-NP and CC O Oct-2 NN B-NP . . O Southwestern NN B-NP blotting NN I-NP and CC O UV NN B-NP cross-linking NN I-NP studies NNS I-NP confirmed VBD B-VP that IN B-SBAR the DT B-NP BAT NN I-NP box NN I-NP binding NN I-NP proteins NNS I-NP were VBD B-VP Oct-1 NN B-NP and CC O Oct-2 NN B-NP . . O The DT B-NP affinity NN I-NP of IN B-PP the DT B-NP BAT NN I-NP box NN I-NP binding NN I-NP proteins NNS I-NP for IN B-PP the DT B-NP BAT NN I-NP box NN I-NP was VBD B-VP approximately RB B-ADJP 25-fold RB I-ADJP less JJR I-ADJP than IN B-PP for IN B-PP the DT B-NP octamer NN I-NP sequence NN I-NP and CC O the DT B-NP BAT NN I-NP box NN I-NP binding NN I-NP proteins NNS I-NP dissociated VBD B-VP from IN B-PP the DT B-NP BAT NN I-NP box NN I-NP 10-fold RB B-ADVP more RBR I-ADVP rapidly RB B-ADVP than IN B-PP from IN B-PP the DT B-NP octamer NN I-NP sequence NN I-NP . . O Despite IN B-PP this DT B-NP lower JJR I-NP affinity NN I-NP COMMA COMMA O a DT B-NP trimer NN I-NP of IN B-PP the DT B-NP BAT NN I-NP box NN I-NP sequence NN I-NP was VBD O as IN B-ADVP efficiently RB I-ADVP transactivated VBN B-VP by IN B-PP an DT B-NP Oct-2 NN I-NP expression NN I-NP vector NN I-NP as IN B-SBAR was VBD O a DT B-NP trimer NN I-NP of IN B-PP the DT B-NP octamer NN I-NP sequence NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP . . O The DT B-NP BAT NN B-NP box NN I-NP and CC O Oct-2 NN B-NP were VBD B-VP also RB I-VP implicated VBN I-VP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP CD20 NN B-NP in IN B-PP the DT B-NP pre-B JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O PB-697 NN B-NP COMMA COMMA O via IN B-PP phorbol NN B-NP esters NNS I-NP . . O The DT B-NP induction NN I-NP of IN B-PP CD20 NN B-NP mRNA NN I-NP was VBD B-VP temporally RB I-VP associated VBN I-VP with IN B-PP induction NN B-NP of IN B-PP Oct-2 NN B-NP mRNA NN I-NP and CC O a DT B-NP BAT NN I-NP box-deleted JJ I-NP CD20-CAT NN I-NP construct NN I-NP COMMA COMMA O in IN B-PP contrast NN I-PP to TO I-PP the DT B-NP wild JJ I-NP type NN I-NP COMMA COMMA O was VBD B-VP poorly RB I-VP induced VBN I-VP by IN B-PP phorbol NN B-NP esters NNS I-NP . . O Together RB B-ADVP these DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP BAT NN I-NP box NN I-NP binding NN I-NP proteins NNS I-NP are VBP B-VP important JJ B-ADJP in IN B-PP the DT O B NN B-NP cell NN I-NP specific JJ B-NP expression NN I-NP of IN B-PP CD20 NN B-NP and CC O perhaps RB B-ADVP CD21 NN B-NP . . O Transcription NN B-NP factor NN I-NP jun-B NN I-NP is VBZ B-VP target NN B-NP of IN B-PP autoreactive JJ B-NP T-cells NNS I-NP in IN B-PP IDDM NN B-NP . . O Target NN B-NP antigens NNS I-NP defined VBN B-VP by IN B-PP autoantibodies NNS B-NP in IN B-PP IDDM NN B-NP include VBP B-VP insulin NN B-NP COMMA COMMA O a DT B-NP putative JJ I-NP glycolipid NN I-NP that WDT B-NP reacts VBZ B-VP with IN B-PP islet NN B-NP cell NN I-NP antibodies NNS I-NP COMMA COMMA O and CC O a DT B-NP 64COMMA000-M(r) JJ I-NP protein NN I-NP recently RB B-VP identified VBN I-VP as IN B-PP glutamic JJ B-NP acid NN I-NP decarboxylase NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O some DT B-NP IDDM NN I-NP sera NN I-NP that WDT B-NP contain VBP B-VP antibodies NNS B-NP to TO B-PP glutamic JJ B-NP acid NN I-NP decarboxylase NN I-NP also RB B-ADVP coprecipitate VBP B-VP a DT B-NP 38COMMA000-M(r) JJ I-NP protein NN I-NP from IN B-PP islets NNS B-NP . . O This DT B-NP study NN I-NP used VBD B-VP a DT B-NP high JJ I-NP titer NN I-NP anti-38COMMA000-M(r) JJ I-NP serum NN I-NP to TO B-VP screen VB I-VP bacteriophage NN B-NP lambda NN I-NP cDNA NN I-NP expression NN I-NP libraries NNS I-NP and CC O identified VBD B-VP human JJ B-NP islet NN I-NP and CC O placental JJ B-NP clones NNS I-NP encoding VBG B-VP jun-B NN B-NP COMMA COMMA O the DT B-NP nuclear JJ I-NP transcription NN I-NP protein NN I-NP COMMA COMMA O of IN B-PP predicted VBN B-NP 38COMMA000 CD I-NP M(r) NN I-NP . . O Peripheral JJ B-NP blood NN I-NP T-cells NNS I-NP exhibited VBD B-VP significant JJ B-NP proliferation NN I-NP in IN B-PP response NN I-PP to TO I-PP a DT B-NP recombinant JJ I-NP fragment NN I-NP of IN B-PP jun-B NN B-NP ( ( O amino NN B-NP acids NNS I-NP 1-180 CD I-NP ) ) O in IN B-PP 12 CD O of IN O 17 CD O ( ( O 71 CD B-NP % NN I-NP ) ) O recent-onset JJ B-NP IDDM NN I-NP subjects NNS I-NP COMMA COMMA O 8 CD O of IN O 16 CD O ( ( O 50 CD B-NP % NN I-NP ) ) O ICA-positive JJ B-NP first-degree JJ I-NP relatives NNS I-NP of IN B-PP IDDM NN B-NP subjects NNS I-NP who WP B-NP were VBD B-VP at IN B-PP risk NN B-NP COMMA COMMA O 3 CD O of IN O 12 CD O ( ( O 25 CD B-NP % NN I-NP ) ) O other JJ B-NP autoimmune JJ I-NP disease NN I-NP subjects NNS I-NP COMMA COMMA O and CC O 0 CD B-NP of IN I-NP 10 CD I-NP healthy JJ I-NP control NN I-NP subjects NNS I-NP . . O Proliferation NN B-NP to TO B-PP tetanus NN B-NP toxoid NN I-NP did VBD B-VP not RB I-VP differ VB I-VP significantly RB B-ADVP between IN B-PP the DT B-NP groups NNS I-NP . . O Responses NNS B-NP to TO B-PP jun-B NN B-NP were VBD B-VP not RB O related JJ B-ADJP to TO B-PP age NN B-NP COMMA COMMA O sex NN B-NP COMMA COMMA O or CC O human JJ B-NP leukocyte NN I-NP antigen NN I-NP status NN I-NP . . O Thus RB B-ADVP COMMA COMMA O autoreactive JJ B-NP T-cells NNS I-NP identify VBP B-VP a DT B-NP novel JJ I-NP antigen NN I-NP COMMA COMMA O p38 NN B-NP jun-B NN I-NP COMMA COMMA O in IN B-PP IDDM NN B-NP and CC O appear VBP B-VP to TO I-VP indicate VB I-VP subjects NNS B-NP at IN B-PP risk NN B-NP for IN B-PP the DT B-NP development NN I-NP of IN B-PP clinical JJ B-NP disease NN I-NP . . O Transcriptional JJ B-NP regulation NN I-NP of IN B-PP interleukin NN B-NP 3 CD I-NP ( ( O IL3 NN B-NP ) ) O in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP . . O Role NN B-NP of IN B-PP AP-1- NN B-NP and CC O octamer-binding JJ B-ADJP proteins NNS B-NP in IN B-PP control NN B-NP of IN B-PP IL3 NN B-NP gene NN I-NP expression NN I-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP molecular JJ I-NP and CC I-NP biochemical JJ I-NP basis NN I-NP for IN B-PP activation NN B-NP of IN B-PP interleukin NN B-NP 3 CD I-NP ( ( O IL3 NN B-NP ) ) O gene NN B-NP expression NN I-NP in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP following VBG B-PP CD3 NN B-NP and CC O CD2 NN B-NP receptor NN B-NP stimulation NN B-NP or CC O activation NN B-NP by IN B-PP phytohemagglutinin NN B-NP plus CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP . . O Using VBG B-VP transfection NN B-NP and CC O reporter NN B-NP gene NN I-NP assays NNS B-NP specifically RB B-VP designed VBN I-VP for IN B-PP primary JJ B-NP T NN I-NP lymphocytes NNS I-NP in IN B-PP conjunction NN I-PP with IN I-PP gel NN B-NP retardation NN I-NP assays NNS I-NP COMMA COMMA O Western NN B-NP blot NN I-NP analyses NNS I-NP and CC O UV NN B-NP cross-linking JJ I-NP studies NNS I-NP COMMA COMMA O we PRP B-NP found VBD B-VP that IN B-SBAR c-Jun NN B-NP COMMA COMMA O c-Fos NN B-NP COMMA COMMA O and CC O octamer-binding NN B-ADJP proteins NNS B-NP play VBP B-VP a DT B-NP major JJ I-NP role NN I-NP in IN B-PP transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT B-NP IL3 NN I-NP gene NN I-NP via IN B-PP their PRP$ B-NP interaction NN I-NP with IN B-PP two CD B-NP specific JJ I-NP regions NNS I-NP contained VBN B-VP within IN B-PP the DT B-NP IL3 NN I-NP 5'-flanking JJ I-NP sequence NN I-NP . . O Additionally RB B-ADVP COMMA COMMA O the DT B-NP region NN I-NP between IN B-PP bases NNS B-NP -107 CD B-NP and CC O -59 CD B-NP of IN B-PP the DT B-NP IL3 NN I-NP promoter NN I-NP containing VBG B-VP putative JJ O AP-2 NN B-NP and CC O Sp1 NN B-NP binding NN B-NP motifs NNS I-NP appears VBZ B-VP necessary JJ B-ADJP for IN B-PP basal JJ B-NP level NN I-NP expression NN I-NP of IN B-PP the DT B-NP IL3 NN I-NP gene NN I-NP . . O The DT B-NP data NNS I-NP also RB B-ADVP indicate VBP B-VP that IN B-SBAR CD2 NN B-NP receptor NN I-NP activation NN I-NP and CC O phytohemagglutinin NN B-NP plus CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP stimulation NN B-NP augment VBP B-VP T NN B-NP cell NN I-NP IL3 NN I-NP gene NN I-NP expression NN I-NP through IN B-PP the DT O same JJ O cis- JJ B-NP and CC O trans-activating JJ B-ADJP signals NNS B-NP . . O These DT B-NP results NNS I-NP should MD B-VP contribute VB I-VP to TO B-PP a DT B-NP better JJR I-NP understanding NN I-NP of IN B-PP the DT B-NP regulation NN I-NP of IN B-PP IL3 NN B-NP gene NN I-NP expression NN I-NP in IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP . . O Transcriptional JJ B-NP activation NN I-NP of IN B-PP human JJ B-NP zeta NN I-NP 2 CD I-NP globin NN I-NP promoter NN I-NP by IN B-PP the DT B-NP alpha NN I-NP globin NN I-NP regulatory JJ I-NP element NN I-NP ( ( O HS-40 NN B-NP ) ) O : : O functional JJ B-NP role NN I-NP of IN B-PP specific JJ B-NP nuclear JJ I-NP factor-DNA JJ I-NP complexes NNS I-NP . . O We PRP B-NP studied VBD B-VP the DT B-NP functional JJ I-NP interaction NN I-NP between IN B-PP human JJ B-NP embryonic JJ I-NP zeta NN I-NP 2 CD I-NP globin NN I-NP promoter NN I-NP and CC O the DT B-NP alpha NN I-NP globin NN I-NP regulatory JJ I-NP element NN I-NP ( ( O HS-40 NN B-NP ) ) O located JJ O 40 CD B-NP kb NN I-NP upstream RB B-ADJP of IN B-PP the DT B-NP zeta NN I-NP 2 CD I-NP globin NN I-NP gene NN I-NP . . O It PRP B-NP was VBD B-VP shown VBN I-VP by IN B-PP transient JJ B-NP expression NN I-NP assay NN I-NP that IN B-SBAR HS-40 NN B-NP behaved VBD B-VP as IN B-PP an DT B-NP authentic JJ I-NP enhancer NN I-NP for IN B-PP high-level JJ B-NP zeta NN I-NP 2 CD I-NP globin NN I-NP promoter NN I-NP activity NN I-NP in IN B-PP K562 NN B-NP cells NNS I-NP COMMA COMMA O an DT B-NP erythroid JJ I-NP cell NN I-NP line NN I-NP of IN B-PP embryonic JJ B-NP and\/or CC I-NP fetal JJ I-NP origin NN I-NP . . O Although IN B-SBAR sequences NNS B-NP located JJ B-ADJP between IN B-PP -559 CD B-NP and CC O -88 CD B-NP of IN B-PP the DT B-NP zeta NN I-NP 2 CD I-NP globin NN I-NP gene NN I-NP were VBD B-VP dispensable JJ B-ADJP for IN B-PP its PRP$ B-NP expression NN I-NP on IN B-PP enhancerless NN B-NP plasmids NNS I-NP COMMA COMMA O they PRP B-NP were VBD B-VP required VBN I-VP for IN B-PP the DT B-NP HS-40 NN I-NP enhancer-mediated JJ I-NP activity NN I-NP of IN B-PP the DT B-NP zeta NN I-NP 2 CD I-NP globin NN I-NP promoter NN I-NP . . O Site-directed JJ B-NP mutagenesis NN I-NP demonstrated VBD B-VP that IN B-SBAR this DT B-NP HS-40 NN I-NP enhancer-zeta NN I-NP 2 CD I-NP globin NN I-NP promoter NN I-NP interaction NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP the DT B-NP two CD I-NP GATA-1 NN I-NP factor NN I-NP binding NN I-NP motifs NNS I-NP located JJ B-ADJP at IN B-PP -230 CD B-NP and CC O -104 CD B-NP COMMA COMMA O respectively RB B-ADVP . . O The DT B-NP functional JJ I-NP domains NNS I-NP of IN B-PP HS-40 NN B-NP were VBD B-VP also RB I-VP mapped VBN I-VP . . O Bal NN B-NP 31 CD I-NP deletion NN I-NP mapping VBG I-NP data NNS I-NP suggested VBD B-VP that IN B-SBAR one CD B-NP GATA-1 NN I-NP motif NN I-NP COMMA COMMA O one CD B-NP GT NN I-NP motif NN I-NP COMMA COMMA O and CC O two CD B-NP NF-E2\/AP1 NN I-NP motifs NNS I-NP together RB B-ADVP formed VBD B-VP the DT B-NP functional JJ I-NP core NN I-NP of IN B-PP HS-40 NN B-NP in IN B-PP the DT B-NP erythroid-specific JJ I-NP activation NN I-NP of IN B-PP the DT B-NP zeta NN I-NP 2 CD I-NP globin NN I-NP promoter NN I-NP . . O Site-directed JJ B-NP mutagenesis NN I-NP further RBR B-ADVP demonstrated VBD B-VP that IN B-SBAR the DT B-NP enhancer NN I-NP function NN I-NP of IN B-PP one CD B-NP of IN B-PP the DT B-NP two CD I-NP NF-E2\/AP1 NN I-NP motifs NNS I-NP of IN B-PP HS-40 NN B-NP is VBZ B-VP mediated VBN I-VP through IN B-PP its PRP$ B-NP binding NN I-NP to TO B-PP NF-E2 NN B-NP but CC B-CONJP not RB I-CONJP AP1 NN B-NP transcription NN I-NP factor NN I-NP . . O Finally RB B-ADVP COMMA COMMA O we PRP B-NP did VBD B-VP genomic JJ B-NP footprinting NN I-NP of IN B-PP the DT B-NP HS-40 NN I-NP enhancer NN I-NP region NN I-NP in IN B-PP K562 NN B-NP cells NNS I-NP COMMA COMMA O adult JJ B-NP nucleated JJ I-NP erythroblasts NNS I-NP COMMA COMMA O and CC O different JJ B-NP nonerythroid JJ I-NP cells NNS I-NP . . O All DT B-NP sequence NN I-NP motifs NNS I-NP within IN B-PP the DT B-NP functional JJ I-NP core NN I-NP of IN B-PP HS-40 NN B-NP COMMA COMMA O as IN B-SBAR mapped VBN B-VP by IN B-PP transient JJ B-NP expression NN I-NP analysis NN I-NP COMMA COMMA O appeared VBD B-VP to TO I-VP bind VB I-VP a DT B-NP nuclear JJ I-NP factor NN I-NP ( ( I-NP s NNS I-NP ) ) O in IN B-PP living VBG B-NP K562 NN I-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP nonerythroid JJ B-NP cells NNS I-NP . . O On IN B-PP the DT B-NP other JJ I-NP hand NN I-NP COMMA COMMA O only RB B-NP one CD I-NP of IN B-PP the DT B-NP apparently RB I-NP nonfunctional JJ I-NP sequence NN I-NP motifs NNS I-NP was VBD B-VP bound VBN I-VP with IN B-PP factors NNS B-NP in FW B-ADVP vivo FW I-ADVP . . O In IN B-PP comparison NN I-PP to TO I-PP K562 NN B-NP COMMA COMMA O nucleated JJ B-NP erythroblasts NNS I-NP from IN B-PP adult JJ B-NP human JJ I-NP bone NN I-NP marrow NN I-NP exhibited VBD B-VP a DT B-NP similar JJ I-NP but CC I-NP nonidentical JJ I-NP pattern NN I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP binding NN I-NP in FW B-ADVP vivo FW I-ADVP at IN B-PP the DT B-NP HS-40 NN I-NP region NN I-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR transcriptional JJ B-NP activation NN I-NP of IN B-PP human JJ B-NP embryonic JJ I-NP zeta NN I-NP 2 CD I-NP globin NN I-NP gene NN I-NP and CC O the DT B-NP fetal\/adult JJ I-NP alpha NN I-NP globin NN I-NP genes NNS I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP erythroid JJ B-NP cell-specific JJ I-NP and CC I-NP developmental JJ I-NP stage-specific JJ I-NP nuclear JJ I-NP factor-DNA NN I-NP complexes NNS I-NP which WDT B-NP form VBP B-VP at IN B-PP the DT B-NP enhancer NN I-NP ( ( O HS-40 NN B-NP ) ) O and CC O the DT B-NP globin NN I-NP promoters NNS I-NP . . O Interaction NN B-NP between IN B-PP NF-kappa NN B-NP B- NN I-NP and CC O serum NN B-ADJP response NN I-ADJP factor-binding JJ I-ADJP elements NNS B-NP activates VBZ B-VP an DT B-NP interleukin-2 NN I-NP receptor NN I-NP alpha-chain JJ I-NP enhancer NN I-NP specifically RB B-ADVP in IN B-PP T NN B-NP lymphocytes NNS I-NP . . O We PRP B-NP find VBP B-VP that IN B-SBAR a DT B-NP short JJ I-NP enhancer NN I-NP element NN I-NP containing VBG B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP site NN I-NP from IN B-PP the DT B-NP interleukin-2 NN I-NP receptor NN I-NP alpha-chain JJ I-NP gene NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O is VBZ B-VP preferentially RB I-VP activated VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP . . O The DT B-NP IL-2R NN I-NP alpha NN I-NP enhancer NN I-NP binds VBZ B-VP NF-kappa NN B-NP B NN I-NP poorly RB B-ADVP and CC O is VBZ B-VP only RB I-VP weakly RB I-VP activated VBN I-VP by IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP site NN I-NP alone RB B-ADVP . . O Serum NN B-NP response NN I-NP factor NN I-NP ( ( O SRF NN B-NP ) ) O binds VBZ B-VP to TO B-PP a DT B-NP site NN I-NP adjacent JJ B-ADJP to TO B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP site NN I-NP in IN B-PP the DT B-NP IL-2R NN I-NP enhancer NN I-NP COMMA COMMA O and CC O both DT B-NP sites NNS I-NP together RB B-ADVP have VBP B-VP strong JJ B-NP transcriptional JJ I-NP activity NN I-NP specifically RB B-ADVP in IN B-PP T NN B-NP cells NNS I-NP . . O Surprisingly RB B-ADVP COMMA COMMA O the DT B-NP levels NNS I-NP of IN B-PP SRF NN B-NP constitutively RB B-VP expressed VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP are VBP B-VP consistently RB B-ADVP higher JJR B-ADJP than IN B-PP in IN B-PP other JJ B-NP cell NN I-NP types NNS I-NP . . O Overexpression NN B-NP of IN B-PP SRF NN B-NP in IN B-PP B NN B-NP cells NNS I-NP causes VBZ B-VP the DT B-NP IL-2R NN I-NP enhancer NN I-NP to TO B-VP function VB I-VP as RB B-SBAR well RB I-SBAR as IN I-SBAR it PRP B-NP does VBZ B-VP in IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR the DT B-NP high JJ I-NP level NN I-NP of IN B-PP SRF NN B-NP binding NN I-NP in IN B-PP T NN B-NP cells NNS I-NP is VBZ B-VP functionally RB B-ADVP important JJ B-ADJP . . O The DT B-NP transcriptionally RB I-NP active JJ I-NP factors NNS I-NP mediating VBG B-VP the DT B-NP effect NN I-NP of IN B-PP the DT B-NP HTLV-I NN I-NP Tax NN I-NP transactivator NN I-NP on IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP kappa NN I-NP B NN I-NP enhancer NN I-NP include VBP B-VP the DT B-NP product NN I-NP of IN B-PP the DT B-NP c-rel NN I-NP proto-oncogene NN I-NP . . O The DT B-NP transactivator NN I-NP HTLV-I NN I-NP Tax NN I-NP activates VBZ B-VP the DT B-NP promoter NN I-NP of IN B-PP the DT B-NP gene NN I-NP coding VBG B-VP for IN B-PP the DT B-NP interleukin NN I-NP 2 CD I-NP alpha-chain JJ I-NP receptor NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O via IN B-PP a DT B-NP kappa NN I-NP B NN I-NP site NN I-NP that WDT B-NP can MD B-VP bind VB I-VP several JJ B-NP protein NN I-NP species NNS I-NP of IN B-PP the DT B-NP rel NN I-NP family NN I-NP . . O Tax1 NN B-NP strongly RB B-ADVP activates VBZ B-VP the DT B-NP enhancer NN I-NP activity NN I-NP of IN B-PP this DT B-NP motif NN I-NP COMMA COMMA O in IN B-PP both CC O epithelial JJ B-NP HeLa NN I-NP and CC O lymphoid JJ B-NP Jurkat NN I-NP cells NNS B-NP . . O This DT B-NP activation NN I-NP was VBD B-VP not RB I-VP observed VBN I-VP in IN B-PP undifferentiated JJ B-NP embryocarcinoma NN I-NP F9 NN I-NP cells NNS I-NP . . O Overexpression NN B-NP of IN B-PP the DT O p50 NN B-NP COMMA COMMA O p65 NN B-NP and CC O Rel NN B-NP proteins NNS B-NP in IN B-PP these DT B-NP cells NNS I-NP showed VBD B-VP that IN B-SBAR significant JJ B-NP activation NN I-NP of IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP kappa NN I-NP B NN I-NP site NN I-NP was VBD B-VP observed VBN I-VP only RB B-PP with IN I-PP Rel NN B-NP and CC O Rel NN B-NP plus CC O p65 NN B-NP . . O Moreover RB B-ADVP COMMA COMMA O whereas IN B-SBAR both CC O Tax NN B-NP and CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O are VBP B-VP able JJ B-ADJP to TO B-VP efficiently RB I-VP induce VB I-VP the DT B-NP binding NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP to TO B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP kappa NN I-NP B NN I-NP site NN I-NP COMMA COMMA O PMA NN B-NP is VBZ B-VP functionally RB B-ADVP inactive JJ B-ADJP . . O Using VBG B-VP the DT B-NP DNA NN I-NP affinity NN I-NP precipitation NN I-NP assay NN I-NP COMMA COMMA O we PRP B-NP observed VBD B-VP that IN B-SBAR Tax1 NN B-NP is VBZ B-VP able JJ B-ADJP to TO B-VP efficiently RB I-VP induce VB I-VP the DT B-NP binding NN I-NP of IN B-PP Rel NN B-NP COMMA COMMA O whereas IN O PMA NN B-NP is VBZ B-VP not RB O . . O This DT B-NP established VBD B-VP a DT B-NP clear JJ I-NP difference NN I-NP between IN B-PP both DT B-NP stimuli NNS I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR Rel NN B-NP is VBZ B-VP the DT B-NP functionally RB I-NP active JJ I-NP factor NN I-NP . . O We PRP B-NP conclude VBP B-VP from IN B-PP these DT B-NP results NNS I-NP that IN B-SBAR the DT B-NP functional JJ I-NP activity NN I-NP of IN B-PP members NNS B-NP of IN B-PP the DT B-NP rel NN I-NP family NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP their PRP$ B-NP interaction NN I-NP with IN B-PP DNA NN B-NP and CC O that IN B-SBAR Rel NN B-NP can MD B-VP be VB I-VP a DT B-NP potent JJ I-NP transcriptional JJ I-NP activator NN I-NP on IN B-PP specific JJ B-NP kappa NN I-NP B NN I-NP sites NNS I-NP . . O NF-kappa NN B-NP B NN I-NP controls VBZ B-VP expression NN B-NP of IN B-PP inhibitor NN B-NP I NN I-NP kappa NN I-NP B NN I-NP alpha NN I-NP : : O evidence NN B-NP for IN B-PP an DT B-NP inducible JJ I-NP autoregulatory JJ I-NP pathway NN I-NP . . O The DT B-NP eukaryotic JJ I-NP transcription NN I-NP factor NN I-NP nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O participates VBZ B-VP in IN B-PP many JJ B-NP parts NNS I-NP of IN B-PP the DT B-NP genetic JJ I-NP program NN I-NP mediating VBG B-VP T NN B-NP lymphocyte NN I-NP activation NN B-NP and CC O growth NN B-NP . . O Nuclear JJ B-NP expression NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP occurs VBZ B-VP after IN B-PP its PRP$ B-NP induced VBN I-NP dissociation NN I-NP from IN B-PP its PRP$ B-NP cytoplasmic JJ I-NP inhibitor NN I-NP I NN I-NP kappa NN I-NP B NN I-NP alpha NN I-NP . . O Phorbol NN B-NP ester NN I-NP and CC O tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP induction NN B-NP of IN B-PP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP both CC O the DT B-NP degradation NN I-NP of IN B-PP performed VBN B-NP I NN I-NP kappa NN I-NP B NN I-NP alpha NN I-NP and CC O the DT B-NP activation NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP gene NN I-NP expression NN I-NP . . O Transfection NN B-NP studies NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP I NN I-NP kappa NN I-NP B NN I-NP alpha NN I-NP gene NN I-NP is VBZ B-VP specifically RB I-VP induced VBN I-VP by IN B-PP the DT B-NP 65-kilodalton JJ I-NP transactivating VBG I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O Association NN B-NP of IN B-PP the DT B-NP newly RB I-NP synthesized VBN I-NP I NN I-NP kappa NN I-NP B NN I-NP alpha NN I-NP with IN B-PP p65 NN B-NP restores VBZ B-VP intracellular JJ B-NP inhibition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP DNA NN I-NP binding NN I-NP activity NN I-NP and CC O prolongs VBZ B-VP the DT B-NP survival NN I-NP of IN B-PP this DT B-NP labile JJ I-NP inhibitor NN I-NP . . O Together RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP controls VBZ B-VP the DT B-NP expression NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP by IN B-PP means NNS I-PP of IN I-PP an DT B-NP inducible JJ I-NP autoregulatory JJ I-NP pathway NN I-NP . . O p105 NN B-NP and CC O p98 NN B-NP precursor NN B-NP proteins NNS I-NP play VBP B-VP an DT B-NP active JJ I-NP role NN I-NP in IN B-PP NF-kappa NN B-NP B-mediated JJ I-NP signal NN I-NP transduction NN I-NP . . O The DT B-NP Rel\/NF-kappa NN I-NP B NN I-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP is VBZ B-VP composed VBN I-VP of IN B-PP two CD B-NP distinct JJ I-NP subgroups NNS I-NP COMMA COMMA O proteins NNS B-NP that WDT B-NP undergo VBP B-VP proteolytic JJ B-NP processing NN I-NP and CC O contain VBP B-VP SWI6\/ankyrin NN B-NP repeats NNS I-NP in IN B-PP their PRP$ B-NP carboxyl NN I-NP termini NNS I-NP ( ( O p105 NN B-NP COMMA COMMA O p98 NN B-NP ) ) O COMMA COMMA O and CC O those DT B-NP without IN B-PP such JJ B-NP repeats NNS I-NP that WDT B-NP do VBP B-VP not RB I-VP require VB I-VP processing NN B-NP ( ( O p65 NN B-NP COMMA COMMA O c-Rel NN B-NP COMMA COMMA O RelB NN B-NP COMMA COMMA O and CC O Dorsal NN B-NP ) ) O . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT O p105 NN B-NP and CC O p98 NN B-NP precursors NNS B-NP share VBP B-VP functional JJ B-NP properties NNS I-NP with IN B-PP the DT B-NP I NN I-NP kappa NN I-NP B NN I-NP proteins NNS I-NP COMMA COMMA O which WDT B-NP also RB B-ADVP contain VBP B-VP SWI6\/ankyrin NN B-NP repeats NNS I-NP . . O Both CC O p105 NN B-NP and CC O p98 NN B-NP were VBD B-VP found VBN I-VP to TO I-VP form VB I-VP stable JJ B-NP complexes NNS I-NP with IN B-PP other JJ B-NP Rel\/NF-kappa NN I-NP B NN I-NP family NN I-NP members NNS I-NP COMMA COMMA O including VBG B-PP p65 NN B-NP and CC O c-Rel NN B-NP . . O Association NN B-NP with IN B-PP the DT B-NP precursors NNS I-NP is VBZ B-VP sufficient JJ B-ADJP for IN B-PP cytoplasmic JJ B-NP retention NN I-NP of IN B-PP either CC O p65 NN B-NP or CC O c-Rel NN B-NP COMMA COMMA O both DT B-NP of IN B-PP which WDT B-NP are VBP B-VP otherwise RB B-ADVP nuclear JJ B-ADJP . . O These DT B-NP complexes NNS I-NP undergo VBP B-VP stimulus-responsive JJ B-NP processing NN I-NP to TO B-VP produce VB I-VP active JJ B-NP p50\/c-Rel NN I-NP and CC I-NP p55\/c-Rel NN I-NP complexes NNS I-NP . . O These DT B-NP observations NNS I-NP suggest VBP B-VP a DT B-NP second JJ I-NP pathway NN I-NP leading VBG B-VP to TO B-PP NF-kappa NN B-NP B NN I-NP induction NN I-NP COMMA COMMA O in IN B-PP which WDT B-NP processing NN B-NP of IN B-PP the DT B-NP precursors NNS I-NP rather RB B-CONJP than IN I-CONJP phosphorylation NN B-NP of IN B-PP I NN B-NP kappa NN I-NP B NN I-NP plays VBZ B-VP a DT B-NP major JJ I-NP role NN I-NP . . O Mutual JJ B-NP regulation NN I-NP of IN B-PP the DT B-NP transcriptional JJ I-NP activator NN I-NP NF-kappa NN I-NP B NN I-NP and CC O its PRP$ B-NP inhibitor NN I-NP COMMA COMMA O I NN B-NP kappa NN I-NP B-alpha NN I-NP . . O The DT B-NP NK-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP complex NN I-NP is VBZ B-VP sequestered VBN I-VP in IN B-PP the DT B-NP cytoplasm NN I-NP by IN B-PP the DT B-NP inhibitory JJ I-NP protein NN I-NP I NN B-NP kappa NN I-NP B-alpha NN I-NP ( ( O MAD-3 NN B-NP ) ) O . . O Various JJ B-NP cellular JJ I-NP stimuli NNS I-NP relieve VBP B-VP this DT B-NP inhibition NN I-NP by IN B-PP mechanisms NNS B-NP largely RB B-ADJP unknown JJ I-ADJP COMMA COMMA O leading VBG B-VP to TO B-PP NF-kappa NN B-NP B NN I-NP nuclear JJ I-NP localization NN I-NP and CC O transactivation NN B-NP of IN B-PP its PRP$ B-NP target NN I-NP genes NNS I-NP . . O It PRP B-NP is VBZ B-VP demonstrated VBN I-VP here RB B-ADVP with IN B-PP human JJ B-NP T NN B-NP lymphocytes NNS I-NP and CC O monocytes NNS B-NP that IN B-SBAR different JJ B-NP stimuli NNS I-NP COMMA COMMA O including VBG B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP and CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP COMMA COMMA O cause VB B-VP rapid JJ B-NP degradation NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B-alpha NN I-NP COMMA COMMA O with IN B-PP concomitant JJ B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O followed VBN B-VP by IN B-PP a DT B-NP dramatic JJ I-NP increase NN I-NP in IN B-PP I NN O kappa NN O B-alpha NN O mRNA NN B-NP and CC O protein NN B-NP synthesis NN B-NP . . O Transfection NN B-NP studies NNS I-NP reveal VBP B-VP that IN B-SBAR the DT B-NP I NN I-NP kappa NN I-NP B-alpha NN I-NP mRNA NN I-NP and CC O the DT B-NP encoded VBN I-NP protein NN I-NP are VBP B-VP potently RB I-VP induced VBN I-VP by IN B-PP NF-kappa NN B-NP B NN I-NP and CC B-PP by IN B-PP homodimers NNS B-NP of IN B-PP p65 NN B-NP and CC B-PP of IN B-PP c-Rel NN B-NP . . O We PRP B-NP propose VBP B-VP a DT B-NP model NN I-NP in IN B-PP which WDT B-NP NF-kappa NN B-NP B NN I-NP and CC O I NN B-NP kappa NN I-NP B-alpha NN I-NP mutually RB B-ADVP regulate VBP B-VP each DT B-NP other JJ I-NP in IN B-PP a DT B-NP cycle NN I-NP : : O saturating JJ B-NP amounts NNS I-NP of IN B-PP the DT B-NP inhibitory JJ I-NP I NN I-NP kappa NN I-NP B-alpha NN I-NP protein NN I-NP are VBP B-VP destroyed VBN I-VP upon IN B-PP stimulation NN B-NP COMMA COMMA O allowing VBG B-VP rapid JJ B-VP activation NN I-VP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O Subsequently RB B-ADVP COMMA COMMA O I NN O kappa NN O B-alpha NN O mRNA NN B-NP and CC O protein NN B-NP levels NNS B-NP are VBP B-VP quickly RB I-VP induced VBN I-VP by IN B-PP the DT B-NP activated VBN I-NP NF-kappa NN I-NP B NN I-NP . . O This DT B-NP resurgence NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B-alpha NN I-NP protein NN I-NP acts VBZ B-VP to TO I-VP restore VB I-VP an DT B-NP equilibrium NN I-NP in IN B-PP which WDT B-NP NF-kappa NN B-NP B NN I-NP is VBZ B-VP again RB I-VP inhibited VBN I-VP . . O Induced VBN B-NP myeloid JJ I-NP differentiation NN I-NP of IN B-PP K562 NN B-NP cells NNS I-NP with IN B-PP downregulation NN B-NP of IN B-PP erythroid JJ B-NP and CC I-NP megakaryocytic JJ I-NP transcription NN I-NP factors NNS I-NP : : O a DT B-NP novel JJ I-NP experimental JJ I-NP model NN I-NP for IN B-PP hemopoietic JJ B-NP lineage NN I-NP restriction NN I-NP . . O The DT B-NP human JJ I-NP erythroleukemia NN I-NP cell NN I-NP line NN I-NP K562 NN I-NP can MD B-VP be VB I-VP induced VBN I-VP to TO I-VP differentiate VB I-VP along IN B-PP the DT B-NP erythroid JJ I-NP and CC I-NP megakaryocytic JJ I-NP lineages NNS I-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR hexamethylene NN B-NP bisacetamide NN I-NP ( ( O HMBA NN B-NP ) ) O induced VBD B-VP K562 NN B-NP cells NNS I-NP to TO B-VP differentiate VB I-VP along IN B-PP a DT B-NP third JJ I-NP pathway NN I-NP . . O This DT B-NP was VBD B-VP accompanied VBN I-VP by IN B-PP downregulation NN B-NP of IN B-PP two CD B-NP transcription NN I-NP factors NNS I-NP normally RB B-VP expressed VBN I-VP in IN B-PP erythroid JJ B-NP COMMA COMMA I-NP mast NN I-NP and CC I-NP megakaryocyte NN I-NP lineages NNS I-NP . . O Northern NN B-NP analysis NN I-NP demonstrated VBD B-VP coordinate JJ B-NP downregulation NN I-NP of IN B-PP alpha NN B-NP globin NN I-NP and CC O gamma NN B-NP globin NN I-NP in IN B-CONJP addition NN O to TO O the DT B-NP two CD I-NP lineage-restricted JJ I-NP transcription NN I-NP factors NNS I-NP COMMA COMMA O SCL NN B-NP and CC O GATA-1 NN B-NP . . O Proliferation NN B-NP of IN B-PP the DT B-NP K562 NN I-NP cells NNS I-NP was VBD B-VP also RB I-VP suppressed VBN I-VP . . O Clonal JJ B-NP assay NN I-NP showed VBD B-VP that IN B-SBAR the DT B-NP suppression NN I-NP was VBD B-VP irreversible JJ B-ADJP and CC O appeared VBD B-VP analogous JJ B-ADJP to TO B-PP the DT B-NP commitment NN I-NP of IN B-PP murine JJ B-NP erythroleukemia NN I-NP ( ( O MEL NN B-NP ) ) O cells NNS B-NP to TO B-PP terminal JJ B-NP differentiation NN I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP MEL NN B-NP cells NNS I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O K562 NN B-NP cells NNS I-NP acquired VBD B-VP a DT B-NP macrophage-like JJ I-NP morphology NN I-NP and CC O exhibited VBD B-VP a DT B-NP complete JJ I-NP failure NN I-NP to TO B-VP generate VB I-VP benzidine-positive JJ B-NP cells NNS I-NP . . O Electron NN B-NP microscopy NN I-NP revealed VBD B-VP a DT B-NP marked JJ I-NP increase NN I-NP in IN B-PP granules NNS B-NP resembling VBG B-VP those DT B-NP specific JJ B-ADJP for IN B-PP eosinophils NNS B-NP . . O Surface NN B-NP marker NN I-NP analysis NN I-NP showed VBD B-VP that IN B-SBAR HMBA-induced JJ B-NP cells NNS I-NP expressed VBD B-VP reduced VBN B-NP levels NNS I-NP of IN B-PP glycophorin NN B-NP A NN I-NP COMMA COMMA O CD5 NN B-NP COMMA COMMA O CD7 NN B-NP and CC O CD11b NN B-NP . . O No DT B-NP upregulation NN I-NP of IN B-PP megakaryocyte NN B-NP or CC I-NP lymphoid JJ I-NP markers NNS I-NP occurred VBD B-VP . . O Thus RB B-ADVP the DT B-NP response NN I-NP of IN B-PP K562 NN B-NP cells NNS I-NP to TO B-PP HMBA NN B-NP may MD B-VP provide VB I-VP a DT B-NP useful JJ I-NP experimental JJ I-NP system NN I-NP for IN B-PP studying VBG B-VP the DT B-NP molecular JJ I-NP mechanisms NNS I-NP responsible JJ B-ADJP for IN B-PP downmodulation NN B-NP of IN B-PP lineage-restricted JJ B-NP transcription NN I-NP factors NNS I-NP during IN B-PP hemopoietic JJ B-NP lineage NN I-NP commitment NN I-NP . . O The DT B-NP Sp1 NN I-NP transcription NN I-NP factor NN I-NP binds VBZ B-VP the DT B-NP CD11b NN I-NP promoter NN I-NP specifically RB B-PP in IN I-PP myeloid JJ B-NP cells NNS I-NP in FW B-ADVP vivo FW I-ADVP and CC O is VBZ B-VP essential JJ B-ADJP for IN B-PP myeloid-specific JJ B-NP promoter NN I-NP activity NN I-NP . . O The DT B-NP myeloid JJ I-NP integrin NN I-NP CD11b NN I-NP is VBZ B-VP expressed VBN I-VP selectively RB B-ADVP on IN B-PP the DT B-NP surface NN I-NP of IN B-PP mature JJ B-NP macrophages NNS I-NP COMMA COMMA O monocytes NNS B-NP COMMA COMMA O neutrophils NNS B-NP COMMA COMMA O and CC O natural JJ B-NP killer NN I-NP cells NNS I-NP . . O Lineage-specific JJ B-NP expression NN I-NP is VBZ B-VP controlled VBN I-VP at IN B-PP the DT B-NP level NN I-NP of IN B-PP mRNA NN B-NP transcription NN I-NP . . O Recent JJ B-NP isolation NN I-NP of IN B-PP the DT B-NP CD11b NN I-NP promoter NN I-NP shows VBZ B-VP that IN B-SBAR 92 CD B-NP base NN B-NP pairs NNS I-NP ( ( O bp NN B-NP ) ) O of IN B-PP 5'-flanking JJ B-NP DNA NN I-NP are VBP B-VP sufficient JJ B-ADJP to TO B-VP direct VB I-VP myeloid-specific JJ B-NP expression NN I-NP of IN B-PP a DT B-NP reporter NN I-NP gene NN I-NP . . O To TO B-VP characterize VB I-VP regulatory JJ B-NP sequences NNS I-NP important JJ B-ADJP for IN B-PP promoter NN B-NP activity NN I-NP COMMA COMMA O we PRP B-NP performed VBD B-VP linker NN B-NP scanning NN I-NP analysis NN I-NP of IN B-PP the DT B-NP 92-bp JJ I-NP CD11b NN I-NP promoter NN I-NP and CC O demonstrate VB B-VP that IN B-SBAR a DT B-NP sequence NN I-NP at IN B-PP bp NN B-NP -60 CD I-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP CD11b NN B-NP promoter NN I-NP activity NN I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR this DT B-NP sequence NN I-NP binds VBZ B-VP the DT B-NP transcription NN I-NP factor NN I-NP Sp1 NN I-NP in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP . . O In FW B-ADVP vivo FW I-ADVP the DT B-NP Sp1 NN I-NP site NN I-NP is VBZ B-VP bound VBN I-VP only RB B-PP in IN I-PP myeloid JJ O ( ( O U937 NN B-NP ) ) O cells NNS B-NP COMMA COMMA O not RB B-PP in IN I-PP cervical JJ B-NP carcinoma NN I-NP ( ( O HeLa NN B-NP ) ) O cells NNS B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O the DT B-NP macrophage NN I-NP transcription NN I-NP factor NN I-NP PU.1 NN I-NP binds VBZ B-VP the DT B-NP CD11b NN I-NP promoter NN I-NP in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP close RB B-ADVP to TO B-PP the DT B-NP Sp1 NN I-NP site NN I-NP . . O We PRP B-NP propose VBP B-VP a DT B-NP model NN I-NP in IN B-PP which WDT B-NP binding NN B-NP of IN B-PP a DT B-NP myeloid-specific JJ I-NP factor NN I-NP ( ( O PU.1 NN B-NP ) ) O allows VBZ B-VP a DT B-NP general JJ I-NP factor NN I-NP ( ( O Sp1 NN B-NP ) ) O to TO B-VP bind VB I-VP in IN B-PP a DT B-NP tissue-specific JJ I-NP fashion NN I-NP thereby RB B-ADVP contributing VBG B-VP to TO B-PP the DT B-NP myeloid-specific JJ I-NP expression NN I-NP of IN B-PP CD11b NN B-NP . . O Costimulation NN B-NP of IN B-PP peripheral JJ B-NP blood NN I-NP T NN I-NP cell NN I-NP activation NN I-NP by IN B-PP human JJ B-NP endothelial JJ I-NP cells NNS I-NP . . O Enhanced VBD B-NP IL-2 NN I-NP transcription NN I-NP correlates VBZ B-VP with IN B-PP increased VBN B-NP c-fos NN I-NP synthesis NN I-NP and CC O increased VBN B-NP Fos NN I-NP content NN I-NP of IN B-PP AP-1 NN B-NP . . O Endothelial JJ B-NP cells NNS I-NP ( ( O EC NN B-NP ) ) O act VBP B-VP as IN B-PP APC NN B-NP for IN B-PP resting VBG B-NP PBL NN I-NP in FW B-ADVP vitro FW I-ADVP COMMA COMMA O and CC O may MD B-VP have VB I-VP important JJ B-NP roles NNS I-NP in FW B-ADVP vivo FW I-ADVP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP allograft NN B-NP rejection NN I-NP and CC O delayed VBN B-NP hypersensitivity NN I-NP . . O We PRP B-NP previously RB B-ADVP reported VBD B-VP that IN B-SBAR human JJ B-NP umbilical JJ I-NP vein NN I-NP EC NN I-NP provide VBP B-VP costimulatory JJ B-NP signals NNS I-NP to TO B-PP PHA-stimulated JJ B-NP PBL NN I-NP via IN B-PP CD2:lymphocyte NN B-NP function-associated JJ I-NP Ag-3 NN I-NP and CC O an DT B-NP unidentified JJ I-NP ligand NN I-NP pair NN I-NP COMMA COMMA O resulting VBG B-VP in IN B-PP a DT B-NP three- CD I-NP to TO I-NP eight-fold JJ I-NP enhancement NN I-NP of IN B-PP IL-2 NN B-NP production NN I-NP . . O The DT B-NP physiologic JJ I-NP relevance NN I-NP of IN B-PP this DT B-NP increase NN I-NP was VBD B-VP demonstrated VBN I-VP by IN B-PP the DT B-NP proliferative JJ I-NP advantage NN I-NP provided VBN B-VP by IN B-PP EC NN B-NP to TO B-PP PBL NN B-NP suboptimally RB B-VP stimulated VBN I-VP with IN B-PP mAb NN B-NP OKT3 NN I-NP . . O We PRP B-NP now RB B-ADVP report VBP B-VP that IN B-SBAR EC NN B-NP costimulation NN I-NP causes VBZ B-VP increased VBN B-NP levels NNS I-NP of IN B-PP IL-2 NN B-NP mRNA NN I-NP as IN B-PP a DT B-NP result NN I-NP of IN B-PP increased VBN B-NP IL-2 NN I-NP transcription NN I-NP in IN B-PP PBL NN B-NP . . O We PRP B-NP therefore RB B-ADVP examined VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP EC NN B-NP on IN B-PP T NN B-NP cell NN I-NP nuclear JJ I-NP factors NNS I-NP known VBN B-VP to TO I-VP regulate VB I-VP IL-2 NN B-NP transcription NN I-NP COMMA COMMA O including VBG B-PP c-jun NN B-NP and CC O c-fos-two NN B-NP components NNS B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP AP-1 NN I-NP COMMA COMMA O NFAT NN B-NP COMMA COMMA O and CC O others NNS B-NP . . O PBL NN B-NP constitutively RB B-ADVP express VBP B-VP c-jun NN B-NP transcripts NNS I-NP COMMA COMMA O and CC O the DT B-NP level NN I-NP of IN B-PP c-jun NN B-NP mRNA NN I-NP is VBZ B-VP not RB I-VP altered VBN I-VP by IN B-PP PHA NN B-NP activation NN I-NP in IN B-PP the DT B-NP absence NN B-NP or CC O presence NN B-NP of IN B-PP EC NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O c-fos NN B-NP mRNA NN I-NP is VBZ B-VP absent JJ B-ADJP from IN B-PP resting VBG B-NP T NN I-NP cells NNS I-NP and CC O is VBZ B-VP induced VBN I-VP on IN B-PP PHA NN B-NP activation NN I-NP . . O EC NN B-NP alone RB B-ADVP do VBP B-VP not RB I-VP induce VB I-VP c-fos NN B-NP mRNA NN I-NP but CC O augment VBP B-VP the DT B-NP level NN I-NP of IN B-PP c-fos NN B-NP mRNA NN I-NP in IN B-PP PHA-activated JJ B-NP T NN I-NP cells NNS I-NP by IN B-PP 3- CD B-NP to TO I-NP 10-fold RB I-NP . . O This DT B-NP effect NN I-NP is VBZ B-VP largely RB B-ADJP independent JJ I-ADJP of IN B-PP the DT B-NP CD2:lymphocyte NN I-NP function-associated JJ I-NP Ag-3 NN I-NP pathway NN I-NP . . O Gel-shift NN B-NP analysis NN I-NP reveals VBZ B-VP the DT B-NP constitutive JJ I-NP presence NN I-NP of IN B-PP nuclear JJ B-NP factors NNS I-NP in IN B-PP resting VBG B-NP PBL NN I-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP proximal JJ I-NP AP-1 NN I-NP site NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP and CC O that IN B-NP contain VBP B-VP immunoreactive JJ O c-Jun NN B-NP but CC B-CONJP not RB I-CONJP c-Fos NN B-NP protein NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O AP-1 NN B-NP from IN B-PP PHA-activated JJ B-NP cells NNS I-NP contains VBZ B-VP c-Jun NN B-NP and CC O low JJ B-NP levels NNS I-NP of IN B-PP c-Fos NN B-NP . . O Strikingly RB B-ADVP COMMA COMMA O costimulation NN B-NP with IN B-PP EC NN B-NP results VBZ B-VP in IN B-PP a DT B-NP dramatic JJ I-NP increase NN I-NP ( ( O up NN B-NP to TO I-NP 15-fold JJ I-NP ) ) O in IN B-PP the DT B-NP c-Fos NN I-NP content NN I-NP of IN B-PP AP-1 NN B-NP . . O Levels NNS B-NP of IN B-PP other JJ B-NP nuclear JJ I-NP factors NNS I-NP involved VBN B-VP in IN B-PP IL-2 NN B-NP regulation NN I-NP were VBD B-VP not RB I-VP altered VBN I-VP by IN B-PP EC NN B-NP COMMA COMMA O although IN B-SBAR NFAT-DNA NN B-NP complexes NNS I-NP migrated VBD B-VP at IN B-PP a DT B-NP slightly RB I-NP different JJ I-NP mobility NN I-NP . . O In IN B-PP summary NN B-NP COMMA COMMA O our PRP$ B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR changes NNS B-NP in IN B-PP the DT B-NP composition NN I-NP of IN B-PP transcription NN B-NP factor NN I-NP AP-1 NN I-NP is VBZ B-VP a DT B-NP key JJ I-NP molecular JJ I-NP mechanism NN I-NP for IN B-PP increasing VBG B-NP IL-2 NN I-NP transcription NN I-NP and CC O may MD B-VP underlie VB I-VP the DT B-NP phenomenon NN I-NP of IN B-PP costimulation NN B-NP by IN B-PP EC NN B-NP . . O A DT B-NP protein NN I-NP of IN B-PP the DT B-NP AP-1 NN I-NP family NN I-NP is VBZ B-VP a DT B-NP component NN I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O Nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O is VBZ B-VP a DT B-NP transcriptional JJ I-NP activator NN I-NP involved VBN B-VP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP IL-2 NN B-NP gene NN I-NP expression NN I-NP . . O The DT B-NP response NN I-NP element NN I-NP for IN B-PP NF-AT NN B-NP is VBZ B-VP a DT B-NP sequence NN I-NP localized JJ B-VP between IN B-PP -285\/-254 CD B-NP in IN B-PP the DT B-NP IL-2 NN I-NP regulatory JJ I-NP region NN I-NP . . O The DT B-NP composition NN I-NP of IN B-PP NF-AT NN B-NP protein NN I-NP is VBZ B-VP still RB I-VP not RB I-VP fully RB I-VP elucidated VBN I-VP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR COMMA COMMA O in IN B-PP normal JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP COMMA COMMA O an DT B-NP AP-1 NN I-NP protein NN I-NP is VBZ B-VP a DT B-NP component NN I-NP of IN B-PP the DT B-NP NF-AT NN I-NP protein NN I-NP complex NN I-NP . . O This DT B-NP was VBD B-VP evidenced VBN I-VP by IN B-PP the DT B-NP ability NN I-NP of IN B-PP the DT B-NP AP-1 NN I-NP site NN I-NP to TO B-VP compete VB I-VP with IN B-PP the DT B-NP NF-AT NN I-NP site NN I-NP for IN B-PP binding NN B-VP to TO B-PP NF-AT NN B-NP and CC B-PP by IN B-PP the DT B-NP capacity NN I-NP of IN B-PP immobilized VBN B-NP anti-Jun JJ I-NP and CC I-NP anti-Fos JJ I-NP antibodies NNS I-NP to TO B-VP deplete VB I-VP NF-AT-binding NN B-NP activity NN I-NP from IN B-PP nuclear JJ B-NP extracts NNS I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O There EX B-NP was VBD B-VP no DT B-NP detectable JJ I-NP binding NN I-NP of IN B-PP in FW B-ADVP vitro FW I-ADVP translated VBN B-NP Jun\/Fos NN B-NP heterodimer NN I-NP ( ( O AP-1 NN B-NP ) ) O to TO B-PP the DT B-NP NF-AT NN I-NP sequence NN I-NP COMMA COMMA O and CC O the DT B-NP NF-AT NN I-NP sequence NN I-NP was VBD B-VP unable JJ B-ADJP to TO B-VP inhibit VB I-VP the DT B-NP binding NN I-NP of IN B-PP Jun\/Fos NN B-NP to TO B-PP the DT B-NP AP-1 NN I-NP sequence NN I-NP . . O The DT B-NP presence NN I-NP of IN B-PP an DT B-NP AP-1 NN I-NP protein NN I-NP in IN B-PP the DT B-NP NF-AT NN I-NP protein NN I-NP complex NN I-NP may MD B-VP regulate VB I-VP NF-AT-binding JJ B-NP activity NN I-NP through IN B-PP protein-protein JJ B-NP interaction NN I-NP . . O Functional JJ B-NP antagonism NN I-NP between IN B-PP vitamin NN B-NP D3 NN I-NP and CC O retinoic JJ B-NP acid NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP CD14 NN B-NP and CC O CD23 NN B-NP expression NN B-NP during IN B-PP monocytic JJ B-NP differentiation NN I-NP of IN B-PP U-937 NN B-NP cells NNS I-NP . . O 1COMMA25 CD B-NP alpha-Dihydroxicholecalciferol NN I-NP ( ( O VitD3 NN B-NP ) ) O and CC O retinoic JJ B-NP acid NN I-NP ( ( O RA NN B-NP ) ) O are VBP B-VP important JJ B-NP regulators NNS I-NP of IN B-PP the DT B-NP proliferation NN B-NP and CC O differentiation NN B-NP of IN B-PP several JJ B-NP cell NN I-NP types NNS I-NP . . O This DT B-NP paper NN I-NP describes VBZ B-VP how WRB B-ADVP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP monocyte-macrophage JJ I-NP Ag NN I-NP COMMA COMMA O CD14 NN B-NP COMMA COMMA O and CC O the DT B-NP low JJ I-NP affinity NN I-NP Fc NN I-NP receptor NN I-NP for IN B-PP IgE NN B-NP COMMA COMMA O CD23 NN B-NP COMMA COMMA O were VBD B-VP inversely RB I-VP regulated VBN I-VP during IN B-PP VitD3- NN B-NP and CC O RA-induced JJ B-ADJP monocytic JJ B-NP differentiation NN I-NP of IN B-PP human JJ B-NP U-937 NN I-NP monoblasts NNS I-NP . . O PMA NN B-NP induced VBD B-VP the DT B-NP expression NN I-NP of IN B-PP both CC O CD14 NN B-NP and CC O CD23 NN B-NP mRNA NN B-NP and CC O protein NN B-NP . . O Exposure NN B-NP to TO B-PP VitD3 NN B-NP rapidly RB B-ADVP induced VBD B-VP the DT B-NP de FW I-NP novo FW I-NP expression NN I-NP of IN B-PP CD14 NN B-NP mRNA NN B-NP and CC O protein NN B-NP . . O The DT B-NP addition NN I-NP of IN B-PP cycloheximide NN B-NP completely RB B-ADVP blocked VBD B-VP the DT B-NP VitD3 NN I-NP induction NN I-NP of IN B-PP CD14 NN B-NP mRNA NN I-NP expression NN I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP induction NN I-NP was VBD B-VP dependent JJ B-ADJP on IN B-PP ongoing JJ B-NP protein NN I-NP synthesis NN I-NP . . O While IN B-SBAR inducing VBG B-VP CD14 NN B-NP expression NN I-NP COMMA COMMA O VitD3 NN B-NP concomitantly RB B-ADVP suppressed VBD B-VP the DT O basal JJ O COMMA COMMA O PMA- NN B-NP COMMA COMMA O and CC O RA-inducible JJ B-ADJP CD23 NN B-NP expression NN I-NP in IN B-PP a DT B-NP dose-dependent JJ I-NP manner NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O U-937 NN B-NP cells NNS I-NP induced VBN B-VP by IN B-PP RA NN B-NP strongly RB B-ADVP increased VBD B-VP their PRP$ B-NP expression NN I-NP of IN B-PP CD23 NN B-NP mRNA NN B-NP and CC O protein NN B-NP COMMA COMMA O whereas IN O they PRP B-NP completely RB B-ADVP lacked VBD B-VP detectable JJ O CD14 NN O cell NN B-NP surface NN I-NP or CC O mRNA NN B-NP expression NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP VitD3- NN B-NP and CC O the DT B-NP PMA-induced JJ I-NP CD14 NN B-NP expression NN I-NP was VBD B-VP inhibited VBN I-VP as IN B-PP a DT B-NP temporal JJ I-NP consequence NN I-NP of IN B-PP the DT B-NP RA-induced JJ I-NP differentiation NN I-NP . . O The DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR there EX B-NP exists VBZ B-VP a DT B-NP functional JJ I-NP antagonism NN I-NP between IN B-PP VitD3 NN B-NP and CC O RA NN B-NP that WDT B-NP may MD B-VP have VB I-VP important JJ B-NP implications NNS I-NP for IN B-PP the DT B-NP regulation NN I-NP of IN B-PP certain JJ B-NP immune JJ I-NP and CC I-NP inflammatory JJ I-NP responses NNS I-NP through IN B-PP their PRP$ B-NP inverse JJ I-NP effects NNS I-NP on IN B-PP CD14 NN B-NP and CC O CD23 NN B-NP gene NN B-NP expression NN I-NP . . O The DT B-NP lytic JJ I-NP transition NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP is VBZ B-VP imitated VBN I-VP by IN B-PP recombinant JJ B-NP B-cells NNS I-NP . . O Lytic JJ B-NP transition NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O is VBZ B-VP initiated VBN I-VP by IN B-PP distinct JJ B-NP immediate JJ I-NP early JJ I-NP regulators NNS I-NP of IN B-PP the DT B-NP viral JJ I-NP cycle NN I-NP COMMA COMMA O in IN B-PP synchronization NN B-NP to TO B-PP temporary JJ B-NP COMMA COMMA I-NP permissive JJ I-NP conditions NNS I-NP during IN B-PP host NN B-NP cell NN I-NP differentiation NN I-NP . . O We PRP B-NP developed VBD B-VP eukaryotic JJ B-NP vectors NNS I-NP suitable JJ B-ADJP to TO B-VP imitate VB I-VP the DT B-NP processes NNS I-NP involved VBN B-VP in IN B-PP lytic JJ B-NP transition NN I-NP in IN B-PP cell NN B-NP culture NN I-NP systems NNS I-NP . . O Two CD B-NP stable JJ I-NP B NN I-NP cell NN I-NP lines NNS I-NP were VBD B-VP established VBN I-VP : : O R59Z NN B-NP activator NN I-NP cells NNS I-NP were VBD B-VP used VBN I-VP to TO B-VP induce VB I-VP lytic JJ B-NP EBV NN I-NP expression NN I-NP in IN B-PP a DT B-NP constitutive JJ I-NP manner NN I-NP by IN B-PP the DT B-NP production NN I-NP of IN B-PP the DT B-NP BZLF NN I-NP 1 CD I-NP trans-activator NN I-NP ( ( O Zta NN B-NP ) ) O . . O R7-57 NN B-NP reporter NN I-NP cells NNS I-NP COMMA COMMA O on IN B-PP the DT B-NP other JJ I-NP hand NN I-NP COMMA COMMA O signaled VBD B-VP induced VBN B-NP activity NN I-NP of IN B-PP the DT B-NP lytic JJ I-NP origin NN I-NP of IN B-PP EBV NN B-NP replication NN I-NP ( ( O ori NN B-NP Lyt NN I-NP ) ) O . . O Different JJ B-NP modes NNS I-NP COMMA COMMA O like IN B-PP chemical JJ B-NP induction NN I-NP COMMA COMMA O lytic JJ B-NP superinfection NN I-NP with IN B-PP EBV NN B-NP and CC O single JJ B-NP gene NN I-NP trans-activation NN I-NP converted VBD B-VP the DT B-NP recombinant JJ I-NP ori NN I-NP Lyt NN I-NP element NN I-NP in IN B-PP R7-57 NN B-NP reporter NN I-NP cells NNS I-NP . . O BZLF NN B-NP 1 CD I-NP COMMA COMMA O transiently RB B-VP expressed VBN I-VP in IN B-PP R7-57 NN B-NP reporter NN I-NP cells NNS I-NP COMMA COMMA O was VBD B-VP the DT B-NP only JJ I-NP EBV NN I-NP trans-activator NN I-NP found VBN B-VP COMMA COMMA O sufficient JJ B-ADJP in NN O inducing VBG B-VP the DT B-NP viral JJ I-NP lytic JJ I-NP cycle NN I-NP . . O Basing VBG B-PP on IN B-PP these DT B-NP experiments NNS I-NP COMMA COMMA O trans-cellular JJ B-NP activation NN I-NP of IN B-PP EBV NN B-NP was VBD B-VP tested VBN I-VP by IN B-PP cocultivation NN B-NP of IN B-PP BZLF NN B-NP 1-expressing JJ I-NP R59Z NN I-NP activator NN I-NP cells NNS I-NP with IN B-PP the DT B-NP R7-57 NN I-NP reporter NN I-NP line NN I-NP . . O No DT B-NP lytic JJ I-NP effect NN I-NP on IN B-PP the DT B-NP reporter NN I-NP cells NNS I-NP could MD B-VP be VB I-VP measured VBN I-VP COMMA COMMA O neither CC O by IN B-PP cocultivation NN B-NP of IN B-PP activator NN B-NP cells NNS I-NP nor CC B-PP by IN B-PP coincubation NN B-NP of IN B-PP BZLF NN B-NP 1-containing JJ I-NP cell NN I-NP lysates NNS I-NP . . O Latency NN B-NP breaking NN I-NP activity NN I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O was VBD B-VP transferred VBN I-VP from IN B-PP activator NN B-NP to TO B-PP reporter NN B-NP cells NNS I-NP when WRB B-ADVP active JJ B-NP COMMA COMMA I-NP exogenous JJ I-NP virus NN I-NP was VBD B-VP added VBN I-VP . . O The DT B-NP cell NN I-NP system NN I-NP described VBN B-VP in IN B-PP these DT B-NP experiments NNS I-NP provides VBZ B-VP a DT B-NP tool NN I-NP for IN B-PP the DT B-NP detection NN I-NP of IN B-PP EBV NN B-NP reactivation NN I-NP and CC O demonstrates VBZ B-VP the DT B-NP potential NN I-NP of IN B-PP the DT B-NP lytic JJ I-NP regulatory JJ I-NP gene NN I-NP BZLF NN I-NP 1 CD I-NP . . O Immobilization NN B-NP and CC O recovery NN B-NP of IN B-PP fusion NN B-NP proteins NNS I-NP and CC O B-lymphocyte NN B-NP cells NNS I-NP using VBG B-VP magnetic JJ B-NP separation NN I-NP . . O A DT B-NP new JJ I-NP approach NN I-NP to TO B-VP facilitate VB I-VP immobilization NN B-NP and CC O affinity NN B-NP purification NN I-NP of IN B-PP recombinant JJ B-NP proteins NNS I-NP and CC O selected VBN B-NP human JJ I-NP B NN I-NP lymphocytes NNS I-NP has VBZ B-VP been VBN I-VP developed VBN I-VP . . O Using VBG B-VP magnetic JJ B-NP beads NNS I-NP with IN B-PP attached VBN B-NP DNA NN I-NP containing VBG B-VP the DT B-NP Escherichia FW I-NP coli FW I-NP lac NN I-NP operator NN I-NP COMMA COMMA O fusion NN B-NP proteins NNS I-NP comprising VBG B-VP the DT B-NP DNA-binding JJ I-NP lac NN I-NP repressor NN I-NP could MD B-VP be VB I-VP affinity-purified JJ I-VP and CC O recovered VBN B-VP by IN B-PP gentle JJ B-NP elution NN I-NP conditions NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP with IN B-PP a DT B-NP lactose NN I-NP analogue NN I-NP or CC B-PP by IN B-PP enzymatic JJ B-NP means NNS I-NP using VBG B-VP either CC O deoxyribonuclease NN B-NP ( ( O DNase NN B-NP ) ) O or CC O restriction NN B-NP endonucleases NNS I-NP . . O The DT B-NP results NNS I-NP show VBP B-VP for IN B-PP the DT B-NP first JJ I-NP time NN I-NP that IN B-SBAR a DT B-NP DNA-binding JJ I-NP protein NN I-NP can MD B-VP be VB I-VP used VBN I-VP for IN B-PP affinity NN B-NP purification NN I-NP of IN B-PP fusion NN B-NP proteins NNS I-NP as IN B-SBAR exemplified VBN B-VP by IN B-PP the DT B-NP specific JJ I-NP and CC I-NP gentle JJ I-NP recovery NN I-NP of IN B-PP beta-galactosidase NN B-NP and CC O alkaline NN B-NP phosphatase NN I-NP from IN B-PP bacterial JJ B-NP lysates NNS I-NP using VBG B-VP immunomagnetic JJ B-NP separation NN I-NP . . O The DT B-NP approach NN I-NP was VBD B-VP further RB I-VP extended VBN I-VP to TO B-PP cell NN B-NP separation NN I-NP by IN B-PP the DT B-NP efficient JJ I-NP recovery NN B-NP and CC O elution NN B-NP of IN B-PP human JJ B-NP CD37 NN I-NP B NN I-NP lymphocytes NNS I-NP from IN B-PP peripheral JJ B-NP blood NN I-NP . . O Negative JJ B-NP transcriptional JJ I-NP regulation NN I-NP of IN B-PP human JJ O interleukin NN B-NP 2 CD I-NP ( ( O IL-2 NN B-NP ) ) O gene NN B-NP by IN B-PP glucocorticoids NNS B-NP through IN B-PP interference NN B-NP with IN B-PP nuclear JJ B-NP transcription NN I-NP factors NNS I-NP AP-1 NN B-NP and CC O NF-AT NN B-NP . . O IL-2 NN B-NP gene NN I-NP transcription NN I-NP is VBZ B-VP affected VBN I-VP by IN B-PP several JJ B-NP nuclear JJ I-NP proteins NNS I-NP . . O We PRP B-NP asked VBD B-VP whether IN B-SBAR dexamethasone NN B-NP ( ( O Dex NN B-NP ) ) O and CC O cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O inhibit VBP B-VP IL-2 NN B-NP gene NN I-NP transcription NN I-NP by IN B-PP interfering VBG B-VP with IN B-PP the DT B-NP activity NN I-NP of IN B-PP nuclear JJ B-NP proteins NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP . . O Nuclear JJ B-NP extracts NNS I-NP from IN B-PP primary JJ B-PP human JJ I-PP T NN O lymphocytes NNS O were VBD B-VP analyzed VBN I-VP by IN B-PP electrophoretic JJ B-NP DNA NN I-NP mobility NN I-NP shift NN I-NP assays NNS I-NP . . O Both CC O Dex NN B-NP and CC O CsA NN B-NP inhibited VBD B-VP the DT B-NP binding NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP AP-1 NN B-NP and CC O NF-AT NN B-NP COMMA COMMA B-PP but CC I-PP not RB B-PP of IN I-PP NF-kB NN B-NP and CC O OCT-1\/OAF NN B-NP COMMA COMMA O to TO B-PP their PRP$ B-NP corresponding JJ I-NP sites NNS I-NP on IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP promoter NN I-NP . . O To TO B-VP correlate VB I-VP changes NNS B-NP in IN B-PP nuclear JJ B-NP factor NN I-NP binding NN I-NP in FW B-ADVP vitro FW I-ADVP with IN B-PP transcriptional JJ B-NP activity NN I-NP in FW B-ADVP vivo FW I-ADVP and CC O define VB B-VP the DT B-NP structural JJ I-NP requirements NNS I-NP for IN B-PP IL-2 NN B-NP promoter NN I-NP repression NN I-NP COMMA COMMA O we PRP B-NP used VBD B-VP transient JJ B-NP DNA NN I-NP transfections NNS I-NP . . O Jurkat NN B-NP cells NNS I-NP were VBD B-VP transfected VBN I-VP with IN B-PP plasmids NNS B-NP containing VBG B-VP either CC O the DT B-NP intact JJ I-NP IL-2 NN I-NP promoter NN I-NP or CC O its PRP$ O AP-1 NN B-NP COMMA COMMA O NF-AT NN B-NP COMMA COMMA O and CC O NF-kB NN B-NP motifs NNS B-NP . . O Dex NN B-NP inhibited VBD B-VP the DT B-NP IL-2 NN I-NP promoter NN I-NP and CC O the DT B-NP AP-1 NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP the DT B-NP NF-AT NN B-NP and CC O NF-kB NN B-NP plasmids NNS B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O CsA NN B-NP inhibited VBD B-VP the DT B-NP IL-2 NN I-NP promoter NN I-NP and CC O the DT B-NP NF-AT NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP the DT B-NP AP-1 NN B-NP and CC O NF-kB NN B-NP plasmids NNS B-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR in IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP both CC O Dex NN B-NP and CC O CsA NN B-NP inhibited VBD B-VP IL-2 NN B-NP gene NN I-NP transcription NN I-NP through IN B-PP interference NN B-NP with IN B-PP transcription NN B-NP factors NNS I-NP AP-1 NN B-NP and CC O NF-AT NN B-NP . . O We PRP B-NP propose VBP B-VP that IN B-SBAR COMMA COMMA O while IN B-NP maximum NN I-NP inhibition NN B-VP may MD I-VP involve VB B-NP interaction NN O with IN B-NP both DT I-NP transcription NN I-NP factors NNS O COMMA COMMA O AP-1 NN B-VP is VBZ B-NP the DT I-NP primary JJ I-NP target NN O of IN B-NP Dex NN O Lymphocytes NNS B-NP from IN B-PP the DT B-NP site NN I-NP of IN B-PP disease NN B-NP suggest VBP B-VP adenovirus NN B-NP is VBZ B-VP one CD B-NP cause NN I-NP of IN B-PP persistent JJ B-NP or CC I-NP recurrent JJ I-NP inflammatory JJ I-NP arthritis NN I-NP . . O The DT B-NP assessment NN I-NP of IN B-PP synovial JJ B-NP lymphocyte NN I-NP reactivity NN I-NP to TO B-PP adenovirus NN B-NP antigen NN I-NP stimulation NN I-NP was VBD B-VP undertaken VBN I-VP in IN B-PP patients NNS B-NP with IN B-PP persistent JJ B-NP or CC I-NP recurrent JJ I-NP inflammatory JJ I-NP arthritis NN I-NP . . O The DT B-NP 3H-thymidine JJ I-NP uptake NN I-NP procedure NN I-NP was VBD B-VP employed VBN I-VP COMMA COMMA O incorporating VBG B-VP multiple JJ B-NP microbiological JJ I-NP antigens NNS I-NP . . O Five CD B-NP patients NNS I-NP were VBD B-VP found VBN I-VP with IN B-PP repeated VBN B-NP maximal JJ I-NP responses NNS I-NP to TO B-PP adenovirus NN B-NP antigen NN I-NP ; : O in IN B-PP one CD B-NP of IN B-PP these DT B-NP adenovirus NN B-NP nucleotide NN I-NP sequences NNS I-NP were VBD B-VP present JJ B-ADJP in IN B-PP a DT B-NP synovial JJ I-NP biopsy NN I-NP specimen NN I-NP . . O It PRP B-NP is VBZ B-VP concluded VBN I-VP that IN B-SBAR adenovirus NN B-NP may MD B-VP be VB I-VP one CD B-NP cause NN I-NP of IN B-PP persistent JJ B-NP or CC I-NP recurrent JJ I-NP inflammatory JJ I-NP arthritis NN I-NP . . O Human JJ B-NP CD3-CD16+ JJ I-NP natural JJ I-NP killer NN I-NP cells NNS I-NP express VBP B-VP the DT B-NP hGATA-3 NN I-NP T NN I-NP cell NN I-NP transcription NN I-NP factor NN I-NP and CC O an DT B-NP unrearranged JJ I-NP 2.3-kb JJ I-NP TcR NN I-NP delta NN I-NP transcript NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP analyzed VBD B-VP the DT O T NN B-NP cell NN I-NP receptor NN I-NP ( ( O TcR NN B-NP ) ) O delta NN B-NP transcripts NNS I-NP expressed VBN B-VP by IN B-PP CD3-CD16+ JJ B-NP cells NNS I-NP and CC O we PRP B-NP investigated VBD B-VP whether IN B-SBAR these DT B-NP cells NNS I-NP expressed VBD B-VP the DT B-NP hGATA-3 NN I-NP T NN I-NP cell NN I-NP transcription NN I-NP factor NN I-NP and CC O the DT B-NP recombination-activating JJ I-NP gene NN I-NP ( ( I-NP RAG NN I-NP ) ) I-NP -1 CD I-NP . . O Multiple JJ B-NP TcR NN I-NP delta NN I-NP transcripts NNS I-NP deriving VBG B-VP from IN B-PP an DT B-NP unrearranged JJ I-NP TcR NN I-NP delta NN I-NP gene NN I-NP were VBD B-VP detected VBN I-VP in IN B-PP both CC O polyclonal JJ O and CC O clonal JJ O CD3-CD16+ JJ O natural JJ B-NP killer NN I-NP ( ( O NK NN B-NP ) ) O cell NN B-NP lines NNS I-NP . . O Two CD B-NP unrearranged JJ I-NP TcR NN I-NP delta NN I-NP transcripts NNS I-NP had VBD B-VP a DT B-NP size NN I-NP similar JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP the DT B-NP functional JJ I-NP TcR NN I-NP delta NN I-NP mRNA NN I-NP ( ( O 2.3 CD B-NP and CC I-NP 1.3 CD I-NP kb NN I-NP ) ) O found VBN B-VP in IN B-PP TcR NN B-NP gamma\/delta+ JJ I-NP T NN I-NP lymphocytes NNS I-NP . . O Sequence NN B-NP analysis NN I-NP of IN B-PP nine CD B-NP different JJ I-NP 2.3-kb JJ I-NP cDNA NN I-NP clones NNS I-NP obtained VBN B-VP from IN B-PP NK-derived JJ B-NP polyA+ JJ I-NP RNA NN I-NP confirmed VBD B-VP that IN B-SBAR they PRP B-NP corresponded VBD B-VP to TO B-PP an DT B-NP unrearranged JJ I-NP TcR NN I-NP delta NN I-NP gene NN I-NP . . O These DT B-NP cDNA NN I-NP were VBD B-VP 2343 CD B-NP bp NN I-NP long JJ B-ADJP and CC O their PRP$ B-NP transcription NN I-NP initiation NN I-NP site NN I-NP was VBD B-VP located JJ O 814 CD B-NP bp NN I-NP upstream RB B-ADJP from IN B-PP the DT B-NP J NN I-NP delta NN I-NP 1 CD I-NP segment NN I-NP . . O The DT B-NP sequence NN I-NP located JJ B-ADJP upstream RB I-ADJP of IN B-PP the DT B-NP J NN I-NP delta NN I-NP 1 CD I-NP segment NN I-NP corresponded VBD B-VP to TO B-PP the DT B-NP previously RB I-NP reported VBN I-NP germ-line JJ I-NP sequence NN I-NP . . O The DT B-NP J NN I-NP delta NN I-NP 1 CD I-NP segment NN I-NP was VBD B-VP correctly RB I-VP spliced VBN I-VP to TO B-PP C NN B-NP delta NN I-NP ; : O in IN B-PP addition NN B-NP the DT B-NP four CD I-NP C NN I-NP delta NN I-NP exons NNS I-NP were VBD B-VP found VBN I-VP to TO I-VP be VB I-VP already RB I-VP assembled VBN I-VP . . O Two CD B-NP polyadenylation NN I-NP sites NNS I-NP were VBD B-VP present JJ B-ADJP in IN B-PP the DT B-NP fourth JJ I-NP C NN I-NP delta NN I-NP exon NN I-NP . . O However RB B-ADVP COMMA COMMA O only JJ B-NP that WDT I-NP located JJ B-ADJP at IN B-PP the DT B-NP 3' JJ I-NP end NN I-NP appeared VBD B-VP to TO I-VP be VB I-VP utilized VBN I-VP in IN B-PP the DT B-NP 2.3-kb JJ I-NP cDNA NN I-NP . . O The DT B-NP expression NN I-NP of IN B-PP hGATA-3 NN B-NP COMMA COMMA O a DT B-NP T NN I-NP cell-specific JJ I-NP factor NN I-NP known VBN B-VP to TO I-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP transcription NN I-NP of IN B-PP TcR NN B-NP delta NN I-NP locus NN I-NP COMMA COMMA O was VBD B-VP analyzed VBN I-VP by IN B-PP Northern NN B-NP blot NN I-NP COMMA COMMA O in IN B-PP cultured VBN B-NP NK NN I-NP cell NN B-NP population NN I-NP and CC O clones NNS B-NP ( ( B-PP but CC I-PP not RB B-PP in IN I-PP freshly RB B-NP derived VBN I-NP cell NN I-NP populations NNS I-NP ) ) O . . O All DT B-NP NK NN I-NP clones NNS B-NP and CC O cell NN B-NP lines NNS I-NP studied VBN B-VP were VBD B-VP found VBN I-VP to TO I-VP express VB I-VP hGATA-3-specific JJ B-NP mRNA NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR hGATA-3 NN B-NP may MD B-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP unrearranged JJ I-NP TcR NN I-NP delta NN I-NP gene NN I-NP expression NN I-NP in IN B-PP NK NN B-NP cells NNS I-NP . . O Finally RB B-ADVP COMMA COMMA O no DT B-NP transcription NN I-NP of IN B-PP the DT B-NP RAG-1 NN I-NP gene NN I-NP could MD B-VP be VB I-VP detected VBN I-VP in IN B-PP all DT B-NP NK NN I-NP cell NN B-NP lines NNS I-NP or CC O clones NNS B-NP analyzed VBN B-VP . . O Cell-specific JJ B-NP expression NN I-NP of IN B-PP helix-loop-helix JJ B-NP transcription NN I-NP factors NNS I-NP encoded VBN B-VP by IN B-PP the DT B-NP E2A NN I-NP gene NN I-NP . . O The DT B-NP E2A NN I-NP gene NN I-NP encodes VBZ B-VP transcription NN B-NP factors NNS I-NP of IN B-PP the DT B-NP helix-loop-helix JJ I-NP family NN I-NP that WDT B-NP are VBP B-VP implicated VBN I-VP in IN B-PP cell-specific JJ B-NP gene NN I-NP expression NN I-NP as IN B-PP part NN B-NP of IN B-PP dimeric JJ B-NP complexes NNS I-NP that WDT B-NP interact VBP B-VP with IN B-PP E NN B-NP box NN I-NP enhancer NN I-NP elements NNS I-NP . . O It PRP B-NP has VBZ B-VP previously RB I-VP been VBN I-VP shown VBN I-VP that IN B-SBAR transcripts NNS B-NP of IN B-PP the DT B-NP E2A NN I-NP gene NN I-NP can MD B-VP be VB I-VP detected VBN I-VP in IN B-PP a DT B-NP wide JJ I-NP range NN I-NP of IN B-PP cell NN B-NP types NNS I-NP . . O We PRP B-NP have VBP B-VP now RB I-VP examined VBN I-VP expression NN B-NP of IN B-PP the DT B-NP mouse NN I-NP E2A NN I-NP gene NN I-NP at IN B-PP the DT B-NP protein NN I-NP level NN I-NP using VBG B-VP polyclonal JJ B-NP antisera NNS I-NP directed VBN B-VP against IN B-PP distinct JJ B-NP portions NNS I-NP of IN B-PP the DT B-NP E2A NN I-NP protein NN I-NP to TO B-VP probe NN I-VP blots NNS B-NP of IN B-PP cellular JJ B-NP extracts NNS I-NP . . O A DT B-NP 73 CD I-NP kDa NN I-NP protein NN I-NP was VBD B-VP identified VBN I-VP by IN B-PP this DT B-NP analysis NN I-NP : : O this DT B-NP protein NN I-NP is VBZ B-VP highly RB B-ADJP enriched VBN I-ADJP in IN B-PP cell NN B-NP lines NNS I-NP of IN B-PP B NN B-NP lymphoid JJ I-NP origin NN I-NP as IN B-SBAR compared VBN B-VP to TO B-PP pancreatic JJ B-NP beta-cells NNS I-NP and CC O fibroblast NN B-NP cells NNS I-NP . . O The DT B-NP detection NN I-NP of IN B-PP this DT B-NP protein NN I-NP selectively RB B-PP in IN I-PP extracts NNS B-NP of IN B-PP lymphoid JJ B-NP cells NNS I-NP correlates VBZ B-VP with IN B-PP the DT B-NP presence NN I-NP of IN B-PP the DT B-NP E NN I-NP box-binding JJ I-NP activity NN I-NP LEF1\/BCF1 NN I-NP in IN B-PP these DT B-NP cells NNS I-NP ; : O this DT B-NP binding NN I-NP activity NN I-NP was VBD B-VP previously RB I-VP shown VBN I-VP to TO I-VP be VB I-VP efficiently RB I-VP recognized VBN I-VP by IN B-PP antiserum NN B-NP directed VBN B-VP against IN B-PP E2A NN B-NP gene NN I-NP products NNS I-NP . . O Transfection NN B-NP of IN B-PP cells NNS B-NP with IN B-PP full JJ B-NP length NN I-NP E2A NN I-NP cDNA NN I-NP leads VBZ B-VP to TO B-PP appearance NN B-NP of IN B-PP protein NN B-NP co-migrating VBG B-VP with IN B-PP the DT B-NP 73 CD I-NP kDa NN I-NP protein NN I-NP on IN B-PP SDS NN B-NP gel NN I-NP electrophoresis NN I-NP and CC O co-migrating VBG B-VP with IN B-PP LEF1\/BCF1 NN B-NP on IN B-PP mobility NN B-NP shift NN I-NP analysis NN I-NP . . O Our PRP$ B-NP results NNS I-NP are VBP B-VP consistent JJ B-ADJP with IN B-PP the DT B-NP view NN I-NP that IN B-SBAR the DT B-NP DNA-binding JJ I-NP activity NN I-NP LEF1\/BCF1 NN I-NP is VBZ B-VP a DT B-NP homodimer NN I-NP of IN B-PP E2A NN B-NP proteins NNS I-NP ; : O the DT B-NP selective JJ I-NP appearance NN I-NP of IN B-PP this DT B-NP putative JJ I-NP cell-specific JJ I-NP transcription NN I-NP factor NN I-NP in IN B-PP B NN B-NP lymphoid JJ I-NP cells NNS I-NP seems VBZ B-VP to TO I-VP be VB I-VP attributable JJ B-ADJP COMMA COMMA O at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP COMMA COMMA B-PP to TO I-PP the DT B-NP elevated JJ I-NP E2A NN I-NP protein NN I-NP concentrations NNS I-NP in IN B-PP these DT B-NP cells NNS I-NP . . O HIV-1 NN B-NP Nef NN I-NP protein NN I-NP inhibits VBZ B-VP the DT B-NP recruitment NN I-NP of IN B-PP AP-1 NN B-NP DNA-binding JJ I-NP activity NN I-NP in IN B-PP human JJ B-NP T-cells NNS I-NP . . O The DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP COMMA COMMA O HIV-1-LTR NN B-NP COMMA COMMA O contains VBZ B-VP binding VBG B-NP sites NNS I-NP for IN B-PP several JJ B-NP cellular JJ I-NP transcription NN I-NP factors NNS I-NP which WDT B-NP contribute VBP B-VP to TO B-PP HIV-1 NN B-NP gene NN I-NP expression NN I-NP . . O Our PRP$ B-NP previous JJ I-NP studies NNS I-NP on IN B-PP the DT B-NP function NN I-NP of IN B-PP the DT B-NP HIV-1-encoded JJ I-NP Nef NN I-NP protein NN I-NP suggested VBD B-VP that IN B-SBAR Nef NN B-NP may MD B-VP be VB I-VP an DT B-NP inhibitor NN I-NP HIV-1 NN I-NP transcription NN I-NP . . O To TO B-VP determine VB I-VP whether IN B-SBAR Nef NN B-NP affects VBZ B-VP the DT B-NP binding NN I-NP of IN B-PP cellular JJ B-NP factors NNS I-NP implicated VBN B-VP in IN B-PP HIV-1 NN B-NP regulation NN I-NP COMMA COMMA O 32P-labeled JJ B-NP oligonucleotides NNS I-NP corresponding VBG B-VP to TO B-PP the DT B-NP binding VBG I-NP sites NNS I-NP were VBD B-VP incubated VBN I-VP with IN B-PP nuclear JJ B-NP extracts NNS I-NP prepared VBN B-VP from IN B-PP Nef-expressing JJ B-NP T-cell NN I-NP lines NNS I-NP that WDT B-NP were VBD B-VP not RB I-VP stimulated VBN I-VP or CC O were VBD B-VP stimulated VBN I-VP with IN B-PP T-cell NN B-NP mitogens NNS I-NP . . O We PRP B-NP found VBD B-VP that IN B-SBAR Nef NN B-NP inhibited VBD B-VP the DT B-NP recruitment NN I-NP of IN B-PP AP-1 NN B-NP DNA-binding JJ I-NP activity NN I-NP in IN B-PP mitogen-stimulated JJ B-NP human JJ I-NP T-cells NNS I-NP . . O Additionally RB B-ADVP COMMA COMMA O Nef NN B-NP expressing NN I-NP cells NNS I-NP were VBD B-VP transiently RB I-VP transfected VBN I-VP with IN B-PP a DT B-NP plasmid NN I-NP in IN B-PP which WDT B-NP HIV-1 NN B-NP AP-1 NN I-NP DNA NN I-NP recognition NN I-NP sequences NNS I-NP were VBD B-VP cloned VBN I-VP downstream RB B-ADVP of IN B-PP the DT O chloramphenicol NN B-NP acetyltransferase NN I-NP ( ( O CAT NN B-NP ) ) O gene NN B-NP . . O Mitogen-mediated JJ B-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP the DT B-NP CAT NN I-NP gene NN I-NP in IN B-PP this DT B-NP construct NN I-NP was VBD B-VP inhibited VBN I-VP in IN B-PP Nef-expressing JJ B-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP control NN B-NP cells NNS I-NP . . O These DT B-NP studies NNS I-NP suggest VBP B-VP that IN B-SBAR COMMA COMMA O by IN O inhibiting VBG B-NP AP-1 NN I-NP activation NN O COMMA COMMA O Nef NN B-VP may MD I-VP play VB B-NP a DT I-NP role NN O in IN O regulating VBG B-NP HIV-1 NN I-NP gene NN I-NP expression NN O in IN B-NP infected JJ I-NP T-cells NNS O Hypertension NN B-NP in IN B-PP pregnancy NN B-NP . . O Pregnancy-induced JJ B-NP hypertension NN I-NP ( ( O PIH NN B-NP ) ) O is VBZ B-VP a DT B-NP frequent JJ I-NP cause NN I-NP of IN B-PP maternal JJ B-NP and CC I-NP neonatal JJ I-NP morbidity NN B-NP and CC O mortality NN B-NP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP we PRP B-NP focused VBD B-VP on IN B-PP the DT B-NP pathophysiology NN I-NP of IN B-PP PIH NN B-NP COMMA COMMA O mainly RB B-PP on IN I-PP the DT B-NP role NN I-NP of IN B-PP mineralocorticoids NNS B-NP COMMA COMMA O reversed VBN B-NP blood NN I-NP pressure NN I-NP patterns NNS I-NP COMMA COMMA O and CC O the DT B-NP resulting VBG I-NP necessity NN I-NP of IN B-PP continuous JJ B-NP monitoring NN I-NP of IN B-PP the DT B-NP preeclamptic JJ I-NP mother NN I-NP . . O Problems NNS B-NP of IN B-PP antihypertensive JJ B-NP therapy NN I-NP are VBP B-VP discussed VBN I-VP and CC O the DT B-NP first JJ I-NP results NNS I-NP of IN B-PP a DT B-NP pilot NN I-NP study NN I-NP with IN B-PP Urapidil NN B-NP are VBP B-VP presented VBN I-VP . . O To TO B-VP examine VB I-VP the DT B-NP role NN I-NP of IN B-PP mineralocorticoids NNS B-NP in IN B-PP the DT B-NP pathophysiology NN I-NP of IN B-PP PIH NN B-NP COMMA COMMA O we PRP B-NP studied VBD B-VP plasma NN B-NP aldosterone NN I-NP and CC O 18-hydroxy-corticosterone NN B-NP ( ( O 18-OH-B NN B-NP ) ) O levels NNS B-NP in IN B-PP 25 CD B-NP women NNS I-NP with IN B-PP PIH NN B-NP and CC B-PP in IN B-PP 25 CD B-NP healthy JJ I-NP pregnant JJ I-NP women NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP evaluated VBD B-VP the DT B-NP mineralocorticoid NN I-NP receptor NN I-NP ( ( O MR NN B-NP ) ) O count NN B-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP in IN B-PP the DT B-NP 2 CD I-NP groups NNS I-NP . . O The DT B-NP MR-count NN I-NP was VBD B-VP significantly RB I-VP decreased VBN I-VP in IN B-PP the DT B-NP PIH-group NN I-NP . . O The DT B-NP values NNS I-NP of IN B-PP plasma NN B-NP aldosterone NN I-NP and CC O 18-OH-B NN B-NP were VBD B-VP also RB B-ADVP low JJ B-ADJP . . O These DT B-NP results NNS I-NP can MD B-VP not RB I-VP be VB I-VP explained VBN I-VP by IN B-PP receptor NN B-NP down-regulation NN I-NP due JJ B-PP to TO I-PP higher JJR B-NP level NN I-NP of IN B-PP mineralocorticoids NNS B-NP of IN B-PP the DT B-NP zona NN I-NP glomerulosa NN I-NP . . O Perhaps RB B-ADVP deoxycorticosterone NN B-NP or CC O a DT B-NP hitherto RB I-NP unknown JJ I-NP mineralocorticoid NN I-NP is VBZ B-VP responsible JJ B-ADJP for IN B-PP the DT B-NP hypertension NN B-NP and CC O altered JJ B-NP MR-status NN I-NP . . O The DT B-NP first JJ I-NP results NNS I-NP of IN B-PP continuous JJ B-NP blood NN I-NP pressure NN I-NP measurements NNS I-NP with IN B-PP a DT B-NP noninvasive JJ I-NP COMMA COMMA I-NP real-time JJ I-NP blood NN I-NP pressure NN I-NP monitor NN I-NP ( ( O Finapres NN B-NP ) ) O are VBP B-VP presented VBN I-VP . . O The DT B-NP comparison NN I-NP of IN B-PP the DT B-NP obtained VBN I-NP values NNS I-NP with IN B-PP intraarterial JJ B-NP measurements NNS I-NP demonstrates VBZ B-VP a DT B-NP good JJ I-NP correlation NN I-NP between IN B-PP the DT B-NP two CD I-NP methods NNS I-NP . . O We PRP B-NP also RB B-ADVP report VBP B-VP on IN B-PP the DT B-NP first JJ I-NP experiences NNS I-NP with IN B-PP Urapidil NN B-NP in IN B-PP the DT B-NP treatment NN I-NP of IN B-PP hypertension NN B-NP in IN B-PP severe JJ B-NP preeclampsia NN I-NP . . O The DT B-NP data NNS I-NP show VBP B-VP that IN B-SBAR hypertension NN B-NP in IN B-PP preeclamptic JJ B-NP women NNS I-NP can MD B-VP be VB I-VP treated VBN I-VP by IN B-PP Urapidil NN B-NP without IN B-PP side JJ B-NP effects NNS I-NP or CC O reflex-tachycardia NN B-NP . . O Further JJ B-NP studies NNS I-NP will MD B-VP have VB I-VP to TO I-VP prove VB I-VP if IN B-SBAR Urapidil NN B-NP is VBZ B-VP suited VBN O for IN B-PP prepartal JJ B-NP treatment NN I-NP of IN B-PP PIH NN B-NP as RB B-ADJP well RB I-ADJP . . O Adenovirus NN B-NP E1A NN I-NP inhibits VBZ B-VP IFN-induced JJ B-NP resistance NN I-NP to TO B-PP cytolysis NN B-NP by IN B-PP natural JJ B-NP killer NN I-NP cells NNS I-NP . . O Infection NN B-NP of IN B-PP target NN B-NP cells NNS I-NP with IN B-PP cytopathic JJ B-NP viruses NNS I-NP inhibits VBZ B-VP IFN NN B-NP induction NN I-NP of IN B-PP cytolytic JJ B-NP resistance NN I-NP to TO B-PP NK NN B-NP cell-mediated JJ I-NP cytolysis NN I-NP { ( O IFN-mediated JJ B-NP cytoprotection NN I-NP ( ( O IFN-MCP NN B-NP ) ) O } ) O . . O It PRP B-NP has VBZ B-VP been VBN I-VP thought VBN I-VP that IN B-SBAR the DT B-NP virally RB I-NP induced VBN I-NP inhibition NN I-NP of IN B-PP IFN-MCP NN B-NP is VBZ B-VP secondary JJ B-ADJP to TO B-PP the DT B-NP shutdown NN I-NP of IN B-PP cellular JJ B-NP macromolecular JJ I-NP synthesis NN I-NP that WDT B-NP accompanies VBZ B-VP cytopathic JJ B-NP virus NN I-NP infections NNS I-NP . . O Group NN O C NN O COMMA COMMA O adenovirus NN B-NP serotype NN I-NP 5 CD I-NP ( ( O Ad5 NN B-NP ) ) O infection NN B-NP inhibits VBZ B-VP both CC O IFN-MCP NN B-NP and CC O cellular JJ B-NP protein NN I-NP synthesis NN I-NP . . O This DT B-NP study NN I-NP determined VBD B-VP if IN B-SBAR the DT B-NP Ad5-induced JJ I-NP inhibition NN I-NP of IN B-PP IFN-MCP NN B-NP was VBD B-VP independent JJ B-ADJP of IN B-PP adenovirus NN B-NP ( ( O Ad NN B-NP ) ) O infection NN B-NP and CC O secondary JJ B-ADJP only RB B-PP to TO I-PP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP Ad NN I-NP early JJ B-NP region NN I-NP 1A NN I-NP gene NN I-NP ( ( O E1A NN B-NP ) ) O . . O To TO B-VP test VB I-VP this DT B-NP hypothesis NN I-NP COMMA COMMA O 4-h JJ B-NP NK NN I-NP cytolysis NN I-NP assays NNS I-NP were VBD B-VP performed VBN I-VP on IN B-PP IFN-gamma-treated JJ B-NP human JJ I-NP cells NNS I-NP infected VBN B-ADJP with IN B-PP an DT B-NP Ad5 NN I-NP E1A NN I-NP deletion NN I-NP mutant NN I-NP COMMA COMMA O dl343 NN B-NP COMMA COMMA O or CC O transfected VBN B-ADJP with IN B-PP the DT B-NP Ad5 NN I-NP E1A NN I-NP gene NN I-NP . . O IFN-MCP NN B-NP was VBD B-VP not RB I-VP inhibited VBN I-VP by IN B-PP infection NN B-NP with IN B-PP dl343 NN B-NP COMMA COMMA O despite IN B-PP the DT B-NP production NN I-NP of IN B-PP large JJ B-NP amounts NNS I-NP of IN B-PP both CC O early JJ B-NP ( ( O E1B NN B-NP COMMA COMMA O p55 NN B-NP ) ) O and CC O late JJ B-NP ( ( O hexon NN B-NP ) ) O Ad NN B-NP proteins NNS I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP E1A-negative JJ B-NP COMMA COMMA I-NP parental JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O IFN-MCP NN B-NP was VBD B-VP blocked VBN I-VP in IN B-PP Ad5 NN B-NP E1A-transfected JJ I-NP epithelial JJ I-NP and CC I-NP fibroblastic JJ I-NP cell NN I-NP lines NNS I-NP . . O Genetic JJ B-NP mapping NN I-NP studies NNS I-NP within IN B-PP the DT B-NP E1A NN I-NP gene NN I-NP demonstrated VBD B-VP that IN B-SBAR expression NN B-NP of IN B-PP only RB B-NP the DT I-NP first JJ I-NP exon NN I-NP of IN B-PP E1A NN B-NP was VBD B-VP sufficient JJ B-ADJP to TO B-VP inhibit VB I-VP IFN-MCP NN B-NP . . O DNA NN B-NP sequence NN I-NP homology NN I-NP of IN B-PP E1A NN B-NP genes NNS I-NP between IN B-PP different JJ B-NP Ad NN I-NP groups NNS I-NP ( ( O group NN B-NP A NN I-NP COMMA COMMA O Ad12 NN B-NP ; : O group NN B-NP C NN I-NP COMMA COMMA O Ad5 NN B-NP ) ) O is VBZ B-VP limited VBN I-VP almost RB B-ADVP entirely RB I-ADVP to TO B-PP three CD B-NP conserved VBN I-NP regions NNS I-NP located JJ B-ADJP within IN B-PP the DT B-NP first JJ I-NP exon NN I-NP of IN B-PP E1A NN B-NP . . O Because IN B-SBAR IFN-MCP NN B-NP was VBD B-VP also RB I-VP blocked VBN I-VP in IN B-PP Ad12 NN B-NP E1A-transfected JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O expression NN B-NP of IN B-PP one CD B-NP or CC I-NP more JJR I-NP of IN B-PP the DT B-NP E1A-conserved JJ I-NP regions NNS I-NP may MD B-VP be VB I-VP necessary JJ B-ADJP to TO B-VP inhibit VB I-VP IFN-MCP NN B-NP . . O In IN B-PP summary NN B-NP COMMA COMMA O the DT B-NP expression NN I-NP of IN B-PP E1A NN B-NP gene NN I-NP products NNS I-NP inhibited VBD B-VP IFN-MCP NN B-NP independently RB B-ADVP of IN B-PP virus NN B-NP infection NN I-NP . . O E1A NN B-NP 's POS B-NP inhibition NN O of IN B-NP IFN-MCP NN B-VP has VBZ B-NP the DT I-NP net JJ I-NP effect NN O of IN O promoting VBG B-NP the DT I-NP selective JJ I-NP NK NN I-NP cell-mediated JJ I-NP clearance NN O of IN B-NP Ad-infected JJ I-NP or CC I-NP Ad-transformed JJ I-NP human JJ I-NP cells NNS O A DT B-NP chimeric JJ I-NP type NN I-NP II CD I-NP \/ : I-NP type NN I-NP I CD I-NP interleukin-1 NN I-NP receptor NN I-NP can MD B-VP mediate VB I-VP interleukin-1 NN B-NP induction NN I-NP of IN B-PP gene NN B-NP expression NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O The DT B-NP type NN I-NP I CD I-NP interleukin-1 NN B-NP receptor NN I-NP ( ( O IL-1R NN B-NP ) ) O is VBZ B-VP capable JJ B-ADJP of IN B-PP transducing VBG B-VP a DT B-NP signal NN I-NP resulting VBG B-VP in IN B-PP promoter NN B-NP activation NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O This DT B-NP signal NN I-NP transduction NN I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP cytoplasmic JJ I-NP domain NN I-NP COMMA COMMA O which WDT B-NP consists VBZ B-VP of IN B-PP 213 CD B-NP amino NN I-NP acids NNS I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP the DT B-NP type NN I-NP I CD I-NP receptor NN I-NP COMMA COMMA O the DT B-NP type NN I-NP II CD I-NP IL-1R NN I-NP has VBZ B-VP a DT B-NP small JJ I-NP cytoplasmic JJ I-NP tail NN I-NP COMMA COMMA O and CC O it PRP B-NP is VBZ B-VP not RB O clear JJ B-ADJP whether IN B-SBAR this DT B-NP receptor NN I-NP is VBZ B-VP a DT B-NP signal-transducing JJ I-NP or CC O a DT B-NP regulatory JJ I-NP molecule NN B-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR the DT B-NP type NN I-NP II CD I-NP IL-1R NN I-NP does VBZ B-VP not RB I-VP mediate VB I-VP gene NN B-NP activation NN I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP . . O However RB B-ADVP COMMA COMMA O a DT B-NP hybrid NN I-NP receptor NN I-NP composed VBN B-VP of IN B-PP the DT B-NP extracellular JJ I-NP and CC I-NP transmembrane NN I-NP regions NNS I-NP of IN B-PP the DT B-NP human JJ I-NP type NN I-NP II CD I-NP interleukin-1 NN I-NP fused VBN B-VP to TO B-PP the DT B-NP cytoplasmic JJ I-NP domain NN I-NP of IN B-PP the DT B-NP human JJ I-NP type NN I-NP I CD I-NP IL-1R NN I-NP was VBD B-VP capable JJ B-ADJP of IN B-PP transducing VBG B-VP a DT B-NP signal NN I-NP across IN B-PP the DT B-NP membrane NN I-NP resulting VBG B-VP in IN B-PP a DT B-NP pattern NN I-NP of IN B-PP gene NN B-NP activation NN I-NP identical JJ B-ADJP to TO B-PP that DT B-NP mediated VBN B-VP by IN B-PP the DT B-NP type NN I-NP I CD I-NP IL-1R NN I-NP . . O Our PRP$ B-NP results NNS I-NP indicated VBD B-VP that IN B-SBAR the DT B-NP extracellular JJ I-NP domain NN I-NP of IN B-PP the DT B-NP type NN I-NP II CD I-NP IL-1R NN I-NP was VBD B-VP capable JJ B-ADJP of IN B-PP functionally RB B-VP interacting VBG I-VP with IN B-PP interleukin-1 NN B-NP and CC O transmitting VBG B-VP the DT B-NP resulting VBG I-NP signal NN I-NP to TO B-PP a DT B-NP heterologous JJ I-NP cytoplasmic JJ I-NP domain NN I-NP . . O A DT B-NP mutation NN I-NP of IN B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP in IN B-PP primary JJ B-NP cortisol NN I-NP resistance NN I-NP . . O The DT B-NP precise JJ I-NP molecular JJ I-NP abnormalities NNS I-NP that WDT B-NP cause VBP B-VP primary JJ B-NP cortisol NN I-NP resistance NN I-NP have VBP B-VP not RB I-VP been VBN I-VP completely RB I-VP described VBN I-VP . . O In IN B-PP a DT B-NP subject NN I-NP with IN B-PP primary JJ B-NP cortisol NN I-NP resistance NN I-NP we PRP B-NP have VBP B-VP observed VBN I-VP glucocorticoid NN B-NP receptors NNS I-NP ( ( O hGR NN B-NP ) ) O with IN B-PP a DT B-NP decreased VBN I-NP affinity NN I-NP for IN B-PP dexamethasone NN B-NP . . O We PRP B-NP hypothesize VBP B-VP that IN B-SBAR a DT B-NP mutation NN I-NP of IN B-PP the DT B-NP hGR NN I-NP glucocorticoid-binding JJ I-NP domain NN I-NP is VBZ B-VP the DT B-NP cause NN I-NP of IN B-PP cortisol NN B-NP resistance NN I-NP . . O Total JJ B-NP RNA NN I-NP isolated VBN B-VP from IN B-PP the DT B-NP index NN I-NP subject NN I-NP 's POS B-NP mononuclear JJ I-NP leukocytes NNS I-NP was VBD B-VP used VBN I-VP to TO B-VP produce VB I-VP first JJ B-NP strand NN I-NP hGR NN I-NP cDNAs NNS I-NP COMMA COMMA O and CC O the DT B-NP entire JJ I-NP hGR NN I-NP cDNA NN I-NP was VBD B-VP amplified VBN I-VP in IN B-PP segments NNS B-NP and CC O sequenced VBN B-VP . . O At IN B-PP nucleotide NN B-NP 2COMMA317 CD I-NP we PRP B-NP identified VBD B-VP a DT B-NP homozygous JJ I-NP A NN I-NP for IN B-PP G NN B-NP point NN I-NP mutation NN I-NP that WDT B-NP predicts VBZ B-VP an DT B-NP isoleucine NN I-NP ( ( O ATT NN B-NP ) ) O for IN B-PP valine NN B-NP ( ( I-NP GTT NN I-NP ) ) I-NP substitution NN I-NP at IN B-PP amino NN B-NP acid NN I-NP 729 CD I-NP . . O When WRB B-ADVP the DT B-NP wild-type JJ I-NP hGR NN I-NP and CC O hGR-Ile NN B-NP 729 CD I-NP were VBD B-VP expressed VBN I-VP in IN B-PP COS-1 NN B-NP cells NNS I-NP and CC O assayed VBN B-VP for IN B-PP {3H}-Dexamethasone NN B-NP binding NN I-NP COMMA COMMA O the DT B-NP dissociation NN I-NP constants NNS I-NP were VBD B-VP 0.799 CD B-NP +\/- CC I-NP 0.068 CD I-NP and CC I-NP 1.54 CD I-NP +\/- CC I-NP 0.06 CD I-NP nM NN I-NP ( ( O mean NN B-NP +\/- CC O SEM NN B-NP ) ) O ( ( O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O COMMA COMMA O respectively RB B-ADVP . . O When WRB B-ADVP the DT B-NP wild-type JJ I-NP hGR NN I-NP and CC O hGR-Ile NN B-NP 729 CD I-NP were VBD B-VP expressed VBN I-VP in IN B-PP CV-1 NN B-NP cells NNS I-NP that WDT B-NP were VBD B-VP cotransfected VBN I-VP with IN B-PP the DT B-NP mouse NN I-NP mammary JJ I-NP tumor NN I-NP virus NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP fused VBN B-VP to TO B-PP the DT O chloramphenicol NN B-NP acetyl NN I-NP transferase NN I-NP ( ( O CAT NN B-NP ) ) O gene NN B-NP COMMA COMMA O the DT B-NP hGR-Ile NN I-NP 729 CD I-NP conferred VBD B-VP a DT B-NP fourfold JJ I-NP decrease NN I-NP in IN B-PP apparent JJ B-NP potency NN I-NP on IN B-PP dexamethasone NN B-NP stimulation NN I-NP of IN B-PP CAT NN B-NP activity NN I-NP . . O The DT B-NP isoleucine NN I-NP for IN B-PP valine NN B-NP substitution NN I-NP at IN B-PP amino NN B-NP acid NN I-NP 729 CD I-NP impairs VBZ B-VP the DT B-NP function NN I-NP of IN B-PP the DT B-NP hGR NN I-NP and CC O is VBZ B-VP the DT B-NP likely JJ I-NP cause NN I-NP of IN B-PP primary JJ B-NP cortisol NN I-NP resistance NN I-NP in IN B-PP this DT B-NP subject NN I-NP . . O Mice NNS B-NP deficient NN B-ADJP for IN B-PP the DT B-NP 55 CD I-NP kd JJ I-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP receptor NN I-NP are VBP B-VP resistant JJ B-ADJP to TO B-PP endotoxic JJ B-NP shock NN I-NP COMMA COMMA O yet RB O succumb VBP B-VP to TO B-PP L. FW B-NP monocytogenes NNS I-NP infection NN I-NP . . O The DT B-NP multiple JJ I-NP biological JJ I-NP activities NNS I-NP of IN B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP ( ( O TNF NN B-NP ) ) O are VBP B-VP mediated VBN I-VP by IN B-PP two CD B-NP distinct JJ I-NP cell NN I-NP surface NN I-NP receptors NNS I-NP of IN B-PP 55 CD B-NP kd NNS I-NP ( ( O TNFRp55 NN B-NP ) ) O and CC O 75 CD B-NP kd NN I-NP ( ( O TNFRp75 NN B-NP ) ) O . . O Using VBG B-VP gene NN B-NP targeting NN I-NP COMMA COMMA O we PRP B-NP generated VBD B-VP a DT B-NP TNFRp55-deficient JJ I-NP mouse NN I-NP strain NN I-NP . . O Cells NNS B-NP from IN B-PP TNFRp55-\/-mutant JJ B-NP mice NNS I-NP lack VBP B-VP expression NN B-NP of IN B-PP TNFRp55 NN B-NP but CC O display VBP B-VP normal JJ B-NP numbers NNS I-NP of IN B-PP high JJ B-NP affinity NN I-NP TNFRp75 NN I-NP molecules NNS I-NP . . O Thymocyte NN B-NP development NN I-NP and CC O lymphocyte NN B-NP populations NNS I-NP are VBP B-VP unaltered JJ B-ADJP COMMA COMMA O and CC O clonal JJ B-NP deletion NN I-NP of IN B-PP potentially RB B-NP self-reactive JJ I-NP T NN I-NP cells NNS I-NP is VBZ B-VP not RB O impaired JJ B-ADJP . . O However RB B-ADVP COMMA COMMA O TNF NN B-NP signaling NN I-NP is VBZ B-VP largely RB I-VP abolished VBN I-VP COMMA COMMA O as IN B-SBAR judged VBN B-VP by IN B-PP the DT B-NP failure NN I-NP of IN B-PP TNF NN B-NP to TO B-VP induce VB I-VP NF-kappa NN B-NP B NN I-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP from IN B-PP TNFRp55-deficient JJ B-NP mice NNS I-NP . . O The DT B-NP loss NN I-NP of IN B-PP TNFRp55 NN B-NP function NN I-NP renders VBZ B-VP mice NNS B-NP resistant JJ B-ADJP to TO B-PP lethal JJ B-NP dosages NNS I-NP of IN B-PP either CC O lipopolysaccharides NNS B-NP or CC O S. FW B-NP aureus FW I-NP enterotoxin NN I-NP B NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O TNFRp55-deficient JJ B-NP mice NNS I-NP are VBP B-VP severely RB B-ADJP impaired JJ I-ADJP to TO B-VP clear VB I-VP L. FW B-NP monocytogenes FW I-NP and CC O readily RB B-VP succumb VBP I-VP to TO B-PP infection NN B-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP 55 CD I-NP kd NN I-NP TNFR NN I-NP plays VBZ B-VP a DT B-NP decisive JJ I-NP role NN I-NP in IN B-PP the DT B-NP host NN I-NP 's POS B-NP defense NN O against IN B-NP microorganisms NNS B-NP and CC B-NP their PRP$ I-NP pathogenic JJ I-NP factors NNS O Cloning NN B-NP and CC O functional JJ B-NP characterization NN I-NP of IN B-PP early JJ B-NP B-cell NN I-NP factor NN I-NP COMMA COMMA O a DT B-NP regulator NN I-NP of IN B-PP lymphocyte-specific JJ B-NP gene NN I-NP expression NN I-NP . . O Early JJ B-NP B-cell NN I-NP factor NN I-NP ( ( O EBF NN B-NP ) ) O was VBD B-VP identified VBN I-VP previously RB B-ADVP as IN B-PP a DT B-NP tissue-specific JJ I-NP and CC I-NP differentiation NN I-NP stage-specific JJ I-NP DNA-binding JJ I-NP protein NN I-NP that WDT B-NP participates VBZ B-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT O pre-B JJ B-NP and CC O B NN B-NP lymphocyte-specific JJ B-NP mb-1 NN I-NP gene NN I-NP . . O Partial JJ B-NP amino NN I-NP acid NN I-NP sequences NNS I-NP obtained VBN B-VP from IN B-PP purified VBN B-NP EBF NN I-NP were VBD B-VP used VBN I-VP to TO B-VP isolate VB I-VP cDNA NN B-NP clones NNS I-NP COMMA COMMA O which WDT B-NP by IN B-PP multiple JJ B-NP criteria NNS I-NP encode VB B-VP EBF NN B-NP . . O The DT B-NP recombinant JJ I-NP polypeptide NN I-NP formed VBD B-VP sequence-specific JJ B-NP complexes NNS I-NP with IN B-PP the DT B-NP EBF-binding NN I-NP site NN I-NP in IN B-PP the DT B-NP mb-1 NN I-NP promoter NN I-NP . . O The DT B-NP cDNA NN I-NP hybridized VBD B-VP to TO B-PP multiple JJ B-NP transcripts NNS I-NP in IN B-PP pre-B JJ B-NP and CC O B-cell NN B-NP lines NNS B-NP COMMA COMMA O but CC O transcripts NNS B-NP were VBD B-VP not RB I-VP detected VBN I-VP at IN B-PP significant JJ B-NP levels NNS I-NP in IN B-PP plasmacytoma NN B-NP COMMA COMMA O T-cell NN B-NP COMMA COMMA O and CC O nonlymphoid JJ B-ADJP cell NN B-NP lines NNS I-NP . . O Expression NN B-NP of IN B-PP recombinant JJ B-NP EBF NN I-NP in IN B-PP transfected VBN B-NP nonlymphoid JJ I-NP cells NNS I-NP strongly RB B-ADVP activated VBD B-VP transcription NN B-NP from IN B-PP reporter NN B-NP plasmids NNS I-NP containing VBG B-VP functional JJ B-NP EBF-binding JJ I-NP sites NNS I-NP . . O Analysis NN B-NP of IN B-PP DNA NN B-NP binding NN I-NP by IN B-PP deletion NN B-NP mutants NNS I-NP of IN B-PP EBF NN B-NP identified VBD B-VP an DT B-NP amino-terminal JJ I-NP cysteine-rich JJ I-NP DNA-binding JJ I-NP domain NN I-NP lacking VBG B-VP obvious JJ B-NP sequence NN I-NP similarity NN I-NP to TO B-PP known JJ B-NP transcription NN I-NP factors NNS I-NP . . O DNA-binding JJ B-NP assays NNS I-NP with IN B-PP cotranslated VBN B-NP wild-type JJ I-NP and CC O truncated JJ B-NP forms NNS B-NP of IN B-PP EBF NN B-NP indicated VBD B-VP that IN B-SBAR the DT B-NP protein NN I-NP interacts VBZ B-VP with IN B-PP its PRP$ B-NP site NN I-NP as IN B-PP a DT B-NP homodimer NN I-NP . . O Deletions NNS B-NP delineated VBD B-VP a DT B-NP carboxy-terminal JJ I-NP dimerization NN I-NP region NN I-NP containing VBG B-VP two CD B-NP repeats NNS I-NP of IN B-PP 15 CD B-NP amino NN I-NP acids NNS I-NP that WDT B-NP show VBP B-VP similarity NN B-NP with IN B-PP the DT B-NP dimerization NN I-NP domains NNS I-NP of IN B-PP basic-helix-loop-helix JJ B-NP proteins NNS I-NP . . O Together RB B-ADVP COMMA COMMA O these DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR EBF NN B-NP represents VBZ B-VP a DT B-NP novel JJ I-NP regulator NN I-NP of IN B-PP B NN B-NP lymphocyte-specific JJ I-NP gene NN I-NP expression NN I-NP . . O { ( O The DT B-NP trend NN I-NP of IN B-PP molecular JJ B-NP biology NN I-NP study NN I-NP on IN B-PP eosinophils NNS B-NP } ) O Recently RB B-ADVP COMMA COMMA O many JJ B-NP investigators NNS I-NP have VBP B-VP been VBN I-VP interested JJ B-ADJP in IN B-PP the DT B-NP study NN I-NP on IN B-PP eosinophil NN B-NP biology NN I-NP since IN B-SBAR genes NNS B-NP association NN I-NP with IN B-PP eosinophils NNS B-NP such JJ B-PP as IN I-PP interleukin-5 NN B-NP or CC O eosinophil NN B-NP granule NN I-NP proteins NNS I-NP ( ( O EPO NN B-NP COMMA COMMA O ECP NN B-NP COMMA COMMA O EDN NN B-NP COMMA COMMA O MBP NN B-NP COMMA COMMA O and CC O CLC NN B-NP ) ) O COMMA COMMA O were VBD B-VP isolated VBN I-VP . . O However RB B-ADVP COMMA COMMA O the DT B-NP molecular JJ I-NP basis NN I-NP for IN B-PP the DT B-NP commitment NN I-NP of IN B-PP progenitors NNS B-NP to TO B-PP the DT B-NP eosinophil NN I-NP lineage NN I-NP has VBZ B-VP not RB I-VP been VBN I-VP determined VBN I-VP . . O The DT B-NP mechanism NN I-NP by IN B-PP which WDT B-NP eosinophil-specific JJ B-NP genes NNS I-NP encoding VBG B-VP primary JJ B-NP and CC I-NP secondary JJ I-NP granule NN I-NP proteins NNS I-NP ( ( O e.g. FW B-ADVP ECP NN B-NP COMMA COMMA O EDN NN B-NP COMMA COMMA O EPO NN B-NP COMMA COMMA O MBP NN B-NP COMMA COMMA O and CC O CLC NN B-NP ) ) O are VBP B-VP expressed VBN I-VP and CC O regulated VBN B-VP during IN B-PP eosinophilopoiesis NN B-NP is VBZ B-VP also RB B-ADVP unknown JJ B-ADJP . . O In IN B-PP this DT B-NP paper NN I-NP COMMA COMMA O I PRP B-NP described VBD B-VP the DT B-NP characterization NN I-NP of IN B-PP genes NNS B-NP encoding VBG B-VP eosinophil NN B-NP granule NN I-NP proteins NNS I-NP and CC O the DT B-NP mRNA NN I-NP expression NN I-NP of IN B-PP GATA-1 NN B-NP binding NN I-NP transcription NN I-NP factor NN I-NP during IN B-PP eosinophil NN B-NP differentiation NN I-NP . . O Regulation NN B-NP of IN B-PP the DT B-NP Ets-related JJ I-NP transcription NN I-NP factor NN I-NP Elf-1 NN I-NP by IN B-PP binding VBG B-VP to TO B-PP the DT B-NP retinoblastoma NN I-NP protein NN I-NP . . O The DT B-NP retinoblastoma NN I-NP gene NN I-NP product NN I-NP ( ( O Rb NN B-NP ) ) O is VBZ B-VP a DT B-NP nuclear JJ I-NP phosphoprotein NN I-NP that WDT B-NP regulates VBZ B-VP cell NN B-NP cycle NN I-NP progression NN I-NP . . O Elf-1 NN B-NP is VBZ B-VP a DT B-NP lymphoid-specific JJ I-NP Ets NN I-NP transcription NN I-NP factor NN I-NP that WDT B-NP regulates VBZ B-VP inducible JJ B-NP gene NN I-NP expression NN I-NP during IN B-PP T NN B-NP cell NN I-NP activation NN I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O it PRP B-NP is VBZ B-VP demonstrated VBN I-VP that IN B-SBAR Elf-1 NN B-NP contains VBZ B-VP a DT B-NP sequence NN I-NP motif NN I-NP that WDT B-NP is VBZ B-VP highly RB B-ADJP related JJ I-ADJP to TO B-PP the DT B-NP Rb NN I-NP binding NN I-NP sites NNS I-NP of IN B-PP several JJ B-NP viral JJ I-NP oncoproteins NNS I-NP and CC O binds VBZ B-VP to TO B-PP the DT B-NP pocket NN I-NP region NN I-NP of IN B-PP Rb NN B-NP both CC O in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP . . O Elf-1 NN B-NP binds VBZ B-VP exclusively RB B-ADVP to TO B-PP the DT B-NP underphosphorylated JJ I-NP form NN I-NP of IN B-PP Rb NN B-NP and CC O fails VBZ B-VP to TO I-VP bind VB I-VP to TO B-PP Rb NN B-NP mutants NNS I-NP derived VBN B-VP from IN B-PP patients NNS B-NP with IN B-PP retinoblastoma NN B-NP . . O Co-immunoprecipitation NN B-NP experiments NNS I-NP demonstrated VBD B-VP an DT B-NP association NN I-NP between IN B-PP Elf-1 NN B-NP and CC O Rb NN B-NP in IN B-PP resting VBG B-NP normal JJ I-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O After IN B-PP T NN B-NP cell NN I-NP activation NN I-NP COMMA COMMA O the DT B-NP phosphorylation NN I-NP of IN B-PP Rb NN B-NP results VBZ B-VP in IN B-PP the DT B-NP release NN I-NP of IN B-PP Elf-1 NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP correlated VBN I-VP temporally RB B-ADVP with IN B-PP the DT B-NP activation NN I-NP of IN B-PP Elf-1-mediated JJ B-NP transcription NN I-NP . . O Overexpression NN B-NP of IN B-PP a DT B-NP phosphorylation-defective JJ I-NP form NN I-NP of IN B-PP Rb NN B-NP inhibited VBD B-VP Elf-1-dependent JJ B-NP transcription NN I-NP during IN B-PP T NN B-NP cell NN I-NP activation NN I-NP . . O These DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR Rb NN B-NP interacts VBZ B-VP specifically RB B-ADVP with IN B-PP a DT B-NP lineage-restricted JJ I-NP Ets NN I-NP transcription NN I-NP factor NN I-NP . . O This DT B-NP regulated JJ I-NP interaction NN I-NP may MD B-VP be VB I-VP important JJ B-ADJP for IN B-PP the DT B-NP coordination NN I-NP of IN B-PP lineage-specific JJ B-NP effector NN I-NP functions NNS I-NP such JJ B-PP as IN I-PP lymphokine NN B-NP production NN I-NP with IN B-PP cell NN B-NP cycle NN I-NP progression NN I-NP in IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O Activation NN B-NP of IN B-PP primary JJ B-NP human JJ I-NP T-lymphocytes NNS I-NP through IN B-PP CD2 NN B-NP plus CC O CD28 NN B-NP adhesion NN B-NP molecules NNS I-NP induces VBZ B-VP long-term JJ B-NP nuclear JJ I-NP expression NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O Stimulation NN B-NP of IN B-PP highly RB B-NP purified VBN I-NP human JJ I-NP T-cells NNS I-NP via IN B-PP CD2 NN B-NP and CC O CD28 NN B-NP adhesion NN B-NP molecules NNS I-NP induces VBZ B-VP and CC O maintains VBZ B-VP proliferation NN B-NP for IN B-PP more JJR B-NP than IN I-NP 3 CD I-NP weeks NNS I-NP . . O This DT B-NP potent JJ I-NP interleukin NN I-NP 2 CD I-NP ( ( I-NP IL-2 NN I-NP ) ) I-NP -dependent JJ I-NP activation NN I-NP does VBZ B-VP not RB I-VP require VB I-VP monocytes NNS B-NP or CC O accessory JJ B-NP cells NNS I-NP . . O Long-lasting JJ B-NP IL-2 NN I-NP receptivity NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP high-level JJ B-NP expression NN I-NP of IN B-PP the DT O inducible JJ O IL-2 NN B-NP receptor NN I-NP alpha NN I-NP chain NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O gene NN B-NP that WDT B-NP is VBZ B-VP regulated VBN I-VP at IN B-PP both CC B-NP transcriptional JJ I-NP and CC I-NP posttranscriptional JJ I-NP levels NNS I-NP . . O Increase NN B-NP of IN B-PP IL-2R NN B-NP alpha NN I-NP gene NN I-NP transcription NN I-NP involves VBZ B-VP the DT B-NP enhanced VBN I-NP binding NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP to TO B-PP its PRP$ B-NP consensus NN I-NP sequence NN I-NP in IN B-PP the DT B-NP 5'-regulatory JJ I-NP region NN I-NP of IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP gene NN I-NP . . O To TO B-VP dissect VB I-VP the DT B-NP molecular JJ I-NP basis NN I-NP for IN B-PP the DT B-NP unusually RB I-NP persistent JJ I-NP transcription NN I-NP of IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP gene NN I-NP COMMA COMMA O we PRP B-NP analyzed VBD B-VP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP binding VBG I-NP to TO B-PP a DT B-NP radiolabeled VBN I-NP IL-2R NN I-NP alpha NN I-NP kappa NN I-NP B-specific JJ I-NP oligonucleotide NN I-NP probe NN I-NP during IN B-PP the DT B-NP time NN I-NP course NN I-NP of IN B-PP CD2 NN B-NP + CC O CD28 NN B-NP activation NN B-NP . . O Resting VBG B-NP T-cell NN I-NP nuclear JJ I-NP extracts NNS I-NP contained VBD B-VP KBF1\/p50 NN B-NP homodimer NN I-NP . . O After IN B-PP stimulation NN B-NP COMMA COMMA O two CD B-NP new JJ I-NP kappa NN I-NP B-specific JJ I-NP complexes NNS I-NP were VBD B-VP identified VBN I-VP as IN B-PP NF-kappa NN B-NP B NN I-NP p50-p65 NN I-NP heterodimer NN I-NP and CC O putative JJ B-NP c-Rel NN B-NP homodimer NN I-NP or CC O c-Rel-p65 NN B-NP heterodimer NN I-NP . . O Both DT B-NP inducible JJ I-NP complexes NNS I-NP persisted VBD B-VP for IN B-PP at IN B-NP least JJS I-NP 3 CD I-NP weeks NNS I-NP . . O Their PRP$ B-NP relative JJ I-NP levels NNS I-NP were VBD B-VP very RB B-ADJP similar JJ I-ADJP for IN B-PP the DT B-NP duration NN I-NP of IN B-PP proliferation NN B-NP . . O In IN B-PP parallel NN B-NP COMMA COMMA O CD2 NN B-NP + CC O CD28 NN B-NP activation NN B-NP triggered VBD B-VP a DT B-NP significant JJ I-NP intracellular JJ I-NP thiol NN I-NP decrease NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR oxygen NN B-NP radicals NNS I-NP are VBP B-VP involved VBN I-VP in IN B-PP the DT B-NP signaling NN I-NP pathway NN I-NP of IN B-PP adhesion NN B-NP molecules NNS I-NP . . O Finally RB B-ADVP COMMA COMMA O micromolar JJ B-NP amounts NNS I-NP of IN B-PP pyrrolidine NN B-NP dithiocarbamate NN I-NP COMMA COMMA O an DT B-NP oxygen NN I-NP radical NN I-NP scavenger NN I-NP that WDT B-NP efficiently RB B-ADVP blocked VBD B-VP the DT B-NP nuclear JJ I-NP appearance NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP T-lymphocytes NNS B-NP COMMA COMMA O also RB B-ADVP inhibited VBD B-VP IL-2 NN B-NP secretion NN I-NP COMMA COMMA O IL-2R NN B-NP alpha NN I-NP cell NN I-NP surface NN I-NP expression NN I-NP COMMA COMMA O and CC O T-cell NN B-NP proliferation NN I-NP . . O Together RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP plays VBZ B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP long-term JJ B-NP activation NN I-NP of IN B-PP human JJ B-NP primary JJ I-NP T-lymphocytes NNS I-NP via IN B-PP CD2 NN B-NP + CC O CD28 NN B-NP . . O Oxidoreductive JJ B-NP regulation NN I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP . . O Involvement NN B-NP of IN B-PP a DT B-NP cellular JJ I-NP reducing NN I-NP catalyst NN I-NP thioredoxin NN I-NP . . O We PRP B-NP have VBP O investigated VBN O an DT B-NP oxidoreductive JJ I-NP regulatory JJ I-NP pathway NN I-NP for IN B-PP the DT B-NP DNA NN I-NP binding NN I-NP activity NN I-NP of IN B-PP a DT B-NP pleiotropic JJ I-NP cellular JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF NN B-NP kappa NN I-NP B NN I-NP ) ) O COMMA COMMA O has VBZ B-VP been VBN I-VP investigated VBN I-VP by IN B-PP using VBG B-VP NF NN B-NP kappa NN I-NP B NN I-NP prepared VBN B-VP from IN B-PP the DT B-NP nucleus NN I-NP and CC O the DT B-NP cytosol NN I-NP of IN B-PP the DT B-NP primary JJ I-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR a DT B-NP cellular JJ I-NP reducing NN I-NP catalyst NN I-NP thioredoxin NN B-NP ( ( O Trx NN B-NP ) ) O plays VBZ B-VP a DT B-NP major JJ I-NP role NN I-NP in IN B-PP activation NN B-NP of IN B-PP the DT B-NP DNA NN I-NP binding NN I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP in FW B-ADVP vitro FW I-ADVP and CC O stimulation NN B-NP of IN B-PP transcription NN B-NP from IN B-PP the DT B-NP NF NN I-NP kappa NN I-NP B-dependent JJ I-NP gene NN I-NP expression NN I-NP . . O We PRP B-NP demonstrate VBP B-VP evidence NN B-NP suggesting VBG B-VP that IN B-SBAR redox NN B-NP regulation NN I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP by IN B-PP Trx NN B-NP might MD B-VP be VB I-VP exerted VBN I-VP at IN B-PP a DT B-NP step NN I-NP after IN B-PP dissociation NN B-NP of IN B-PP the DT B-NP inhibitory JJ I-NP molecule NN I-NP I NN I-NP kappa NN I-NP B NN I-NP COMMA COMMA O a DT B-NP cytosolic-anchoring JJ I-NP protein NN I-NP for IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP . . O To TO B-VP examine VB I-VP the DT B-NP effect NN I-NP of IN B-PP Trx NN B-NP in IN B-PP intact JJ B-NP cells NNS I-NP COMMA COMMA O we PRP B-NP performed VBD B-VP transient JJ B-NP assay NN I-NP with IN B-PP a DT B-NP chloramphenicol NN I-NP acetyltransferase-expressing JJ I-NP plasmid NN I-NP under IN B-PP the DT B-NP control NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O long JJ B-NP terminal JJ I-NP repeat NN I-NP and CC O an DT B-NP effector NN I-NP plasmid NN I-NP expressing VBG B-VP human JJ B-NP Trx NN I-NP . . O The DT B-NP promoter NN I-NP activity NN I-NP from IN B-PP HIV NN B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP was VBD B-VP greatly RB I-VP augmented VBN I-VP by IN B-PP co-transfecting VBG B-VP the DT B-NP Trx-expressing NN I-NP plasmid NN I-NP COMMA COMMA O whose WP$ B-NP effect NN I-NP was VBD B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP NF NN I-NP kappa NN I-NP B-binding NN I-NP sites NNS I-NP . . O These DT B-NP findings NNS I-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR cysteine NN B-NP residue NN I-NP ( ( I-NP s NNS I-NP ) ) O of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP might MD B-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP DNA-recognition NN I-NP by IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP and CC O that IN B-SBAR the DT B-NP redox NN I-NP control NN I-NP mechanism NN I-NP mediated VBN B-VP by IN B-PP Trx NN B-NP might MD B-VP have VB I-VP a DT B-NP regulatory JJ I-NP role NN I-NP in IN B-PP the DT B-NP NF NN I-NP kappa NN I-NP B-mediated JJ I-NP gene NN I-NP expression NN I-NP . . O These DT B-NP results NNS I-NP may MD B-VP also RB I-VP provide VB I-VP a DT B-NP clue NN I-NP to TO B-PP understanding NN B-NP of IN B-PP the DT B-NP molecular JJ I-NP process NN I-NP of IN B-PP AIDS NN B-NP pathogenesis NN I-NP and CC O its PRP$ B-NP possible JJ I-NP biochemical JJ I-NP intervention NN I-NP . . O Expression NN B-NP levels NNS I-NP of IN B-PP the DT B-NP thyrotropin NN I-NP receptor NN I-NP gene NN I-NP in IN B-PP autoimmune JJ B-NP thyroid NN I-NP disease NN I-NP : : O coregulation NN B-NP with IN B-PP parameters NNS B-NP of IN B-PP thyroid NN B-NP function NN I-NP and CC O inverse JJ B-NP relation NN I-NP to TO B-PP major JJ B-NP histocompatibility NN I-NP complex NN I-NP classes NNS I-NP I CD B-NP and CC O II CD B-NP . . O Using VBG B-VP a DT O human JJ O TSH NN B-NP receptor NN I-NP ( ( O TSH-R NN B-NP ) ) O cDNA NN B-NP probe NN I-NP COMMA COMMA O we PRP B-NP investigated VBD B-VP TSH-R NN B-NP transcript NN I-NP levels NNS I-NP in IN B-PP 13 CD B-NP human JJ I-NP thyroid NN I-NP fragments NNS I-NP by IN B-PP Northern NN B-NP blot NN I-NP analysis NN I-NP ; : O 7 CD O Graves NN B-NP ' POS B-NP disease NN I-NP COMMA COMMA O 2 CD O Hashimoto NN B-NP 's POS B-NP disease NN I-NP COMMA COMMA O 3 CD B-NP endemic JJ I-NP goiter NN I-NP COMMA COMMA O and CC O 1 CD B-NP healthy JJ I-NP thyroid NN I-NP gland NN I-NP were VBD B-VP studied VBN I-VP . . O TSH-R NN B-NP expression NN I-NP levels NNS I-NP were VBD B-VP variable JJ B-ADJP COMMA COMMA O but CC O displayed VBD B-VP a DT B-NP close JJ I-NP correlation NN I-NP to TO B-PP the DT B-NP expression NN I-NP of IN B-PP thyroid NN B-NP peroxidase NN I-NP ( ( O r NN B-NP = JJ B-VP 0.703 CD B-NP ; : O P NN B-NP < JJR B-NP 0.05 CD I-NP ) ) O COMMA COMMA O thyroglobulin NN B-NP ( ( O r NN B-NP = JJ B-VP 0.817 CD B-NP ; : O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O COMMA COMMA O and CC O the DT B-NP nuclear JJ I-NP oncogene NN I-NP c-fos NN I-NP ( ( O r NN B-NP = JJ B-VP 0.935 CD B-NP ; : O P NN B-NP < JJR B-NP 0.001 CD I-NP ) ) O COMMA COMMA O but CC B-CONJP not RB I-CONJP c-myc NN B-NP . . O Overall RB B-ADVP COMMA COMMA O TSH-R NN B-NP transcript NN I-NP levels NNS I-NP were VBD B-VP low JJ B-ADJP or CC O absent JJ B-ADJP in IN B-PP those DT B-NP thyroids NNS I-NP in IN B-PP which WDT B-NP expression NN B-NP of IN B-PP the DT B-NP major JJ I-NP histocompatibility NN I-NP complex NN I-NP class NN I-NP I CD B-NP or CC O II CD B-NP ( ( O MHC NN B-NP I CD B-NP or CC O II CD B-NP ) ) O was VBD B-VP high JJ B-ADJP COMMA COMMA O thus RB B-ADVP establishing VBG B-VP an DT B-NP inverse JJ I-NP relation NN I-NP ( ( O MHC NN O I NN O COMMA COMMA O r NN B-NP = JJ B-VP -0.791 CD B-NP ; : O P NN B-NP < JJR B-NP 0.01 CD I-NP ; : O MHC NN O II CD O COMMA COMMA O r NN B-NP = JJ B-VP -0.784 NN B-NP ; : O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O . . O In FW B-NP situ FW I-NP hybridization NN I-NP showed VBD B-VP that IN B-SBAR apart RB B-PP from IN I-PP lymphocytes NNS B-NP COMMA COMMA O thyroid NN B-NP cells NNS I-NP themselves PRP B-NP were VBD B-VP the DT B-NP source NN I-NP of IN B-PP MHC NN B-NP II CD I-NP transcripts NNS I-NP . . O gamma-Interferon NN B-NP expression NN I-NP was VBD B-VP only RB B-ADJP detectable JJ I-ADJP in IN B-PP 1 CD O Hashimoto NN B-NP 's POS B-NP goiter NN I-NP . . O Our PRP$ B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR next JJ B-ADVP to TO B-PP lymphocyte NN B-NP infiltration NN I-NP COMMA COMMA O active JJ B-NP regulatory JJ I-NP events NNS I-NP in IN B-PP the DT B-NP thyrocyte NN I-NP are VBP B-VP responsible JJ B-ADJP for IN B-PP the DT B-NP inverse JJ I-NP relation NN I-NP between IN B-PP functional JJ B-NP parameters NNS I-NP ( ( O TSH-R NN B-NP COMMA COMMA O thyroid NN B-NP peroxidase NN I-NP COMMA COMMA O thyroglobulin NN B-NP COMMA COMMA O and CC O c-fos NN B-NP ) ) O and CC O immunological JJ B-NP markers NNS I-NP ( ( O MHC NN B-NP I CD B-NP and CC O II CD B-NP ) ) O . . O Regulation NN B-NP of IN B-PP the DT O interleukin-1 NN B-NP beta NN I-NP ( ( O IL-1 NN B-NP beta NN I-NP ) ) O gene NN B-NP by IN B-PP mycobacterial JJ B-NP components NNS I-NP and CC O lipopolysaccharide NN B-NP is VBZ B-VP mediated VBN I-VP by IN B-PP two CD B-NP nuclear JJ I-NP factor-IL6 JJ I-NP motifs NNS I-NP . . O The DT B-NP cytokines NNS I-NP interleukin-1 NN B-NP beta NN I-NP ( ( O IL-1 NN B-NP beta NN I-NP ) ) O and CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O are VBP B-VP released VBN I-VP by IN B-PP mononuclear JJ B-NP phagocytes NNS I-NP in FW B-ADVP vitro FW I-ADVP after IN B-PP stimulation NN B-NP with IN B-PP mycobacteria NNS B-NP and CC O are VBP B-VP considered VBN I-VP to TO I-VP mediate VB I-VP pathophysiologic JJ B-NP events NNS I-NP COMMA COMMA O including VBG B-PP granuloma NN B-NP formation NN I-NP and CC O systemic JJ B-NP symptoms NNS I-NP . . O We PRP B-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP Mycobacterium NN I-NP tuberculosis NN I-NP cell NN I-NP wall NN I-NP component NN I-NP lipoarabinomannan NN B-NP ( ( O LAM NN B-NP ) ) O is VBZ B-VP a DT B-NP very RB I-NP potent JJ I-NP inducer NN I-NP of IN B-PP IL-1 NN B-NP beta NN I-NP gene NN I-NP expression NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP and CC O investigated VBD B-VP the DT B-NP mechanism NN I-NP of IN B-PP this DT B-NP effect NN I-NP . . O We PRP B-NP localized VBD B-VP the DT O LAM- NN B-NP COMMA COMMA O lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O - : O COMMA COMMA O and CC O TNF-alpha-inducible JJ B-ADJP promoter NN B-NP activity NN I-NP to TO B-PP a DT O -131\/+15 CD O ( ( O positions NNS B-NP -131 CD B-NP to TO O +15 CD B-NP ) ) O DNA NN B-NP fragment NN I-NP of IN B-PP the DT B-NP IL-1 NN I-NP beta NN I-NP gene NN I-NP by IN B-PP deletion NN B-NP analysis NN I-NP and CC O chloramphenicol NN B-NP acetyltransferase NN I-NP assay NN I-NP . . O Within IN B-PP this DT B-NP DNA NN I-NP fragment NN I-NP COMMA COMMA O there EX B-NP were VBD B-VP two CD B-NP novel JJ I-NP 9-bp JJ I-NP motifs NNS I-NP ( ( O -90\/-82 CD B-NP and CC O -40\/-32 CD B-NP ) ) O with IN B-PP high JJ B-NP homology NN I-NP to TO B-PP the DT O nuclear JJ B-NP factor-IL6 NN I-NP ( ( O NF-IL6 NN B-NP ) ) O binding NN B-NP site NN I-NP . . O Site-directed JJ B-NP mutagenesis NN I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP two CD I-NP NF-IL-6 NN I-NP motifs NNS I-NP could MD B-VP be VB I-VP independently RB I-VP activated VBN I-VP by IN B-PP LAM NN B-NP COMMA COMMA O LPS NN B-NP COMMA COMMA O or CC O TNF-alpha NN B-NP and CC O that IN B-SBAR they PRP B-NP acted VBD B-VP in IN B-PP an DT B-NP orientation-independent JJ I-NP manner NN I-NP . . O DNA NN B-NP mobility NN I-NP shift NN I-NP assay NN I-NP revealed VBD B-VP specific JJ B-NP binding NN I-NP of IN B-PP nuclear JJ B-NP protein NN I-NP ( ( I-NP s NNS I-NP ) ) O from IN B-PP LAM- NN B-NP COMMA COMMA I-NP LPS- NN I-NP COMMA COMMA I-NP or CC I-NP TNF-alpha- NN I-NP stimulated JJ I-NP THP-1 NN I-NP cells NNS I-NP to TO B-PP the DT B-NP NF-IL6 NN I-NP motifs NNS I-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR the DT B-NP two CD I-NP NF-IL6 NN I-NP sites NNS I-NP mediate VBP B-VP induction NN B-NP of IN B-PP IL-1 NN B-NP beta NN I-NP in IN B-PP response NN I-PP to TO I-PP the DT B-NP stimuli NNS I-NP LAM NN B-NP COMMA COMMA O LPS NN B-NP COMMA COMMA O and CC O TNF-alpha NN B-NP . . O Synergism NN B-NP between IN B-PP the DT O CD3 NN B-NP antigen- NN I-NP and CC O CD2 NN B-ADJP antigen-derived JJ I-ADJP signals NNS B-NP . . O Exploration NN B-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP induction NN B-NP of IN B-PP DNA-binding JJ B-NP proteins NNS I-NP and CC O characterization NN B-NP of IN B-PP the DT B-NP inhibitory JJ I-NP activity NN I-NP of IN B-PP cyclosporine NN B-NP . . O We PRP B-NP have VBP B-VP demonstrated VBN I-VP earlier RBR B-ADVP that IN B-SBAR the DT B-NP crosslinkage NN I-NP of IN B-PP the DT B-NP CD3\/TCR NN I-NP complex NN I-NP with IN B-PP the DT B-NP CD2 NN I-NP antigen NN I-NP results VBZ B-VP in IN B-PP the DT B-NP proliferation NN I-NP of IN B-PP normal JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O The DT B-NP effect NN I-NP of IN B-PP this DT B-NP synergism NN I-NP was VBD B-VP perceptible JJ B-ADJP at IN B-PP the DT B-NP level NN I-NP of IN B-PP induction NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP COMMA COMMA O a DT B-NP process NN I-NP critical JJ B-ADJP for IN B-PP T NN B-NP cell NN I-NP growth NN I-NP . . O To TO B-VP further RB I-VP understand VB I-VP the DT B-NP molecular JJ I-NP and CC I-NP nuclear JJ I-NP basis NN I-NP for IN B-PP this DT B-NP synergism NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP explored VBN I-VP the DT B-NP induction NN I-NP of IN B-PP DNA-binding JJ B-NP proteins NNS I-NP in IN B-PP highly RB B-NP purified VBN I-NP normal JJ I-NP human JJ I-NP T NN I-NP cells NNS I-NP signaled VBN B-VP via IN B-PP the DT O CD3 NN B-NP and\/or CC O CD2 NN B-NP proteins NNS B-NP . . O The DT B-NP effect NN I-NP of IN B-PP transmembrane NN B-NP signaling NN I-NP of IN B-PP T NN B-NP cells NNS I-NP with IN B-PP ionomycin NN B-NP COMMA COMMA O and\/or CC O sn-1COMMA2 NN B-NP dioctanoyl NN I-NP glycerol NN I-NP COMMA COMMA O was VBD B-VP also RB I-VP determined VBN I-VP . . O The DT B-NP emergence NN I-NP of IN B-PP nuclear JJ B-NP binding NN I-NP proteins NNS I-NP was VBD B-VP investigated VBN I-VP using VBG B-VP interleukin-2 NN B-NP sequence NN I-NP specific JJ I-NP oligonucleotide NN I-NP probes NNS I-NP in IN B-PP the DT B-NP electrophoretic JJ I-NP mobility NN I-NP shift NN I-NP assay NN I-NP . . O Our PRP$ B-NP studies NNS I-NP demonstrate VBP B-VP for IN B-PP the DT B-NP first JJ I-NP time NN I-NP that IN B-SBAR CD3 NN B-NP antigen-derived JJ I-NP signals NNS I-NP and CC O CD2 NN B-NP antigen-derived JJ I-NP signals NNS I-NP are VBP B-VP synergistic JJ B-ADJP in IN B-PP inducing VBG B-VP the DT B-NP emergence NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT O NF-AT1 NN B-NP COMMA COMMA O AP-1 NN B-NP COMMA COMMA O and CC O NF-kB NN B-NP sites NNS B-NP located JJ B-ADJP in IN B-PP the DT B-NP promoter\/enhancer NN I-NP region NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O cyclosporine NN B-NP COMMA COMMA O at IN B-PP concentrations NNS B-NP readily RB B-VP accomplished VBN I-VP in IN B-PP clinical JJ B-NP practice NN I-NP COMMA COMMA O was VBD B-VP found VBN I-VP to TO I-VP inhibit VB I-VP the DT B-NP emergence NN I-NP of IN B-PP these DT B-NP DNA-binding JJ I-NP proteins NNS I-NP in IN B-PP normal JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP signaled VBN B-VP via IN B-PP cell NN B-NP surface NN I-NP proteins NNS I-NP implicated VBN B-VP in IN B-PP antigen-dependent JJ B-NP T NN I-NP cell NN I-NP activation NN I-NP and CC B-PP in IN B-PP T NN B-NP cells NNS I-NP stimulated VBN B-VP by IN B-PP mobilization NN B-NP of IN B-PP cellular JJ B-NP calcium NN I-NP and CC O activation NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP . . O Calcium NN B-NP dependent JJ I-NP activation NN I-NP of IN B-PP the DT B-NP NF-AT NN I-NP transcription NN I-NP factor NN I-NP by IN B-PP p59fyn NN B-NP . . O A DT B-NP reporter NN I-NP gene NN I-NP under IN B-PP the DT B-NP control NN I-NP of IN B-PP a DT B-NP T-cell NN I-NP antigen NN I-NP receptor NN I-NP element NN I-NP was VBD B-VP activated VBN I-VP in IN B-PP Jurkat NN B-NP cells NNS I-NP by IN B-PP antigen NN B-NP receptor NN I-NP triggering NN I-NP or CC B-PP by IN B-PP a DT B-NP combination NN I-NP of IN B-PP phorbol NN B-NP myristate NN I-NP acetate NN I-NP COMMA COMMA O which WDT B-NP activates VBZ B-VP protein NN B-NP kinase NN I-NP C NN I-NP COMMA COMMA O and CC O a DT B-NP calcium NN I-NP ionophore NN I-NP . . O Both DT B-NP these DT I-NP signals NNS I-NP were VBD B-VP necessary JJ B-ADJP for IN B-PP expression NN B-NP of IN B-PP the DT B-NP reporter NN I-NP gene NN I-NP . . O When WRB B-ADVP co-transfected VBN B-VP with IN B-PP a DT B-NP construct NN I-NP capable JJ B-ADJP of IN B-PP overexpressing VBG B-VP the DT B-NP tyrosine NN I-NP kinase NN I-NP p59fyn NN I-NP COMMA COMMA O the DT B-NP reporter NN I-NP gene NN I-NP was VBD B-VP activated VBN I-VP by IN B-PP PMA NN B-NP alone RB B-ADVP . . O Thus RB B-ADVP p59fyn NN B-NP could MD B-VP replace VB I-VP the DT B-NP calcium NN I-NP ionophore NN I-NP but CC B-CONJP not RB I-CONJP activation NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP . . O The DT B-NP activation NN I-NP by IN B-PP p59fyn NN B-NP plus CC O PMA NN B-NP was VBD B-VP blocked VBN I-VP by IN B-PP EGTA NN B-NP and CC B-PP by IN B-PP the DT B-NP immunosuppressant JJ I-NP drug NN I-NP cyclosporin NN I-NP A NN I-NP . . O Cell-specific JJ B-NP bifunctional JJ I-NP role NN I-NP of IN B-PP Jun NN B-NP oncogene NN I-NP family NN I-NP members NNS I-NP on IN B-PP glucocorticoid NN B-NP receptor-dependent JJ I-NP transcription NN I-NP . . O Interaction NN B-NP between IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( I-NP PKC NN I-NP ) ) O - : O and CC O glucocorticoid NN B-ADJP receptor NN I-ADJP ( ( I-ADJP GR NN I-ADJP ) ) I-ADJP -mediated JJ I-ADJP signaling NN B-NP is VBZ B-VP suggested VBN I-VP by IN B-PP the DT B-NP ability NN I-NP of IN B-PP the DT B-NP PKC NN I-NP activating NN I-NP phorbol NN I-NP ester NN I-NP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( O TPA NN B-NP ) ) O to TO B-VP inhibit VB I-VP GR-dependent JJ B-NP transcription NN I-NP of IN B-PP the DT B-NP mouse NN B-NP mammary JJ I-NP tumor NN I-NP virus NN I-NP ( ( O MMTV NN B-NP ) ) O long JJ B-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR this DT B-NP interference NN I-NP is VBZ B-VP cell NN B-ADJP specific JJ I-ADJP COMMA COMMA O as IN B-SBAR TPA NN B-NP augmented VBD B-VP dexamethasone-induced JJ B-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP the DT B-NP MMTV NN I-NP LTR NN I-NP in IN B-PP several JJ B-NP T NN I-NP cell NN I-NP lines NNS I-NP but CC O was VBD B-VP inhibitory JJ B-ADJP in IN B-PP NIH-3T3 NN B-NP fibroblasts NNS I-NP . . O TPA-GR NN B-NP synergism NN I-NP was VBD B-VP determined VBN I-VP to TO I-VP have VB I-VP occurred VBN I-VP at IN B-PP the DT O GR-responsive JJ B-NP element NN I-NP ( ( O GRE NN B-NP ) ) O level NN B-NP by IN B-PP functional JJ B-NP analysis NN I-NP of IN B-PP deletion NN B-NP mutants NNS I-NP or CC O synthetic JJ B-NP GRE NN I-NP oligonucleotides NNS I-NP driving VBG B-VP chloramphenicol NN B-NP acetyl-transferase NN I-NP expression NN I-NP . . O Synergism NN B-NP required VBD B-VP an DT B-NP intact JJ I-NP GR NN I-NP DNA-binding JJ I-NP domain NN I-NP COMMA COMMA O whereas IN O amino- NN B-NP or CC I-NP carboxyl-terminal JJ I-NP domains NNS I-NP were VBD B-VP dispensable JJ B-ADJP . . O The DT B-NP effect NN I-NP was VBD B-VP abrogated VBN I-VP by IN B-PP the DT B-NP PKC NN I-NP inhibitor NN I-NP staurosporine NN I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP role NN I-NP for IN B-PP PKC NN B-NP . . O Increased VBN O c-jun NN B-NP COMMA COMMA O jun-B NN B-NP COMMA COMMA O and CC O jun-D NN B-NP expression NN B-NP above IN B-PP basal JJ B-NP levels NNS I-NP and CC O increased VBN B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP AP-1\/TPA NN B-NP responsive JJ I-NP elements NNS I-NP fused VBN B-VP to TO B-PP chloramphenicol NN B-NP acetyl-transferase NN I-NP vectors NNS I-NP were VBD B-VP observed VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP treated VBN B-VP with IN B-PP TPA NN B-NP alone RB B-ADVP or CC O in IN B-PP combination NN B-NP with IN B-PP dexamethasone NN B-NP . . O The DT B-NP ability NN I-NP of IN B-PP Jun NN B-NP proteins NNS I-NP to TO B-VP cooperate VB I-VP with IN B-PP GR NN B-NP in IN B-PP T NN B-NP cells NNS I-NP has VBZ B-VP been VBN I-VP investigated VBN I-VP after IN B-PP transfection NN B-NP of IN B-PP c-jun NN B-NP COMMA COMMA O jun-B NN B-NP COMMA COMMA O or CC O jun-D NN B-NP expression NN B-NP vectors NNS I-NP COMMA COMMA O which WDT B-NP augmented VBD B-VP GR-dependent JJ B-NP transcription NN I-NP from IN B-PP either CC O MMTV NN B-NP LTR NN I-NP or CC O GRE NN B-NP . . O Conversely RB B-ADVP COMMA COMMA O c-jun NN B-NP and CC O jun-B NN B-NP transfection NN B-NP blunted VBD B-VP GR-dependent JJ B-NP transcription NN I-NP in IN B-PP HeLa NN B-NP cells NNS I-NP . . O The DT B-NP presence NN I-NP of IN B-PP c-fos NN B-NP had VBD B-VP a DT B-NP negative JJ I-NP influence NN I-NP on IN B-PP GR NN B-NP function NN I-NP and CC O correlated VBD B-VP with IN B-PP the DT B-NP cell-specific JJ I-NP synergistic JJ I-NP or CC I-NP antagonistic JJ I-NP activity NN I-NP of IN B-PP Jun NN B-NP with IN B-PP respect NN I-PP to TO I-PP GR NN B-NP ; : O high JJ B-NP basal JJ I-NP expression NN I-NP of IN B-PP c-fos NN B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP AP-1 NN B-NP DNA NN I-NP binding NN I-NP and CC O transcriptional JJ B-NP activity NN I-NP were VBD B-VP observed VBN I-VP in IN B-PP HeLa NN B-NP cells NNS I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP in IN I-PP T NN B-NP cells NNS I-NP . . O Furthermore RB B-ADVP overexpression NN B-NP of IN B-PP exogenous JJ B-NP c-fos NN I-NP has VBZ B-VP an DT B-NP inhibitory JJ I-NP effect NN I-NP on IN B-PP GR-dependent JJ B-NP transcription NN I-NP from IN B-PP GRE NN B-NP in IN B-PP T NN B-NP cells NNS I-NP . . O We PRP B-NP propose VBP B-VP that IN B-SBAR Jun NN B-NP plays VBZ B-VP a DT B-NP bifunctional JJ I-NP role NN I-NP on IN B-PP GR-dependent JJ B-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP GRE NN B-NP COMMA COMMA O selecting VBG B-VP either CC B-NP synergistic JJ I-NP or CC I-NP antagonistic JJ I-NP activity NN I-NP depending VBG B-PP on IN B-PP the DT B-NP cell-specific JJ I-NP microenvironment NN I-NP . . O In IN B-PP this DT B-NP regard NN I-NP COMMA COMMA O intracellular JJ B-NP levels NNS I-NP of IN B-PP c-fos NN B-NP appear VBP B-VP to TO I-VP be VB I-VP influential JJ B-ADJP . . O A DT B-NP concatenated JJ I-NP form NN I-NP of IN B-PP Epstein-Barr JJ B-NP viral JJ I-NP DNA NN I-NP in IN B-PP lymphoblastoid JJ B-NP cell NN I-NP lines NNS I-NP induced VBN B-VP by IN B-PP transfection NN B-NP with IN B-PP BZLF1 NN B-NP . . O The DT B-NP replicative JJ I-NP form NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O DNA NN B-NP was VBD B-VP studied VBN I-VP using VBG B-VP two CD B-NP lymphoblastoid JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O X50-7 NN B-NP and CC O 6F11 NN B-NP COMMA COMMA O which WDT B-NP are VBP B-VP latently RB I-VP infected VBN I-VP by IN B-PP Epstein-Barr JJ B-NP virus NN I-NP . . O The DT B-NP lytic JJ I-NP cycle NN I-NP of IN B-PP EBV NN B-NP infection NN I-NP was VBD B-VP induced VBN I-VP by IN B-PP transfection NN B-NP of IN B-PP the DT B-NP cells NNS I-NP with IN B-PP the DT B-NP BRLF1\/BZLF1 NN I-NP coding NN I-NP region NN I-NP of IN B-PP the DT B-NP P3HR-1 NN I-NP defective JJ I-NP genome NN I-NP . . O We PRP B-NP combined VBD B-VP two CD B-NP techniques NNS I-NP to TO B-VP identify VB I-VP the DT B-NP productive JJ I-NP replicative JJ I-NP form NN I-NP of IN B-PP Epstein-Barr JJ B-NP viral JJ I-NP DNA NN I-NP in IN B-PP the DT B-NP lytic JJ I-NP cycle-induced JJ I-NP cells NNS I-NP . . O Restriction NN B-NP enzyme NN I-NP analysis NN I-NP followed VBN B-VP by IN B-PP Southern NN B-NP blot NN I-NP hybridization NN I-NP identified VBD B-VP a DT B-NP significant JJ I-NP increase NN I-NP in IN B-PP the DT B-NP fused VBN I-NP fragment NN I-NP encompassing VBG B-VP both DT B-NP ends NNS I-NP of IN B-PP EBV NN B-NP DNA NN I-NP . . O This DT B-NP indicates VBZ B-VP an DT B-NP increase NN I-NP in IN B-PP either CC O episomal JJ B-NP DNA NN I-NP or CC O concatameric JJ B-NP linear JJ I-NP DNA NN I-NP . . O Southern NN B-NP blot NN I-NP analysis NN I-NP of IN B-PP in FW B-NP situ FW I-NP lysing VBG I-NP gels NNS I-NP revealed VBD B-VP that IN B-SBAR the DT B-NP cellular JJ I-NP content NN I-NP of IN B-PP linear JJ B-NP EBV NN I-NP DNA NN I-NP was VBD B-VP also RB I-VP increased VBN I-VP significantly RB B-ADVP after IN B-PP the DT B-NP initiation NN I-NP of IN B-PP the DT B-NP viral JJ I-NP lytic JJ I-NP cycle NN I-NP COMMA COMMA O while IN B-SBAR the DT B-NP amount NN I-NP of IN B-PP circular JJ B-NP DNA NN I-NP remained VBD B-VP approximately RB B-ADJP constant JJ I-ADJP . . O We PRP B-NP propose VBP B-VP from IN B-PP these DT B-NP results NNS I-NP that IN B-SBAR the DT B-NP source NN I-NP of IN B-PP the DT B-NP fused VBN I-NP fragment NN I-NP encompassing VBG B-VP both DT B-NP ends NNS I-NP of IN B-PP EBV NN B-NP DNA NN I-NP is VBZ B-VP a DT B-NP concatenated VBN I-NP linear JJ I-NP EBV NN I-NP DNA NN I-NP molecule NN I-NP COMMA COMMA O and CC O that IN B-SBAR such PDT B-NP a DT I-NP concatenated VBN I-NP molecule NN I-NP most RBS B-ADVP likely RB I-ADVP represents VBZ B-VP a DT B-NP replicative JJ I-NP form NN I-NP of IN B-PP EBV NN B-NP DNA NN I-NP in IN B-PP productively RB B-NP infected JJ I-NP cells NNS I-NP . . O Regulation NN B-NP of IN B-PP the DT B-NP beta-globin NN I-NP locus NN I-NP . . O Transcription NN B-NP of IN B-PP the DT B-NP human JJ I-NP beta-globin NN I-NP gene NN I-NP cluster NN I-NP depends VBZ B-VP upon IN B-PP upstream JJ B-NP regulatory JJ I-NP sequences NNS I-NP COMMA COMMA O which WDT B-NP are VBP B-VP collectively RB I-VP termed VBN I-VP the DT B-NP locus NN I-NP control NN I-NP region NN I-NP . . O Recent JJ B-NP studies NNS I-NP have VBP B-VP provided VBN I-VP new JJ B-NP insights NNS I-NP into IN B-PP how WRB B-ADVP the DT B-NP individual JJ I-NP genes NNS I-NP of IN B-PP the DT B-NP cluster NN I-NP are VBP B-VP regulated VBN I-VP through IN B-PP development NN B-NP . . O The DT B-NP crux NN I-NP of IN B-PP transcriptional JJ B-NP activation NN I-NP is VBZ B-VP how WRB B-ADVP the DT B-NP locus NN I-NP control NN I-NP region NN I-NP communicates VBZ B-VP with IN B-PP the DT B-NP gene-proximal JJ I-NP regulatory JJ I-NP elements NNS I-NP . . O Ectopic JJ B-NP expression NN I-NP of IN B-PP a DT B-NP conditional JJ I-NP GATA-2\/estrogen NN I-NP receptor NN I-NP chimera NN I-NP arrests VBZ B-VP erythroid JJ B-NP differentiation NN I-NP in IN B-PP a DT B-NP hormone-dependent JJ I-NP manner NN I-NP . . O The DT B-NP GATA NN I-NP factors NNS I-NP are VBP B-VP a DT B-NP family NN I-NP of IN B-PP transcriptional JJ B-NP regulatory JJ I-NP proteins NNS I-NP in IN B-PP eukaryotes NNS B-NP that WDT B-NP share VBP B-VP extensive JJ B-NP homology NN I-NP in IN B-PP their PRP$ B-NP DNA-binding JJ I-NP domains NNS I-NP . . O One CD B-NP enigmatic JJ I-NP aspect NN I-NP of IN B-PP GATA NN B-NP factor NN I-NP expression NN I-NP is VBZ B-VP that IN B-SBAR several JJ B-NP GATA NN I-NP proteins NNS I-NP COMMA COMMA O which WDT B-NP ostensibly RB B-ADVP share VBP B-VP the DT B-NP same JJ I-NP DNA-binding JJ I-NP site NN I-NP specificity NN I-NP COMMA COMMA O are VBP B-VP coexpressed VBN I-VP in IN B-PP erythroid JJ B-NP cells NNS I-NP . . O To TO B-VP elucidate VB I-VP the DT B-NP roles NNS I-NP of IN B-PP individual JJ B-NP GATA NN I-NP factors NNS I-NP in IN B-PP erythropoiesis NN B-NP COMMA COMMA O conditional JJ B-NP alleles NNS I-NP of IN B-PP GATA-1 NN B-NP COMMA COMMA O GATA-2 NN B-NP COMMA COMMA O and CC O GATA-3 NN B-NP were VBD B-VP prepared VBN I-VP by IN B-PP fusing VBG B-VP each DT B-NP of IN B-PP the DT B-NP factors NNS I-NP to TO B-PP the DT B-NP hormone-binding JJ I-NP domain NN I-NP of IN B-PP the DT B-NP human JJ I-NP estrogen NN B-NP receptor NN I-NP ( ( O ER NN B-NP ) ) O . . O These DT B-NP GATA\/ER NN I-NP chimeric JJ I-NP factors NNS I-NP were VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP hormone-inducible JJ B-NP trans-activating JJ I-NP proteins NNS I-NP in IN B-PP transient JJ B-NP transfection NN I-NP assays NNS I-NP . . O When WRB B-ADVP stably RB B-ADVP introduced VBN B-VP into IN B-PP primary JJ B-NP erythroblasts NNS I-NP or CC O conditionally RB B-NP transformed VBN I-NP erythroid JJ I-NP progenitors NNS I-NP cells NNS I-NP COMMA COMMA O exogenous JJ B-NP GATA-2\/ER NN I-NP promoted VBD B-VP proliferation NN B-NP and CC O inhibited VBD B-VP terminal JJ B-NP differentiation NN I-NP in IN B-PP an DT B-NP estrogen-dependent JJ I-NP manner NN I-NP . . O These DT B-NP phenotypic JJ I-NP effects NNS I-NP are VBP B-VP specifically RB B-ADVP attributable JJ B-ADJP to TO B-PP the DT B-NP action NN I-NP of IN B-PP ectopically RB B-NP expressed VBN I-NP GATA-2\/ER NN I-NP because IN B-SBAR erythroblasts NNS B-NP expressing VBG B-VP exogenous JJ B-NP GATA-2 NN I-NP are VBP B-VP constitutively RB I-VP arrested VBN I-VP in IN B-PP differentiation NN B-NP and CC O because IN B-SBAR erythroid JJ B-NP progenitors NNS I-NP expressing VBG B-VP either CC O Gal\/ER NN B-NP or CC O GATA-3\/ER NN B-NP do VBP B-VP not RB I-VP display VB I-VP a DT B-NP hormone-responsive JJ I-NP block NN I-NP in IN B-PP differentiation NN B-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP GATA-2 NN I-NP transcription NN I-NP factor NN I-NP appears VBZ B-VP to TO I-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP regulating VBG B-VP the DT B-NP self-renewal JJ I-NP capacity NN I-NP of IN B-PP early JJ B-NP erythroid JJ I-NP progenitor NN I-NP cells NNS I-NP . . O Lipopolysaccharide NN B-NP induces VBZ B-VP phosphorylation NN B-NP of IN B-PP MAD3 NN B-NP and CC O activation NN B-NP of IN B-PP c-Rel NN B-NP and CC O related JJ B-NP NF-kappa NN I-NP B NN I-NP proteins NNS B-NP in IN B-PP human JJ B-NP monocytic JJ I-NP THP-1 NN I-NP cells NNS I-NP . . O Many JJ B-NP effects NNS I-NP of IN B-PP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O on IN B-PP gene NN B-NP expression NN I-NP COMMA COMMA O including VBG B-PP that DT B-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O COMMA COMMA O in IN B-PP monocytic JJ B-NP cells NNS I-NP are VBP B-VP mediated VBN I-VP by IN B-PP activation NN B-NP of IN B-PP kappa NN B-NP B NN I-NP DNA-binding JJ I-NP proteins NNS I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP specific JJ I-NP members NNS I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B\/Rel NN I-NP transcription NN I-NP factor NN I-NP family NN I-NP involved VBN B-VP in IN B-PP the DT B-NP LPS NN I-NP response NN I-NP COMMA COMMA O and CC O the DT B-NP mechanisms NNS I-NP through IN B-PP which WDT B-NP LPS-generated JJ B-NP signals NNS I-NP are VBP B-VP transduced VBN I-VP remain VBP B-VP unclear JJ B-ADJP . . O Here RB B-ADVP we PRP B-NP show VBP B-VP that IN B-SBAR LPS NN B-NP induces VBZ B-VP nuclear JJ B-NP expression NN I-NP of IN B-PP c-Rel\/p50 NN B-NP heterodimers NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP p50\/p65 NN B-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O kappa NN B-NP B NN I-NP DNA-binding JJ I-NP complexes NNS I-NP in IN B-PP human JJ B-NP monocytic JJ I-NP THP-1 NN I-NP cells NNS I-NP . . O Nuclear JJ B-NP localization NN I-NP of IN B-PP these DT B-NP proteins NNS I-NP occurred VBD B-VP concomitantly RB B-PP with IN I-PP a DT B-NP rapid JJ I-NP decrease NN I-NP in IN B-PP their PRP$ B-NP cytosolic JJ I-NP levels NNS I-NP and CC O was VBD B-VP independent JJ B-ADJP of IN B-PP phorbol NN B-NP ester-sensitive JJ I-NP protein NN I-NP kinase NN I-NP C NN I-NP . . O Within IN B-PP 24 CD B-NP h NN I-NP following VBG B-PP LPS NN B-NP stimulation NN I-NP there EX B-NP was VBD B-VP a DT B-NP striking JJ I-NP increase NN I-NP in IN B-PP the DT B-NP levels NNS I-NP of IN B-PP c-Rel NN B-NP COMMA COMMA O p105 NN B-NP COMMA COMMA O and CC O p50 NN B-NP in IN B-PP the DT B-NP cytosol NN I-NP . . O The DT B-NP increased VBN I-NP levels NNS I-NP of IN B-PP these DT B-NP proteins NNS I-NP correlated VBD B-VP with IN B-PP increases NNS B-NP in IN B-PP the DT B-NP amounts NNS I-NP of IN B-PP their PRP$ B-NP mRNAs NNS I-NP during IN B-PP LPS NN B-NP activation NN I-NP of IN B-PP THP-1 NN B-NP cells NNS I-NP . . O LPS NN B-NP activation NN I-NP of IN B-PP THP-1 NN B-NP cells NNS I-NP resulted VBD B-VP in IN B-PP phosphorylation NN B-NP of IN B-PP MAD3 NN B-NP ( ( O an DT B-NP I NN I-NP kappa NN I-NP B-like JJ I-NP protein NN I-NP ) ) O COMMA COMMA O a DT B-NP rapid JJ I-NP increase NN I-NP in IN B-PP MAD3 NN B-NP mRNA NN I-NP COMMA COMMA O and CC O an DT B-NP increase NN I-NP in IN B-PP MAD3 NN B-NP protein NN I-NP by IN B-PP 2 CD B-NP h NN I-NP . . O Thus RB B-ADVP COMMA COMMA O LPS NN B-NP activation NN I-NP of IN B-PP human JJ B-NP monocytic JJ I-NP cells NNS I-NP results VBZ B-VP in IN B-PP nuclear JJ B-NP expression NN I-NP of IN B-PP c-Rel\/p50 NN B-NP and CC O p50\/p65 NN B-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O and CC O induces VBZ B-VP phosphorylation NN B-NP of IN B-PP MAD3 NN B-NP . . O Induction NN B-NP of IN B-PP CD8 NN O antigen NN B-NP and CC O suppressor NN B-NP activity NN B-NP by IN B-PP glucocorticoids NNS B-NP in IN B-PP a DT B-NP CEM NN I-NP human JJ I-NP leukemic JJ I-NP cell NN I-NP clone NN I-NP . . O The DT B-NP relationship NN I-NP between IN B-PP glucocorticoid NN B-NP effect NN I-NP and CC O regulation NN B-NP of IN B-PP cell NN B-NP surface NN I-NP antigens NNS I-NP was VBD B-VP investigated VBN I-VP in IN B-PP two CD B-NP models NNS I-NP of IN B-PP leukemic JJ B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O CEM NN B-NP C7 NN I-NP denoted VBN B-VP ( ( O r+ JJ B-ADJP COMMA COMMA O ly+ JJ B-ADJP ) ) O and CC O CEM NN B-NP C1 NN I-NP ( ( O r+ JJ B-ADJP COMMA COMMA O ly- JJ B-ADJP ) ) O . . O The DT B-NP reactivity NN I-NP of IN B-PP murine JJ B-NP monoclonal JJ I-NP antibodies NNS I-NP COMMA COMMA O anti-CD4-FITC NN B-NP COMMA COMMA O anti-CD8-FITC NN B-NP COMMA COMMA O anti-CD2-FITC NN B-NP and CC O anti-calla-FITC NN B-NP COMMA COMMA O were VBD B-VP analyzed VBN I-VP using VBG B-VP flow NN B-NP cytometry NN I-NP . . O The DT B-NP suppressor NN I-NP function NN I-NP was VBD B-VP determined VBN I-VP using VBG B-VP {3H}thymidine NN B-NP incorporation NN I-NP into IN B-PP phytohemagglutinin-activated JJ B-NP peripheral JJ I-NP blood NN I-NP lymphocytes NNS I-NP . . O Dexamethasone NN B-NP treatment NN I-NP of IN B-PP a DT B-NP human JJ I-NP leukemic JJ I-NP cell NN I-NP clone NN I-NP CEM NN I-NP C7 NN I-NP caused VBD B-VP an DT B-NP increase NN I-NP in IN B-PP a DT B-NP subset NN I-NP of IN B-PP cells NNS B-NP expressing VBG B-VP the DT B-NP surface NN I-NP antigen NN I-NP CD8 NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP present JJ B-ADJP on IN B-PP suppressor NN B-NP and CC O cytotoxic JJ B-ADJP T-lymphocytes NNS B-NP . . O By IN B-PP comparison NN B-NP COMMA COMMA O there EX B-NP was VBD B-VP no DT B-NP modification NN I-NP of IN B-PP the DT B-NP expression NN I-NP of IN B-PP CD4 NN B-NP antigen NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP expressed VBN I-VP at IN B-PP high JJ B-NP levels NNS I-NP in IN B-PP these DT B-NP cells NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O there EX B-NP was VBD B-VP no DT B-NP regulation NN I-NP by IN B-PP glucocorticoids NNS B-NP of IN B-PP either CC O the DT O CD8 NN B-NP or CC O CD4 NN B-NP antigens NNS B-NP in IN B-PP the DT B-NP leukemic JJ I-NP clone NN I-NP CEM NN I-NP C1 NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O no DT B-NP modification NN I-NP of IN B-PP the DT B-NP suppressor NN I-NP function NN I-NP in IN B-PP CEM NN B-NP C1 NN I-NP cells NNS I-NP by IN B-PP dexamethasone NN B-NP was VBD B-VP observed VBN I-VP . . O In IN B-PP the DT B-NP human JJ I-NP leukemic JJ I-NP cells NNS I-NP studied VBN B-VP here RB B-ADVP COMMA COMMA O the DT B-NP ability NN I-NP to TO B-VP induce VB I-VP CD8 NN B-NP antigen NN I-NP expression NN I-NP in IN B-PP a DT B-NP CD4+ JJ I-NP cells NNS I-NP correlates VBZ B-VP with IN B-PP the DT B-NP ability NN I-NP to TO B-VP induce VB I-VP cell NN B-NP lysis NN I-NP in IN B-PP a DT B-NP glucocorticoid NN I-NP receptor NN I-NP positive JJ I-NP cell NN I-NP population NN I-NP . . O Molecular JJ B-NP basis NN I-NP of IN B-PP a DT B-NP multiple JJ I-NP lymphokine NN I-NP deficiency NN I-NP in IN B-PP a DT B-NP patient NN I-NP with IN B-PP severe JJ B-NP combined JJ I-NP immunodeficiency NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP reported VBN I-VP that IN B-SBAR the DT B-NP T NN I-NP lymphocytes NNS I-NP of IN B-PP a DT B-NP child NN I-NP with IN B-PP severe JJ B-NP combined JJ I-NP immunodeficiency NN I-NP are VBP B-VP defective JJ B-ADJP in IN B-PP the DT B-NP transcription NN I-NP of IN B-PP several JJ B-NP lymphokine NN I-NP genes NNS I-NP that WDT B-NP include VBP B-VP IL2 NN B-NP COMMA COMMA O IL3 NN B-NP COMMA COMMA O IL4 NN B-NP COMMA COMMA O and CC O IL5 NN B-NP COMMA COMMA O which WDT B-NP encode VBP B-VP interleukins NNS B-NP 2 CD B-NP COMMA COMMA O 3 CD B-NP COMMA COMMA O 4 CD B-NP COMMA COMMA O and CC O 5 CD B-NP ( ( O IL-2 NN B-NP COMMA COMMA O -3 CD B-NP COMMA COMMA O -4 CD B-NP COMMA COMMA O and CC O -5 CD B-NP ) ) O . . O To TO B-VP determine VB I-VP whether IN B-SBAR the DT B-NP defect NN I-NP in IN B-PP the DT B-NP patient NN I-NP 's POS B-NP T NN I-NP lymphocytes NNS I-NP involved VBD B-VP a DT B-NP trans-acting JJ I-NP factor NN I-NP common JJ B-ADJP to TO B-PP the DT B-NP affected VBN I-NP lymphokine NN I-NP genes NNS I-NP COMMA COMMA O we PRP B-NP examined VBD B-VP the DT B-NP ability NN I-NP of IN B-PP nuclear JJ B-NP factors NNS I-NP from IN B-PP the DT B-NP patient NN I-NP 's POS B-NP T NN I-NP lymphocytes NNS I-NP to TO B-VP bind VB I-VP response NN B-NP elements NNS I-NP present JJ B-ADJP in IN B-PP the DT B-NP regulatory JJ I-NP region NN I-NP of IN B-PP IL2 NN B-NP . . O Nuclear JJ B-NP factor NN I-NP NF-kB NN I-NP COMMA COMMA O activation NN B-NP protein NN I-NP 1 CD I-NP ( ( O AP-1 NN B-NP ) ) O COMMA COMMA O OCT-1 NN B-NP COMMA COMMA O and CC O NF-IL-2B NN B-NP binding NN I-NP activity NN I-NP were VBD B-VP normal JJ B-ADJP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP binding NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O to TO B-PP its PRP$ B-NP response NN I-NP element NN I-NP in IN B-PP the DT B-NP IL2 NN I-NP enhancer NN I-NP and CC B-PP to TO B-PP an DT B-NP NF-AT-like JJ I-NP response NN I-NP element NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP IL4 NN I-NP enhancer NN I-NP was VBD B-VP abnormal JJ B-ADJP . . O To TO B-VP ascertain VB I-VP whether IN B-SBAR the DT B-NP abnormal JJ I-NP NF-AT NN I-NP binding NN I-NP activity NN I-NP was VBD B-VP related JJ B-ADJP to TO B-PP an DT B-NP impaired JJ I-NP function NN I-NP COMMA COMMA O we PRP B-NP transfected VBD B-VP patient NN B-NP and CC O control NN B-NP T NN B-NP lymphocytes NNS I-NP with IN B-PP constructs NNS B-NP containing VBG B-VP the DT B-NP reporter NN I-NP gene NN I-NP encoding JJ B-VP chloramphenicol NN B-NP acetyl NN I-NP transferase NN I-NP ( ( O CAT NN B-NP ) ) O under IN B-PP the DT B-NP control NN I-NP of IN B-PP the DT B-NP entire JJ I-NP IL2 NN I-NP regulatory JJ I-NP region NN I-NP or CC B-PP of IN B-PP multimers NNS B-NP of IN B-PP individual JJ B-NP enhancer NN I-NP sequences NNS I-NP . . O CAT NN B-NP expression NN I-NP directed VBN B-VP by IN B-PP the DT B-NP IL2 NN I-NP regulatory JJ I-NP region NN I-NP or CC B-PP by IN B-PP a DT B-NP multimer NN I-NP of IN B-PP the DT B-NP NF-AT-binding JJ I-NP site NN I-NP was VBD B-VP markedly RB B-ADJP lower JJR I-ADJP in IN B-PP the DT B-NP patient NN I-NP relative JJ B-PP to TO I-PP controls NNS B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O CAT NN B-NP gene NN I-NP expression NN I-NP directed VBN B-VP by IN B-PP a DT B-NP multimer NN I-NP of IN B-PP the DT B-NP OCT-1 NN I-NP proximal NN I-NP ( ( I-NP OCT-1p NN I-NP ) ) I-NP -binding JJ I-NP site NN I-NP was VBD B-VP equivalent JJ B-ADJP in IN B-PP patient NN B-NP and CC O controls NNS B-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR an DT B-NP abnormality NN I-NP of IN B-PP \/ CC O or CC O influencing JJ B-NP NF-AT NN B-VP may MD I-VP underlie VB B-NP the DT I-NP multiple JJ I-NP lymphokine NN I-NP deficiency NN O in IN B-NP this DT I-NP patient NN O Expression NN B-NP of IN B-PP mRNA NN B-NP for IN B-PP the DT B-NP GATA-binding JJ I-NP proteins NNS I-NP in IN B-PP human JJ B-NP eosinophils NNS B-NP and CC O basophils NNS B-NP : : O potential JJ B-NP role NN I-NP in IN B-PP gene NN B-NP transcription NN I-NP . . O The DT B-NP expression NN I-NP of IN B-PP the DT B-NP hematopoietic JJ I-NP transcription NN I-NP factors NNS I-NP GATA-1 NN B-NP COMMA COMMA O GATA-2 NN B-NP COMMA COMMA O and CC O GATA-3 NN B-NP was VBD B-VP studied VBN I-VP in IN B-PP eosinophils NNS B-NP and CC O basophils NNS B-NP . . O Eosinophils NNS B-NP express VBP B-VP mRNA NN B-NP for IN B-PP GATA-1 NN B-NP COMMA COMMA O GATA-2 NN B-NP COMMA COMMA O and CC O GATA-3 NN B-NP . . O Basophils NNS B-NP express VBP B-VP GATA-2 NN B-NP and CC O GATA-3 NN B-NP . . O Treatment NN B-NP of IN B-PP HL-60 NN B-NP eosinophilic JJ I-NP sublines NNS I-NP with IN B-PP either CC O interleukin-5 NN B-NP or CC O butyric JJ B-NP acid NN I-NP increased VBD B-VP the DT B-NP expression NN I-NP of IN B-PP GATA-1 NN B-NP mRNA NN I-NP concomitant JJ B-ADJP with IN B-PP the DT B-NP expression NN I-NP of IN B-PP eosinophil-specific JJ B-NP genes NNS I-NP COMMA COMMA O whereas IN O levels NNS B-NP of IN B-PP GATA-2 NN B-NP mRNA NN I-NP remained VBD B-VP relatively RB B-ADJP constant JJ I-ADJP . . O The DT B-NP presence NN I-NP of IN B-PP mRNA NN B-NP for IN B-PP these DT B-NP proteins NNS I-NP in IN B-PP eosinophils NNS B-NP and CC O basophils NNS B-NP suggests VBZ B-VP that IN B-SBAR gene NN B-NP transcription NN I-NP in IN B-PP these DT B-NP lineages NNS I-NP may MD B-VP be VB I-VP regulated VBN I-VP by IN B-PP GATA-binding JJ B-NP proteins NNS I-NP . . O Proliferation NN B-NP index NN I-NP as IN B-PP a DT B-NP prognostic JJ I-NP marker NN I-NP in IN B-PP breast NN B-NP cancer NN I-NP . . O BACKGROUND NN B-NP . . O The DT B-NP proliferative JJ I-NP activity NN I-NP of IN B-PP tumors NNS B-NP has VBZ B-VP been VBN I-VP extensively RB I-VP investigated VBN I-VP with IN B-PP different JJ B-NP approaches NNS I-NP COMMA COMMA O among IN B-PP which WDT B-NP the DT B-NP use NN I-NP of IN B-PP the DT B-NP monoclonal JJ I-NP antibody NN I-NP Ki-67 NN I-NP represents VBZ B-VP an DT B-NP easy JJ I-NP and CC I-NP reliable JJ I-NP means NN I-NP of IN B-PP assessing VBG B-VP cell NN B-NP proliferation NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O the DT B-NP proliferative JJ I-NP activity NN I-NP of IN B-PP 129 CD B-NP primary JJ I-NP breast NN I-NP cancers NNS I-NP was VBD B-VP investigated VBN I-VP COMMA COMMA O and CC O the DT B-NP results NNS I-NP were VBD B-VP related JJ I-VP to TO B-PP prognosis NN B-NP . . O METHODS NNS B-NP . . O Tumor NN B-NP samples NNS I-NP COMMA COMMA O obtained VBN B-VP from IN B-PP 129 CD B-NP patients NNS I-NP who WP B-NP underwent VBD B-VP surgery NN B-NP between IN B-PP January NNP B-NP 1987 CD I-NP and CC O December NNP B-NP 1988 CD I-NP COMMA COMMA O were VBD B-VP processed VBN I-VP for IN B-PP staining VBG B-NP by IN B-PP an DT B-NP immunohistochemical JJ I-NP procedure NN I-NP ( ( O avidin-biotin NN B-NP complex NN I-NP ) ) O . . O The DT B-NP median JJ I-NP time NN I-NP of IN B-PP observation NN B-NP was VBD B-VP 42 CD B-NP months NNS I-NP ( ( O range NN B-NP COMMA COMMA O 31-55 CD B-NP months NNS I-NP ) ) O . . O Life-table JJ B-NP analysis NN I-NP ( ( O Mantel-Cox NN B-NP ) ) O was VBD B-VP used VBN I-VP to TO B-VP assess VB I-VP the DT B-NP probability NN I-NP of IN B-PP disease-free JJ B-NP survival NN I-NP ( ( O DFS NN B-NP ) ) O and CC O overall JJ B-NP survival NN I-NP ( ( O OS NN B-NP ) ) O . . O RESULTS NNS B-NP . . O Tumors NNS B-NP with IN B-PP high JJ B-NP Ki-67 NN I-NP proliferation NN I-NP indices NNS I-NP ( ( O > JJR B-NP 20 CD I-NP % NN I-NP ) ) O were VBD B-VP associated VBN I-VP with IN B-PP a DT B-NP higher JJR I-NP 4-year JJ I-NP probability NN I-NP of IN B-PP relapse NN B-NP of IN B-PP disease NN B-NP ( ( O 55.3 CD B-NP % NN I-NP versus CC O 79.1 CD B-NP % NN I-NP ; : O P NN B-NP = JJ B-VP 0.003 CD B-NP ) ) O and CC O death NN B-NP ( ( O 71 CD B-NP % NN I-NP versus CC O 95.6 CD B-NP % NN I-NP ; : O P NN B-NP = JJ B-VP 0.00005 CD B-NP ) ) O when WRB B-ADVP compared VBN B-VP with IN B-PP tumors NNS B-NP with IN B-PP low JJ B-NP Ki-67 NN I-NP values NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O this DT B-NP proliferative JJ I-NP parameter NN I-NP maintained VBD B-VP its PRP$ B-NP prognostic JJ I-NP significance NN I-NP when WRB B-ADVP the DT B-NP patients NNS I-NP were VBD B-VP stratified VBN I-VP according VBG B-PP to TO B-PP lymph NN B-NP node NN I-NP involvement NN I-NP COMMA COMMA O menopausal JJ B-NP status NN I-NP COMMA COMMA O and CC O nuclear JJ B-NP estrogen NN I-NP receptor NN I-NP content NN I-NP . . O CONCLUSIONS NNS B-NP . . O Tumor NN B-NP proliferative JJ I-NP activity NN I-NP as IN B-SBAR evaluated VBN B-VP by IN B-PP the DT B-NP monoclonal JJ I-NP antibody NN I-NP Ki-67 NN I-NP seems VBZ B-VP to TO I-VP be VB I-VP an DT B-NP effective JJ I-NP indicator NN I-NP of IN B-PP prognosis NN B-NP in IN B-PP breast NN B-NP cancer NN I-NP for IN B-PP DFS NN B-NP and CC O OS NN B-NP . . O Defective JJ B-NP translocation NN I-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP in IN B-PP multidrug-resistant JJ B-NP HL-60 NN I-NP cells NNS I-NP confers VBZ B-VP a DT B-NP reversible JJ I-NP loss NN I-NP of IN B-PP phorbol NN B-NP ester-induced JJ I-NP monocytic JJ I-NP differentiation NN I-NP . . O Previous JJ B-NP studies NNS I-NP have VBP B-VP demonstrated VBN I-VP that IN B-SBAR human JJ B-NP HL-60 NN I-NP myeloid JJ I-NP leukemia NN I-NP cells NNS I-NP differentiate VBP B-VP in IN B-PP response NN I-PP to TO I-PP phorbol NN B-NP esters NNS I-NP . . O This DT B-NP event NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP induction NN B-NP of IN B-PP the DT B-NP c-jun NN I-NP early JJ I-NP response NN I-NP gene NN I-NP and CC O appearance NN B-NP of IN B-PP a DT B-NP monocytic JJ I-NP phenotype NN I-NP . . O The DT B-NP present JJ I-NP studies NNS I-NP have VBP B-VP examined VBN I-VP the DT B-NP effects NNS I-NP of IN B-PP vincristine-selected JJ B-NP COMMA COMMA I-NP multidrug JJ I-NP resistance NN I-NP on IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( I-NP TPA NN I-NP ) ) I-NP -induced JJ I-NP HL-60 NN I-NP cell NN I-NP differentiation NN I-NP . . O The DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR multidrug-resistant JJ B-NP HL-60 NN I-NP cells NNS I-NP COMMA COMMA O designated VBN B-VP HL-60\/vinc NN B-NP COMMA COMMA O fail VBP B-VP to TO I-VP respond VB I-VP to TO B-PP TPA NN B-NP with IN B-PP an DT B-NP increase NN I-NP in IN B-PP c-jun NN B-NP transcripts NNS I-NP or CC O other JJ B-NP phenotypic JJ I-NP characteristics NNS I-NP of IN B-PP monocytic JJ B-NP differentiation NN I-NP . . O By IN B-PP contrast NN B-NP COMMA COMMA O treatment NN B-NP of IN B-PP HL-60\/vinc NN B-NP cells NNS I-NP with IN B-PP okadaic JJ B-NP acid NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP serine\/threonine NN B-NP protein NN I-NP phosphatases NNS I-NP COMMA COMMA O induces VBZ B-VP c-jun NN B-NP transcription NN I-NP COMMA COMMA O growth NN B-NP arrest NN I-NP COMMA COMMA O and CC O expression NN B-NP of IN B-PP the DT B-NP c-fms NN I-NP gene NN I-NP . . O Studies NNS B-NP were VBD B-VP also RB I-VP performed VBN I-VP with IN B-PP an DT O HL-60\/vinc NN O revertant NN O ( ( O HL-60\/vinc/R NN B-ADJP ) ) O line NN B-NP that WDT B-NP has VBZ B-VP regained VBN I-VP partial JJ B-NP sensitivity NN I-NP to TO B-PP vincristine NN B-NP . . O The DT B-NP finding NN I-NP that IN B-SBAR HL-60\/vinc/R NN B-NP cells NNS I-NP respond VBP B-VP to TO B-PP TPA NN B-NP with IN B-PP induction NN B-NP of IN B-PP a DT B-NP monocytic JJ I-NP phenotype NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP c-jun NN B-NP expression NN I-NP COMMA COMMA O suggests VBZ B-VP that IN B-SBAR c-jun NN B-NP induction NN I-NP is VBZ B-VP not RB O obligatory JJ B-ADJP for IN B-PP monocytic JJ B-NP differentiation NN I-NP . . O Other JJ B-NP studies NNS I-NP further RB B-ADVP demonstrate VBP B-VP that IN B-SBAR the DT O jun-B NN B-NP and CC O fra-1 NN B-NP genes NNS B-NP are VBP B-VP induced VBN I-VP by IN B-PP TPA NN B-NP in IN B-PP both CC B-NP HL-60\/vinc NN I-NP and CC I-NP HL-60\/vinc/R NN I-NP cells NNS I-NP COMMA COMMA O whereas IN O c-fos NN B-NP expression NN I-NP is VBZ B-VP attenuated VBN I-VP in IN B-PP the DT B-NP HL-60\/vinc NN I-NP line NN I-NP . . O Since IN B-SBAR TPA NN B-NP activates VBZ B-VP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O COMMA COMMA O we PRP B-NP examined VBD B-VP translocation NN B-NP of IN B-PP PKC NN B-NP from IN B-PP the DT B-NP cytosol NN I-NP to TO B-PP the DT B-NP membrane NN I-NP fraction NN I-NP . . O Although IN B-SBAR HL-60 NN B-NP and CC O HL-60\/vinc/R NN B-ADJP cells NNS B-NP demonstrated VBD B-VP translocation NN B-NP of IN B-PP PKC NN B-NP activity NN I-NP COMMA COMMA O this DT B-NP subcellular JJ I-NP redistribution NN I-NP was VBD B-VP undetectable JJ B-ADJP in IN B-PP HL-60\/vinc NN B-NP cells NNS I-NP . . O Activity NN B-NP of IN B-PP the DT B-NP mitogen-activated JJ I-NP protein NN I-NP kinase NN I-NP family NN I-NP with IN B-PP associated JJ B-NP phosphorylation NN I-NP of IN B-PP c-Jun NN B-NP Y-peptide NN I-NP was VBD B-VP markedly RB I-VP diminished VBN I-VP in IN B-PP TPA-treated JJ B-NP HL-60\/vinc NN I-NP cells NNS I-NP COMMA COMMA O but CC O not RB B-PP in IN I-PP response NN I-PP to TO I-PP okadaic JJ B-NP acid NN I-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O these DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR vincristine NN B-NP resistance NN I-NP confers VBZ B-VP insensitivity NN B-NP to TO B-PP TPA-induced JJ B-NP differentiation NN I-NP and CC O can MD B-VP include VB I-VP defects NNS B-NP in IN B-PP PKC-mediated JJ B-NP signaling NN I-NP events NNS I-NP and CC O induction NN B-NP of IN B-PP jun\/fos NN B-NP early JJ I-NP response NN I-NP gene NN I-NP expression NN I-NP . . O Differential JJ B-NP contribution NN I-NP of IN B-PP herpes NN B-NP simplex NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP gene NN B-NP products NNS I-NP and CC O cellular JJ B-NP factors NNS I-NP to TO B-PP the DT B-NP activation NN I-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP provirus NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP reported VBN I-VP that IN B-SBAR infection NN B-NP with IN B-PP herpes NN B-NP simplex NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HSV-1 NN B-NP ) ) O activates VBZ B-VP expression NN B-NP of IN B-PP the DT O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O provirus NN B-NP in IN B-PP T NN B-NP cells NNS I-NP . . O Activation NN B-NP of IN B-PP the DT B-NP HIV-1 NN I-NP provirus NN I-NP correlated VBD B-VP with IN B-PP the DT B-NP activation NN I-NP of IN B-PP binding NN B-NP of IN B-PP 55- CD B-NP and CC O 85-kDa JJ B-ADJP proteins NNS B-NP to TO B-PP the DT B-NP kappa NN I-NP B NN I-NP enhancer NN I-NP and CC O binding NN B-NP of IN B-PP the DT B-NP 50-kDa JJ I-NP HLP-1 NN I-NP protein NN I-NP to TO B-PP the DT B-NP LBP-1 NN I-NP sequences NNS I-NP of IN B-PP the DT B-NP HIV-1 NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP . . O Further RB B-NP examination NN I-NP of IN B-PP this DT B-NP system NN I-NP has VBZ B-VP shown VBN I-VP that IN B-SBAR the DT B-NP inhibition NN I-NP of IN B-PP HSV-1 NN B-NP replication NN I-NP by IN B-PP the DT B-NP antiviral JJ I-NP drug NN I-NP acyclovir NN I-NP does VBZ B-VP not RB I-VP inhibit VB I-VP HSV-1-mediated JJ B-NP induction NN I-NP of IN B-PP HIV-1 NN B-NP provirus NN I-NP . . O Surprisingly RB B-ADVP COMMA COMMA O the DT O NF-kappa NN B-NP B NN I-NP and CC O HLP-1 NN B-NP binding NN B-NP activities NNS I-NP were VBD B-VP substantially RB I-VP inhibited VBN I-VP in IN B-PP acyclovir-treated JJ B-NP cells NNS I-NP . . O In IN B-PP the DT B-NP transient-transfection JJ I-NP assay NN I-NP COMMA COMMA O ICP0 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP ICP4 NN B-NP COMMA COMMA O activated VBD B-VP the DT B-NP HIV-1 NN I-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP promoter NN I-NP region NN I-NP and CC O the DT B-NP effect NN I-NP of IN B-PP ICP0 NN B-NP was VBD B-VP greatly RB I-VP enhanced VBN I-VP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP the DT B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP proteins NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR induction NN B-NP of IN B-PP the DT B-NP HIV-1 NN I-NP provirus NN I-NP involves VBZ B-VP cooperation NN B-NP between IN B-PP the DT B-NP HSV-1-activated JJ I-NP cellular JJ I-NP factor NN I-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP COMMA COMMA O and CC O the DT B-NP virus-encoded JJ I-NP transactivator NN I-NP COMMA COMMA O ICP0 NN B-NP . . O Glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP mononuclear JJ B-NP cells NNS I-NP of IN B-PP patients NNS B-NP with IN B-PP sepsis NN B-NP . . O Glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O hormone-binding NN B-NP activity NN I-NP was VBD B-VP studied VBN I-VP by IN B-PP a DT B-NP whole-cell JJ I-NP method NN I-NP in IN B-PP mononuclear JJ B-NP cells NNS I-NP ( ( O MNC NN B-NP ) ) O from IN B-PP peripheral JJ B-NP blood NN I-NP of IN B-PP 7 CD B-NP patients NNS I-NP during IN B-PP the DT B-NP hemodynamic JJ I-NP compensatory JJ I-NP phase NN I-NP of IN B-PP sepsis NN B-NP . . O 4 CD B-NP patients NNS I-NP were VBD B-VP receiving VBG I-VP dopamine NN B-NP COMMA COMMA O which WDT B-NP did VBD B-VP not RB I-VP affect VB I-VP the DT B-NP GR NN I-NP count NN I-NP . . O The DT B-NP patients NNS I-NP ' POS B-NP plasma NN I-NP cortisol NN I-NP concentrations NNS I-NP were VBD B-VP normal JJ B-ADJP or CC O slightly RB B-ADJP elevated JJ I-ADJP . . O Despite IN B-PP a DT B-NP wide JJ I-NP range NN I-NP COMMA COMMA O the DT B-NP mean NN I-NP GR NN I-NP count NN B-NP and CC O affinity NN B-NP in IN B-PP MNC NN B-NP from IN B-PP septic JJ B-NP patients NNS I-NP did VBD B-VP not RB I-VP differ VB I-VP from IN B-PP those DT B-NP in IN B-PP normal JJ B-NP controls NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR glucocorticoids NNS B-NP could MD B-VP still RB I-VP be VB I-VP effective JJ B-ADJP in IN B-PP the DT B-NP hemodynamic JJ I-NP compensatory JJ I-NP phase NN I-NP of IN B-PP sepsis NN B-NP . . O Dependence NN B-NP for IN B-PP the DT B-NP proliferative JJ I-NP response NN I-NP to TO B-PP erythropoietin NN B-NP on IN B-PP an DT B-NP established JJ I-NP erythroid JJ I-NP differentiation NN I-NP program NN I-NP in IN B-PP a DT B-NP human JJ I-NP hematopoietic JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O UT-7 NN B-NP . . O Erythroid JJ B-NP differentiation NN I-NP involves VBZ B-VP the DT B-NP activation NN I-NP of IN B-PP a DT B-NP number NN I-NP of IN B-PP erythroid-specific JJ B-NP genes NNS I-NP COMMA COMMA O most JJS B-NP of IN B-PP which WDT B-NP COMMA COMMA O including VBG B-PP the DT B-NP globin NN I-NP genes NNS I-NP and CC O the DT B-NP erythropoietin NN I-NP receptor NN I-NP ( ( O Epo-R NN B-NP ) ) O gene NN B-NP COMMA COMMA O are VBP B-VP COMMA COMMA O at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP COMMA COMMA O regulated VBN B-VP by IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP GATA-1 NN I-NP . . O In IN B-SBAR order NN O to TO O understand VB B-VP the DT B-NP relationship NN I-NP COMMA COMMA O if IN B-SBAR any DT B-NP COMMA COMMA O between IN B-PP expression NN B-NP of IN B-PP GATA-1 NN B-NP COMMA COMMA O response NN B-NP to TO B-PP Epo NN B-NP and CC O erythroid JJ B-NP differentiation NN I-NP COMMA COMMA O we PRP B-NP analyzed VBD B-VP the DT B-NP expression NN I-NP of IN B-PP GATA-1 NN B-NP COMMA COMMA O Epo-R NN B-NP and CC O globin NN B-NP genes NNS I-NP in IN B-PP an DT B-NP Epo-dependent JJ I-NP human JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O UT-7 NN B-NP Epo NN I-NP . . O The DT B-NP results NNS I-NP were VBD B-VP compared VBN I-VP to TO B-PP those DT B-NP obtained VBN B-VP with IN B-PP the DT B-NP parental JJ I-NP granulocyte-macrophage JJ I-NP colony-stimulating JJ I-NP factor NN I-NP ( ( I-NP GM-CSF NN I-NP ) ) I-NP -dependent JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O UT-7 NN B-NP COMMA COMMA O which WDT B-NP has VBZ B-VP a DT B-NP predominantly RB I-NP megakaryoblastic JJ I-NP phenotype NN I-NP and CC O is VBZ B-VP unable JJ B-ADJP to TO B-VP proliferate VB I-VP continuously RB B-ADVP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP Epo NN B-NP . . O UT-7 NN B-NP Epo NN I-NP and CC O UT-7 NN B-NP expressed VBD B-VP similar JJ B-NP levels NNS I-NP of IN B-PP GATA-1 NN B-NP mRNA NN I-NP and CC O binding NN B-NP activity NN I-NP . . O The DT B-NP two CD I-NP lines NNS I-NP also RB B-ADVP expressed VBD B-VP comparable JJ B-NP levels NNS I-NP of IN B-PP Epo-R NN B-NP mRNA NN I-NP while IN B-SBAR the DT B-NP number NN I-NP of IN B-PP Epo-binding JJ B-NP sites NNS I-NP on IN B-PP UT-7 NN B-NP Epo NN I-NP cells NNS I-NP was VBD B-VP one-sixth CD B-NP the DT I-NP number NN I-NP of IN B-PP UT-7 NN B-NP cells NNS I-NP ( ( O 2400 CD B-NP +\/- CC I-NP 3 CD I-NP vs. CC O 13COMMA800 CD B-NP +\/- CC I-NP 300 CD I-NP ) ) O . . O This DT B-NP difference NN I-NP in IN B-PP the DT B-NP number NN I-NP of IN B-PP binding VBG B-NP sites NNS I-NP could MD B-VP be VB I-VP due JJ B-PP to TO I-PP differences NNS B-NP in IN B-PP cell NN B-NP surface NN I-NP ( ( O UT-7 NN B-NP cells NNS I-NP are VBP B-VP 20 CD B-NP % NN I-NP smaller JJR B-ADJP than IN B-PP the DT B-NP parental JJ I-NP UT-7 NN I-NP cells NNS I-NP ) ) O or CC B-PP in IN B-PP receptor NN B-NP turnover NN I-NP . . O By IN B-PP Northern NN B-NP analysis NN I-NP COMMA COMMA O UT-7 NN B-NP cells NNS I-NP expressed VBD B-VP detectable JJ B-NP levels NNS I-NP of IN B-PP beta- NN B-NP and CC O gamma-globin NN B-NP but CC B-CONJP not RB I-CONJP alpha-globin NN B-NP . . O In IN B-PP comparison NN B-NP COMMA COMMA O UT-7 NN B-NP Epo NN I-NP cells NNS I-NP expressed VBD B-VP alpha-globin NN B-NP and CC O higher JJR B-NP levels NNS I-NP of IN B-PP gamma-globin NN B-NP ( ( O 5-fold JJ B-ADJP ) ) O and CC O beta-globin NN B-NP ( ( O from IN B-PP barely RB B-ADVP to TO B-PP clearly RB B-ADVP detectable JJ B-ADJP ) ) O . . O Globin NN B-NP chains NNS I-NP ( ( O alpha NN B-NP COMMA COMMA O beta NN B-NP and CC O gamma NN B-NP ) ) O were VBD B-VP clearly RB B-ADJP detectable JJ I-ADJP by IN B-PP affinity NN B-NP chromatography NN I-NP in IN B-PP UT-7 NN B-NP Epo NN I-NP but CC B-CONJP not RB I-CONJP in IN B-PP UT-7 NN B-NP cells NNS I-NP . . O The DT B-NP frequency NN I-NP of IN B-PP the DT B-NP cells NNS I-NP which WDT B-NP expressed VBD B-VP beta- NN B-NP and CC O gamma-globin NN B-NP genes NNS I-NP in IN B-PP the DT B-NP two CD I-NP cell NN I-NP populations NNS I-NP was VBD B-VP measured VBN I-VP by IN B-PP immunofluorescence NN B-NP with IN B-PP beta- NN B-NP and CC O gamma-specific JJ B-ADJP antibodies NNS B-NP . . O The DT B-NP number NN I-NP of IN B-PP gamma-positive JJ B-NP cells NNS I-NP and CC O their PRP$ B-NP fluorescence NN I-NP intensity NN I-NP were VBD B-VP higher JJR B-ADJP in IN B-PP UT-7 NN B-NP Epo NN I-NP than IN B-PP in IN B-PP UT-7 NN B-NP cells NNS I-NP ( ( O 0 CD B-NP to TO I-NP 17 CD I-NP % NN I-NP barely RB B-NP positive JJ I-NP cells NNS I-NP and CC O 23 CD B-NP to TO I-NP 40 CD I-NP % NN I-NP clearly RB B-NP positive JJ I-NP cells NNS I-NP COMMA COMMA O respectively RB B-ADVP ) ) O COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP increase NN I-NP in IN B-PP globin NN B-NP mRNA NN I-NP observed VBN B-VP in IN B-PP UT-7 NN B-NP Epo NN I-NP is VBZ B-VP due JJ B-PP to TO I-PP both CC O an DT B-NP increase NN I-NP of IN B-PP gene NN B-NP expression NN I-NP per IN B-PP cell NN B-NP and CC O an DT B-NP increase NN I-NP in IN B-PP numbers NNS B-NP of IN B-PP cells NNS B-NP containing VBG B-VP gamma-globin NN B-NP . . O The DT B-NP levels NNS I-NP of IN B-PP GATA-1 NN B-NP COMMA COMMA O Epo-R NN B-NP and CC O globin NN B-NP mRNA NN I-NP expressed VBN B-VP were VBD B-VP not RB I-VP affected VBN I-VP by IN B-PP a DT B-NP 24-hour JJ I-NP incubation NN I-NP of IN B-PP either CC B-NP cell NN I-NP line NN I-NP with IN B-PP Epo NN B-NP COMMA COMMA O GM-CSF NN B-NP or CC O interleukin-3 NN B-NP ( ( O IL-3 NN B-NP ) ) O . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 400 CD B-NP WORDS NNS I-NP ) ) O Transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT B-NP macrophage NN I-NP colony-stimulating JJ I-NP factor NN I-NP gene NN I-NP by IN B-PP IL-2 NN B-NP is VBZ B-VP associated VBN I-VP with IN B-PP secretion NN B-NP of IN B-PP bioactive JJ B-NP macrophage NN I-NP colony-stimulating JJ I-NP factor NN I-NP protein NN I-NP by IN B-PP monocytes NNS B-NP and CC O involves VBZ B-VP activation NN B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP . . O Human JJ B-NP peripheral JJ I-NP blood NN I-NP monocytes NNS B-NP ( ( O Mo NN B-NP ) ) O constitutively RB B-ADVP display VBP B-VP the DT B-NP beta-chain NN I-NP of IN B-PP the DT B-NP receptor NN I-NP for IN B-PP IL-2 NN B-NP COMMA COMMA O whereas IN O expression NN B-NP of IN B-PP the DT B-NP IL-2R NN I-NP alpha-chain NN I-NP is VBZ B-VP not RB B-ADJP constitutive JJ B-ADJP but CC O inducible JJ B-ADJP with IN B-PP IL-2 NN B-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR binding NN B-NP of IN B-PP human JJ B-NP IL-2 NN I-NP to TO B-PP its PRP$ B-NP binding VBG I-NP site NN I-NP leads VBZ B-VP to TO B-PP transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT O macrophage NN B-NP CSF NN I-NP ( ( O M-CSF NN B-NP ) ) O gene NN B-NP in IN B-PP Mo NN B-NP resulting VBG B-VP in IN B-PP accumulation NN B-NP of IN B-PP M-CSF NN B-NP mRNA NN I-NP and CC O subsequent JJ B-NP release NN I-NP of IN B-PP bioactive JJ B-NP M-CSF NN I-NP protein NN I-NP as IN B-SBAR demonstrated VBN B-VP by IN B-PP ELISA NN B-NP and CC O inhibition NN B-NP of IN B-PP IL-2 NN B-NP induced JJ I-NP release NN I-NP of IN B-PP an DT B-NP activity-stimulating JJ I-NP growth NN I-NP of IN B-PP monocyte-type JJ B-NP colonies NNS I-NP by IN B-PP a DT B-NP neutralizing VBG I-NP anti-M-CSF JJ I-NP antibody NN I-NP . . O Transcriptional JJ B-NP activation NN I-NP of IN B-PP the DT B-NP M-CSF NN I-NP gene NN I-NP by IN B-PP IL-2 NN B-NP is VBZ B-VP preceded VBN I-VP by IN B-PP enhanced VBN B-NP binding NN I-NP activity NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP to TO B-PP its PRP$ B-NP recognition NN I-NP sequence NN I-NP in IN B-PP the DT B-NP 5' JJ I-NP regulatory JJ I-NP enhancer NN I-NP region NN I-NP of IN B-PP the DT B-NP M-CSF NN I-NP gene NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O using VBG B-VP a DT B-NP heterologous JJ I-NP promoter NN I-NP ( ( O herpes NN B-NP thymidine NN I-NP kinase NN I-NP ) ) O construct NN B-NP containing VBG B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP consensus NN I-NP sequence NN I-NP COMMA COMMA O it PRP B-NP is VBZ B-VP shown VBN I-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP binding NN I-NP by IN B-PP an DT B-NP IL-2-induced JJ I-NP monocyte-derived JJ I-NP nuclear JJ I-NP protein NN I-NP confers VBZ B-VP reporter NN B-NP gene NN I-NP ( ( O human JJ B-NP growth NN I-NP hormone NN I-NP ) ) O activity NN B-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O our PRP$ B-NP findings NNS I-NP indicate VBP B-VP that IN B-SBAR IL-2 NN B-NP induces VBZ B-VP gene NN B-NP expression NN I-NP of IN B-PP M-CSF NN B-NP in IN B-PP human JJ B-NP blood-derived JJ I-NP Mo NN I-NP and CC O provide VBP B-VP evidence NN B-NP for IN B-PP involvement NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP transcriptional JJ B-NP regulation NN I-NP of IN B-PP this DT B-NP gene NN I-NP . . O Comparative JJ B-NP analysis NN I-NP of IN B-PP NFAT NN B-NP ( ( O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ) ) O complex JJ B-NP in IN B-PP human JJ O T NN B-NP and CC O B NN B-NP lymphocytes NNS B-NP . . O Nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NFAT NN B-NP ) ) O is VBZ B-VP a DT B-NP transcriptional JJ I-NP activator NN I-NP that WDT B-NP binds VBZ B-VP to TO B-PP sequences NNS B-NP in IN B-PP the DT O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O promoter NN B-NP and CC O is VBZ B-VP thought VBN I-VP to TO I-VP be VB I-VP largely RB B-ADJP responsible JJ I-ADJP for IN B-PP the DT B-NP T NN I-NP cell-specific JJ I-NP inducibility NN I-NP of IN B-PP IL-2 NN B-NP expression NN I-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP ( ( O EMSA NN B-NP ) ) O showed VBD B-VP that IN B-SBAR specific JJ B-NP NFAT NN I-NP binding NN I-NP activity NN I-NP could MD B-VP also RB I-VP be VB I-VP induced VBN I-VP in IN B-PP human JJ B-NP B NN I-NP cells NNS I-NP . . O The DT B-NP B NN I-NP cell NN I-NP NFAT NN I-NP complex NN I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O was VBD B-VP not RB O functional JJ B-ADJP COMMA COMMA O since IN B-SBAR it PRP B-NP failed VBD B-VP to TO I-VP activate VB I-VP transcription NN B-NP from IN B-PP an DT O NFAT-driven JJ O chloramphenicol NN B-NP acetyltransferase NN I-NP ( ( O CAT NN B-NP ) ) O construct NN B-NP . . O Competition NN B-NP with IN B-PP an DT B-NP AP-1 NN I-NP motif NN I-NP or CC B-PP with IN B-PP anti-Jun JJ B-NP and CC I-NP anti-Fos JJ I-NP antibodies NNS I-NP abolished VBD B-VP binding NN B-NP to TO B-PP the DT B-NP NFAT NN I-NP motif NN I-NP in IN B-PP both CC O T NN B-NP and CC O B NN B-NP cells NNS B-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR Jun NN B-NP and CC O Fos NN B-NP are VBP B-VP critical JJ B-ADJP for IN B-PP NFAT NN B-NP complex NN I-NP formation NN I-NP in IN B-PP both DT B-NP cell NN I-NP types NNS I-NP . . O Purified VBN O recombinant JJ O Jun NN B-NP and CC O Fos NN B-NP proteins NNS B-NP failed VBD B-VP to TO I-VP bind VB I-VP directly RB B-ADVP to TO B-PP the DT B-NP NFAT NN I-NP motif NN I-NP . . O However RB B-ADVP COMMA COMMA O when WRB B-ADVP combined VBN B-VP with IN B-PP unstimulated JJ O B NN B-NP or CC O T NN B-NP cell NN B-NP extracts NNS I-NP COMMA COMMA O full-length JJ B-NP COMMA COMMA I-NP but CC I-NP not RB I-NP truncated VBN I-NP COMMA COMMA I-NP Jun\/Fos NN I-NP heterodimers NNS I-NP were VBD B-VP able JJ B-ADJP to TO B-VP form VB I-VP an DT B-NP NFAT NN I-NP complex NN I-NP COMMA COMMA O indicating VBG B-VP the DT B-NP presence NN I-NP of IN B-PP a DT B-NP constitutively RB I-NP expressed VBN I-NP nuclear JJ I-NP factor NN I-NP ( ( I-NP s NNS I-NP ) ) O in IN B-PP B NN B-NP and CC O T NN B-NP cells NNS B-NP necessary JJ B-ADJP for IN B-PP the DT B-NP formation NN I-NP of IN B-PP the DT B-NP NFAT NN I-NP complex NN I-NP in IN B-PP both DT B-NP cell NN I-NP types NNS I-NP . . O An DT B-NP NFAT NN I-NP oligonucleotide NN I-NP carrying VBG B-VP mutations NNS B-NP in IN B-PP the DT B-NP 5' JJ I-NP purine-rich JJ I-NP part NN I-NP of IN B-PP the DT B-NP NFAT NN I-NP sequence NN I-NP failed VBD B-VP to TO I-VP form VB I-VP a DT B-NP complex NN I-NP and CC O to TO B-VP compete VB I-VP with IN B-PP the DT B-NP wild JJ I-NP type NN I-NP motif NN I-NP for IN B-PP NFAT NN B-NP complex NN I-NP formation NN I-NP in IN B-PP both CC O T NN B-NP and CC O B NN B-NP cells NNS B-NP . . O We PRP B-NP therefore RB B-ADVP propose VBP B-VP a DT B-NP model NN I-NP whereby WRB B-ADVP a DT B-NP core NN I-NP NFAT NN I-NP complex NN I-NP consisting VBG B-VP of IN B-PP Jun NN B-NP COMMA COMMA O Fos NN B-NP COMMA COMMA O and CC O a DT B-NP constitutive JJ I-NP nuclear JJ I-NP factor NN I-NP is VBZ B-VP formed VBN I-VP in IN B-PP both DT B-NP T NN B-NP and CC O B NN B-NP cells NNS B-NP COMMA COMMA O but CC O an DT B-NP additional JJ I-NP factor NN I-NP and\/or CC O post-translational JJ B-NP modification NN I-NP of IN B-PP a DT B-NP factor NN I-NP COMMA COMMA O missing VBG B-ADJP in IN B-PP B NN B-NP cells NNS I-NP COMMA COMMA O might MD B-VP be VB I-VP required VBN I-VP for IN B-PP transactivation NN B-NP by IN B-PP NFAT NN B-NP . . O 1COMMA25-Dihydroxy NN B-NP vitamin NN I-NP D3 NN I-NP and CC O 12-O-tetradecanoyl NN B-NP phorbol-13-acetate NN I-NP synergistically RB B-ADVP induce VBP B-VP monocytic JJ B-NP cell NN I-NP differentiation NN I-NP : : O FOS NN B-NP and CC O RB NN B-NP expression NN B-NP . . O 1COMMA25-dihydroxy NN B-NP vitamin NN I-NP D3 NN I-NP and CC O 12-O-tetradecanoyl NN B-NP phorbol-13-acetate NN I-NP ( ( O TPA NN B-NP ) ) O interact VBP B-VP synergistically RB I-VP to TO I-VP induce VB I-VP monocytic JJ B-NP differentiation NN I-NP of IN B-PP U937 NN B-NP histiocytic JJ I-NP lymphoma NN I-NP cells NNS I-NP . . O Addition NN B-NP of IN B-PP TPA NN B-NP causes VBZ B-VP an DT B-NP otherwise JJ I-NP ineffective JJ I-NP dose NN I-NP of IN B-PP 1COMMA25-dihydroxy NN B-NP vitamin NN I-NP D3 NN I-NP to TO B-VP induce VB I-VP differentiation NN B-NP . . O The DT B-NP induced VBD I-NP differentiation NN I-NP depends VBZ B-VP on IN B-PP the DT B-NP simultaneous JJ I-NP ( ( I-NP vs. CC I-NP sequential JJ I-NP ) ) I-NP presence NN I-NP of IN B-PP both DT B-NP agents NNS I-NP . . O The DT B-NP kinetics NNS I-NP of IN B-PP induced JJ B-NP differentiation NN I-NP are VBP B-VP consistent JJ B-ADJP with IN B-PP a DT B-NP G1 NN I-NP specific JJ I-NP cellular JJ I-NP response NN I-NP to TO B-VP initiate VB I-VP the DT B-NP metabolic JJ I-NP cascade NN I-NP culminating VBG B-VP in IN B-PP cell NN B-NP differentiation NN I-NP . . O The DT B-NP induced VBD I-NP differentiation NN I-NP occurs VBZ B-VP with IN B-PP down-regulation NN B-NP of IN B-PP c-fos NN B-NP protein NN I-NP and CC O an DT B-NP accompanying VBG I-NP up-regulation NN I-NP of IN B-PP RB NN B-NP protein NN I-NP expression NN I-NP COMMA COMMA O consistent JJ B-ADJP with IN B-PP a DT B-NP possible JJ I-NP need NN I-NP for IN B-SBAR up-regulated JJ B-NP RB NN I-NP expression NN I-NP to TO B-VP maintain VB I-VP a DT B-NP given JJ I-NP differentiated VBN I-NP phenotype NN I-NP and CC O suppress VB B-VP transcriptional JJ B-NP activators NNS I-NP that WDT B-NP might MD B-VP typically RB I-VP be VB I-VP associated VBN I-VP with IN B-PP proliferation NN B-NP . . O Regulation NN B-NP of IN B-PP lymphoid-specific JJ B-NP immunoglobulin NN I-NP mu NN I-NP heavy NN I-NP chain NN I-NP gene NN I-NP enhancer NN I-NP by IN B-PP ETS-domain JJ B-NP proteins NNS I-NP . . O The DT B-NP enhancer NN I-NP for IN B-PP the DT B-NP immunoglobulin NN I-NP mu NN I-NP heavy NN I-NP chain NN I-NP gene NN I-NP ( ( O IgH NN B-NP ) ) O activates VBZ B-VP a DT B-NP heterologous JJ I-NP gene NN I-NP at IN B-PP the DT B-NP pre-B JJ I-NP cell NN I-NP stage NN I-NP of IN B-PP B NN B-NP lymphocyte NN I-NP differentiation NN I-NP . . O A DT B-NP lymphoid-specific JJ I-NP element NN I-NP COMMA COMMA O microB NN B-NP COMMA COMMA O is VBZ B-VP necessary JJ B-ADJP for IN B-PP enhancer NN B-NP function NN I-NP in IN B-PP pre-B JJ B-NP cells NNS I-NP . . O A DT B-NP microB NN I-NP binding NN I-NP protein NN I-NP is VBZ B-VP encoded VBN I-VP by IN B-PP the DT B-NP PU.1\/Spi-1 NN I-NP proto-oncogene NN I-NP . . O Another DT B-NP sequence NN I-NP element NN I-NP COMMA COMMA O microA NN B-NP COMMA COMMA O was VBD B-VP identified VBN I-VP in IN B-PP the DT B-NP mu NN I-NP enhancer NN I-NP that WDT B-NP binds VBZ B-VP the DT B-NP product NN I-NP of IN B-PP the DT B-NP ets-1 NN I-NP proto-oncogene NN I-NP . . O The DT B-NP microA NN I-NP motif NN I-NP was VBD B-VP required VBN I-VP for IN B-PP microB-dependent JJ B-NP enhancer NN I-NP activity NN I-NP COMMA COMMA O which WDT B-NP suggests VBZ B-VP that IN B-SBAR a DT B-NP minimal JJ I-NP B NN I-NP cell-specific JJ I-NP enhancer NN I-NP is VBZ B-VP composed VBN I-VP of IN B-PP both CC O the DT O PU.1 NN B-NP and CC O Ets-1 NN B-NP binding NN B-NP sites NNS I-NP . . O Co-expression NN B-NP of IN B-PP both CC O PU.1 NN B-NP and CC O Ets-1 NN B-NP in IN B-PP nonlymphoid JJ B-NP cells NNS I-NP trans-activated JJ B-VP reporter NN B-NP plasmids NNS I-NP that WDT B-NP contained VBD B-VP the DT B-NP minimal JJ I-NP mu NN I-NP enhancer NN I-NP . . O These DT B-NP results NNS I-NP implicate VBP B-VP two CD B-NP members NNS I-NP of IN B-PP the DT B-NP Ets NN I-NP family NN I-NP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP IgH NN B-NP gene NN I-NP expression NN I-NP . . O Differential JJ B-NP autoregulation NN I-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP expression NN I-NP in IN B-PP human JJ O T- NN B-NP and CC O B-cell NN B-NP lines NNS B-NP . . O Regulation NN B-NP of IN B-PP glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O expression NN B-NP by IN B-PP its PRP$ B-NP cognate JJ I-NP ligand NN I-NP was VBD B-VP examined VBN I-VP in IN B-PP the DT B-NP glucocorticoid-sensitive JJ I-NP human JJ I-NP leukemic JJ I-NP T-cell NN I-NP line NN I-NP 6TG1.1 NN I-NP and CC B-PP in IN B-PP the DT B-NP human JJ I-NP B-cell NN I-NP line NN I-NP IM-9 NN I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP the DT B-NP decrease NN I-NP in IN B-PP GR NN B-NP mRNA NN I-NP seen VBN B-VP in IN B-PP IM-9 NN B-NP cells NNS I-NP after IN B-PP treatment NN B-NP with IN B-PP 1 CD B-NP microM NN I-NP dexamethasone NN I-NP for IN B-PP 16-18 CD B-NP h NN I-NP COMMA COMMA O treatment NN B-NP of IN B-PP 6TG1.1 NN B-NP cells NNS I-NP resulted VBD B-VP in IN B-PP an DT B-NP 8-fold JJ I-NP increase NN I-NP in IN B-PP GR NN B-NP mRNA NN I-NP COMMA COMMA O as IN B-SBAR determined VBN B-VP by IN B-PP Northern NN B-NP blot NN I-NP and CC O RNase NN B-NP protection NN I-NP analysis NN B-NP COMMA COMMA O with IN B-PP a DT O corresponding JJ O 3- CD B-NP to TO O 4-fold JJ B-ADJP increase NN B-NP in IN B-PP GR NN B-NP protein NN I-NP . . O Half-maximal JJ B-NP induction NN I-NP of IN B-PP GR NN B-NP mRNA NN B-NP and CC O protein NN B-NP in IN B-PP 6TG1.1 NN B-NP cells NNS I-NP was VBD B-VP observed VBN I-VP between IN B-PP 10-100 CD B-NP nM NN I-NP dexamethasone NN I-NP COMMA COMMA O and CC O inclusion NN B-NP of IN B-PP 1 CD B-NP microM NN I-NP RU NN I-NP 38486 CD I-NP completely RB B-ADVP blocked VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP 100 CD B-NP nM NN I-NP dexamethasone NN I-NP COMMA COMMA O demonstrating VBG B-VP that IN B-SBAR positive JJ B-NP autoregulation NN I-NP of IN B-PP GR NN B-NP expression NN I-NP in IN B-PP 6TG1.1 NN B-NP cells NNS I-NP is VBZ B-VP a DT B-NP receptor-mediated JJ I-NP response NN I-NP . . O Positive JJ B-NP autoregulation NN I-NP of IN B-PP GR NN B-NP expression NN I-NP was VBD B-VP also RB I-VP observed VBN I-VP in IN B-PP glucocorticoid-resistant JJ B-NP CEM-C1 NN I-NP cells NNS I-NP COMMA COMMA O which WDT B-NP contain VBP B-VP functional JJ B-NP GR NN I-NP COMMA COMMA O but CC O whose WP$ B-NP growth NN I-NP is VBZ B-VP unaffected VBN I-VP by IN B-PP glucocorticoids NNS B-NP . . O Thus RB B-ADVP COMMA COMMA O positive JJ B-NP autoregulation NN I-NP is VBZ B-VP neither CC O a DT B-NP consequence NN I-NP nor CC O the DT B-NP sole JJ I-NP cause NN I-NP of IN B-PP growth NN B-NP arrest NN I-NP . . O The DT B-NP degree NN I-NP of IN B-PP negative JJ B-NP autoregulation NN I-NP in IN B-PP IM-9 NN B-NP cells NNS I-NP and CC O positive JJ B-NP autoregulation NN I-NP in IN B-PP 6TG1.1 NN B-NP cells NNS I-NP was VBD B-VP unaffected VBN I-VP by IN B-PP inhibition NN B-NP of IN B-PP protein NN B-NP synthesis NN I-NP with IN B-PP cycloheximide NN B-NP . . O Measurement NN B-NP of IN B-PP GR NN B-NP mRNA NN I-NP turnover NN I-NP in IN B-PP 6TG1.1 NN B-NP cells NNS I-NP treated VBN B-VP with IN B-PP actinomycin-D NN B-NP revealed VBD B-VP a DT B-NP half-life NN I-NP of IN B-PP 2.5 CD B-NP h NN I-NP COMMA COMMA O which WDT B-NP was VBD B-VP unaffected JJ I-VP by IN B-PP dexamethasone NN B-NP treatment NN I-NP . . O A DT B-NP similar JJ I-NP half-life NN I-NP was VBD B-VP determined VBN I-VP in IN B-PP IM-9 NN B-NP cells NNS I-NP and CC O was VBD B-VP also RB I-VP unaffected JJ I-VP by IN B-PP steroid NN B-NP treatment NN I-NP . . O These DT B-NP results NNS I-NP are VBP B-VP consistent JJ B-ADJP with IN B-PP the DT B-NP interpretation NN I-NP that IN B-SBAR glucocorticoid-mediated JJ B-NP autoregulation NN I-NP of IN B-PP GR NN B-NP expression NN I-NP is VBZ B-VP a DT B-NP tissue-specific JJ I-NP primary JJ I-NP transcriptional JJ I-NP response NN I-NP . . O The DT B-NP p65 NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP regulates VBZ B-VP I NN B-NP kappa NN I-NP B NN I-NP by IN B-PP two CD B-NP distinct JJ I-NP mechanisms NNS I-NP . . O Transcription NN B-NP factor NN I-NP NF-kappa NN I-NP B NN I-NP ( ( O p50\/p65 NN B-NP ) ) O is VBZ B-VP generally RB I-VP localized JJ I-VP to TO B-PP the DT B-NP cytoplasm NN I-NP by IN B-PP its PRP$ B-NP inhibitor NN I-NP I NN I-NP kappa NN I-NP B NN I-NP . . O Overproduced JJ B-NP I NN I-NP kappa NN I-NP B NN I-NP COMMA COMMA O free JJ B-ADJP from IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O is VBZ B-VP rapidly RB I-VP degraded VBN I-VP . . O Overexpression NN B-NP of IN B-PP p65 NN B-NP increases VBZ B-VP endogenous JJ B-NP I NN I-NP kappa NN I-NP B NN I-NP protein NN I-NP in IN B-PP both CC O carcinoma NN B-NP and CC O lymphoid JJ B-NP cells NNS I-NP by IN B-PP two CD B-NP mechanisms NNS I-NP : : O protein NN B-NP stabilization NN I-NP and CC O increased VBN B-NP transcription NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B NN I-NP mRNA NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O p65 NN B-NP delta NN I-NP COMMA COMMA O a DT B-NP naturally RB I-NP occurring VBG I-NP splice NN I-NP variant NN I-NP COMMA COMMA O fails VBZ B-VP to TO I-VP markedly RB I-VP augment VB I-VP I NN B-NP kappa NN I-NP B NN I-NP protein NN I-NP levels NNS I-NP . . O Both CC O overexpressed JJ B-NP p65 NN I-NP and CC O coexpressed JJ B-NP p50 NN I-NP are VBP B-VP cytoplasmic JJ B-ADJP COMMA COMMA O whereas IN O p65 NN B-NP delta NN I-NP is VBZ B-VP partly RB B-ADJP nuclear JJ I-ADJP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP I NN I-NP kappa NN I-NP B NN I-NP induced VBN B-VP by IN B-PP p65 NN B-NP can MD B-VP maintain VB I-VP NF-kappa NN B-NP B NN I-NP in IN B-PP the DT B-NP cytoplasm NN I-NP . . O Thus RB B-ADVP COMMA COMMA O p65 NN B-NP and CC O I NN B-NP kappa NN I-NP B NN I-NP are VBP B-VP linked VBN I-VP in IN B-PP an DT B-NP autoregulatory JJ I-NP loop NN I-NP COMMA COMMA O ensuring VBG B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP is VBZ B-VP held VBN I-VP in IN B-PP the DT B-NP cytoplasm NN I-NP until IN B-SBAR cells NNS B-NP are VBP B-VP specifically RB I-VP induced VBN I-VP to TO I-VP translocate VB I-VP it PRP B-NP to TO B-PP the DT B-NP nucleus NN I-NP . . O Cell NN B-NP cycle NN I-NP analysis NN I-NP of IN B-PP E2F NN B-NP in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP reveals VBZ B-VP novel JJ B-NP E2F NN I-NP complexes NNS I-NP and CC O biochemically RB B-NP distinct JJ I-NP forms NNS I-NP of IN B-PP free JJ B-NP E2F NN I-NP . . O The DT B-NP transcription NN I-NP factor NN I-NP E2F NN I-NP activates VBZ B-VP the DT B-NP expression NN I-NP of IN B-PP multiple JJ B-NP genes NNS I-NP involved VBN B-VP in IN B-PP cell NN B-NP proliferation NN I-NP COMMA COMMA O such JJ B-PP as IN I-PP c-myc NN B-NP and CC O the DT B-NP dihydrofolate JJ I-NP reductase NN I-NP gene NN I-NP . . O Regulation NN B-NP of IN B-PP E2F NN B-NP involves VBZ B-VP its PRP$ B-NP interactions NNS I-NP with IN B-PP other JJ B-NP cellular JJ I-NP proteins NNS I-NP COMMA COMMA O including VBG B-PP the DT B-NP retinoblastoma NN I-NP protein NN I-NP ( ( O Rb NN B-NP ) ) O COMMA COMMA O the DT B-NP Rb-related JJ I-NP protein NN I-NP p107 NN I-NP COMMA COMMA O cyclin NN B-NP A NN I-NP COMMA COMMA O and CC O cdk2 NN B-NP . . O We PRP B-NP undertook VBD B-VP a DT B-NP detailed JJ I-NP analysis NN I-NP of IN B-PP E2F NN B-NP DNA-binding JJ I-NP activities NNS I-NP and CC O their PRP$ B-NP cell NN I-NP cycle NN I-NP behavior NN I-NP in IN B-PP primary JJ B-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O Three CD B-NP E2F NN I-NP DNA-binding JJ I-NP activities NNS I-NP were VBD B-VP identified VBN I-VP in IN B-PP resting VBG B-NP ( ( I-NP G0 NN I-NP ) ) I-NP T NN I-NP cells NNS I-NP with IN B-PP mobilities NNS B-NP in IN B-PP gel NN B-NP shift NN I-NP assays NNS I-NP distinct JJ B-ADJP from IN B-PP those DT B-NP of IN B-PP previously RB B-NP defined VBN I-NP E2F NN I-NP complexes NNS I-NP . . O One CD B-NP of IN B-PP these DT B-NP activities NNS I-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP a DT B-NP novel JJ I-NP COMMA COMMA I-NP less RBR I-NP abundant JJ I-NP COMMA COMMA I-NP Rb-E2F NN I-NP complex NN I-NP . . O The DT B-NP most RBS I-NP prominent JJ I-NP E2F NN I-NP activity NN I-NP in IN B-PP resting VBG B-NP T NN I-NP cells NNS I-NP ( ( O termed VBN B-VP complex JJ B-NP X NN I-NP ) ) O was VBD B-VP abundant JJ B-ADJP in IN B-PP both CC O G0 NN B-NP and CC O G1 NN B-NP but CC O disappeared VBD B-VP as IN B-SBAR cells NNS B-NP entered VBD B-VP S NN B-NP phase NN I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP possible JJ I-NP role NN I-NP in IN B-PP negatively RB B-NP regulating VBG I-NP E2F NN I-NP function NN I-NP . . O Complex NN B-NP X NN I-NP could MD B-VP be VB I-VP dissociated VBN I-VP by IN B-PP adenovirus NN B-NP E1A NN I-NP with IN B-PP a DT B-NP requirement NN I-NP for IN B-PP an DT B-NP intact JJ I-NP E1A NN I-NP conserved VBN I-NP region NN I-NP 2 CD I-NP . . O However RB B-ADVP COMMA COMMA O X NN B-NP failed VBD B-VP to TO I-VP react VB I-VP with IN B-PP a DT B-NP variety NN I-NP of IN B-PP antibodies NNS B-NP against IN B-PP Rb NN B-NP or CC O p107 NN B-NP COMMA COMMA O implicating VBG B-VP the DT B-NP involvement NN I-NP of IN B-PP an DT B-NP E1A-binding JJ I-NP protein NN I-NP other JJ B-PP than IN I-PP Rb NN B-NP or CC O p107 NN B-NP . . O In IN B-PP addition NN I-PP to TO I-PP these DT B-NP novel JJ I-NP E2F NN I-NP complexes NNS I-NP COMMA COMMA O three CD B-NP distinct JJ I-NP forms NNS I-NP of IN B-PP unbound JJ O ( ( O free JJ B-ADJP ) ) O E2F NN B-NP were VBD B-VP resolved VBN I-VP in IN B-PP gel NN B-NP shift NN I-NP experiments NNS I-NP . . O These DT B-NP species NNS I-NP showed VBD B-VP different JJ B-NP cell NN I-NP cycle NN I-NP kinetics NNS I-NP . . O UV NN B-NP cross-linking JJ I-NP experiments NNS I-NP suggested VBD B-VP that IN B-SBAR a DT B-NP distinct JJ I-NP E2F NN I-NP DNA-binding JJ I-NP protein NN I-NP is VBZ B-VP uniquely RB I-VP associated VBN I-VP with IN B-PP the DT B-NP S-phase NN I-NP p107 NN I-NP complex NN I-NP and CC O is VBZ B-VP not RB I-VP associated VBN I-VP with IN B-PP Rb NN B-NP . . O Together RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR E2F NN B-NP consists VBZ B-VP of IN B-PP multiple JJ B-NP COMMA COMMA I-NP biochemically RB I-NP distinct JJ I-NP DNA-binding JJ I-NP proteins NNS I-NP which WDT B-NP function VBP B-VP at IN B-PP different JJ B-NP points NNS I-NP in IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP . . O Occurrence NN B-NP of IN B-PP a DT B-NP silencer NN I-NP of IN B-PP the DT B-NP interleukin-2 NN I-NP gene NN I-NP in IN B-PP naive JJ B-NP but CC B-PP not RB B-PP in IN I-PP memory NN B-NP resting VBG I-NP T NN B-NP helper NN I-NP lymphocytes NNS I-NP . . O In IN B-PP the DT B-NP immune JJ I-NP system NN I-NP the DT B-NP first JJ I-NP activation NN I-NP of IN B-PP a DT B-NP naive JJ I-NP T NN I-NP cell NN I-NP by IN B-PP antigen NN B-NP is VBZ B-VP a DT B-NP key JJ I-NP step NN I-NP in IN B-PP the DT B-NP shaping NN B-NP of IN B-PP the DT B-NP peripheral JJ I-NP T NN I-NP cell NN I-NP specificity NN I-NP repertoire NN I-NP and CC O maintenance NN B-NP of IN B-PP self-tolerance NN B-NP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP COMMA COMMA O analysis NN B-NP of IN B-PP the DT O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O gene NN B-NP activation NN I-NP shows VBZ B-VP that IN B-SBAR naive JJ B-NP human JJ I-NP helper NN I-NP T NN I-NP cells NNS I-NP ( ( O cord NN B-NP blood NN I-NP CD4+ JJ I-NP T NN I-NP cells NNS I-NP COMMA COMMA O adult JJ B-NP CD4+CD45RO- JJ I-NP T NN I-NP cells NNS I-NP ) ) O regulate VBP B-VP IL-2 NN B-NP transcription NN I-NP by IN B-PP a DT B-NP mechanism NN I-NP involving VBG B-VP both CC O a DT B-NP silencer NN I-NP and CC O an DT B-NP activator NN I-NP acting VBG B-VP on IN B-PP the DT B-NP purine-rich JJ I-NP IL-2 NN I-NP promoter NN I-NP elements NNS I-NP ( ( O NF-AT NN B-NP binding NN I-NP sites NNS I-NP ) ) O . . O By IN B-PP contrast NN B-NP COMMA COMMA O memory NN B-NP cells NNS I-NP COMMA COMMA O either CC O in FW B-ADVP vitro FW I-ADVP activated VBN B-NP helper NN I-NP T NN I-NP cells NNS I-NP reverting VBG B-VP to TO B-PP a DT B-NP resting JJ I-NP state NN I-NP COMMA COMMA O or CC O CD4+ JJ B-NP T NN I-NP ( ( I-NP memory NN I-NP ) ) I-NP clones NNS I-NP COMMA COMMA O or CC O CD4+CD45RO+ JJ B-NP T NN I-NP cells NNS I-NP isolated VBN B-VP ex FW B-ADVP vivo FW I-ADVP COMMA COMMA O no RB B-ADVP longer RB I-ADVP have VBP B-VP a DT B-NP silencer NN I-NP . . O Their PRP$ B-NP IL-2 NN I-NP transcription NN I-NP seems VBZ B-VP to TO I-VP be VB I-VP controlled VBN I-VP solely RB B-PP by IN I-PP the DT B-NP transition NN I-NP from IN B-PP inactive JJ B-NP to TO B-PP active JJ B-NP functional JJ B-NP state NN I-NP of IN B-PP a DT B-NP positive JJ I-NP transcription NN I-NP factor NN I-NP binding VBG B-VP to TO B-PP these DT B-NP promoter NN I-NP elements NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP its PRP$ B-NP cytoplasmic JJ I-NP or CC I-NP nuclear JJ I-NP location NN I-NP : : O in IN B-PP resting VBG B-NP memory NN I-NP T NN I-NP cells NNS I-NP the DT B-NP activator NN I-NP is VBZ B-VP located JJ B-ADJP in IN B-PP the DT B-NP cytoplasm NN I-NP and CC O is VBZ B-VP inactive JJ B-ADJP COMMA COMMA O whereas IN O in IN B-PP stimulated VBN B-NP cells NNS I-NP it PRP B-NP is VBZ B-VP functional JJ B-ADJP in IN B-PP promoting VBG B-VP transcription NN B-NP and CC O now RB B-VP resides VBZ I-VP in IN B-PP the DT B-NP nucleus NN I-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP gene NN I-NP coding VBG I-NP for IN B-PP the DT B-NP main JJ I-NP T NN I-NP cell NN I-NP growth NN I-NP factor NN I-NP changes VBZ B-VP irreversibly RB B-ADVP after IN B-PP the DT B-NP first JJ I-NP encounter NN I-NP of IN B-PP T NN B-NP cells NNS I-NP with IN B-PP antigen NN B-NP . . O It PRP B-NP is VBZ B-VP most RBS B-ADJP likely JJ I-ADJP that IN B-SBAR the DT B-NP presence NN I-NP of IN B-PP a DT B-NP silencer NN I-NP contributes VBZ B-VP to TO B-PP the DT B-NP more RBR I-NP stringent JJ I-NP activation NN I-NP requirements NNS I-NP of IN B-PP naive JJ B-NP CD4+ JJ I-NP T NN I-NP cells NNS I-NP . . O Single JJ B-NP strand NN I-NP conformation NN I-NP polymorphism NN I-NP analysis NN I-NP of IN B-PP androgen NN B-NP receptor NN I-NP gene NN I-NP mutations NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP androgen NN B-NP insensitivity NN I-NP syndromes NNS I-NP : : O application NN B-NP for IN B-PP diagnosis NN B-NP COMMA COMMA O genetic JJ B-NP counseling NN I-NP COMMA COMMA O and CC O therapy NN B-NP . . O Recent JJ B-NP studies NNS I-NP indicate VBP B-VP that IN B-SBAR mutations NNS B-NP in IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP are VBP B-VP associated VBN I-VP with IN B-PP androgen NN B-NP insensitivity NN I-NP syndromes NNS I-NP COMMA COMMA O a DT B-NP heterogeneous JJ I-NP group NN I-NP of IN B-PP related JJ B-NP disorders NNS I-NP involving VBG B-VP defective JJ B-NP sexual JJ I-NP differentiation NN I-NP in IN B-PP karyotypic JJ B-NP males NNS I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP address VBP B-VP the DT B-NP possibility NN I-NP of IN B-PP rapid JJ B-NP mutational JJ I-NP analysis NN I-NP of IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP for IN B-PP initial JJ B-NP diagnosis NN I-NP COMMA COMMA O genetic JJ B-NP counseling NN I-NP COMMA COMMA O and CC O molecular JJ B-NP subclassification NN I-NP of IN B-PP affected VBN B-NP patients NNS I-NP and CC O their PRP$ B-NP families NNS I-NP . . O DNA NN B-NP from IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP of IN B-PP six CD B-NP patients NNS I-NP from IN B-PP five CD B-NP families NNS I-NP with IN B-PP various JJ B-NP degrees NNS I-NP of IN B-PP androgen NN B-NP insensitivity NN I-NP was VBD B-VP studied VBN I-VP . . O Exons NNS B-NP 2 CD B-NP to TO O 8 CD B-NP of IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP were VBD B-VP analyzed VBN I-VP using VBG B-VP a DT B-NP combination NN I-NP of IN B-PP single JJ B-NP strand NN I-NP conformation NN I-NP polymorphism NN I-NP analysis NN I-NP and CC O direct JJ B-NP DNA NN I-NP sequencing NN I-NP . . O Female JJ B-NP family NN I-NP members NNS I-NP were VBD B-VP also RB I-VP studied VBN I-VP to TO B-VP identify VB I-VP heterozygote NN B-NP carriers NNS I-NP . . O Point NN B-NP mutations NNS I-NP in IN B-PP the DT B-NP AR NN I-NP gene NN I-NP were VBD B-VP identified VBN I-VP in IN B-PP all DT B-NP six CD I-NP patients NNS I-NP COMMA COMMA O and CC O all DT B-NP mutations NNS I-NP caused VBD B-VP amino NN B-NP acid NN I-NP substitutions NNS I-NP . . O One CD B-NP patient NN I-NP with IN B-PP incomplete JJ B-NP androgen NN I-NP insensitivity NN I-NP was VBD B-VP a DT B-NP mosaic NN I-NP for IN B-PP the DT B-NP mutation NN I-NP . . O Four CD B-NP of IN B-PP the DT B-NP five CD I-NP mothers NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP a DT B-NP young JJ I-NP sister NN I-NP of IN B-PP one CD B-NP patient NN I-NP COMMA COMMA O were VBD B-VP carriers NNS B-NP of IN B-PP the DT B-NP mutation NN I-NP present JJ B-ADJP in IN B-PP the DT B-NP affected VBN I-NP child NN I-NP . . O Our PRP$ B-NP data NNS I-NP show VBP B-VP that IN B-SBAR new JJ B-NP mutations NNS I-NP may MD B-VP occur VB I-VP in IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP leading VBG B-VP to TO B-PP sporadic JJ B-NP androgen NN I-NP insensitivity NN I-NP syndrome NN I-NP . . O Molecular JJ B-NP genetic JJ I-NP characterization NN I-NP of IN B-PP the DT B-NP variant JJ I-NP allele NN I-NP can MD B-VP serve VB I-VP as IN B-PP a DT B-NP primary JJ I-NP tool NN I-NP for IN B-PP diagnosis NN B-NP and CC O subsequent JJ B-NP therapy NN I-NP COMMA COMMA O and CC O can MD B-VP provide VB I-VP a DT B-NP basis NN I-NP for IN B-PP distinguishing VBG B-VP heterozygous JJ B-NP carriers NNS I-NP in IN B-PP familial JJ B-NP androgen NN I-NP resistance NN I-NP . . O The DT B-NP identification NN I-NP of IN B-PP carriers NNS B-NP is VBZ B-VP of IN B-PP substantial JJ B-NP clinical JJ I-NP importance NN I-NP for IN B-PP genetic JJ B-NP counseling NN I-NP . . O Minimally RB B-NP modified VBN I-NP low JJ I-NP density NN I-NP lipoprotein-induced JJ I-NP inflammatory JJ I-NP responses NNS I-NP in IN B-PP endothelial JJ B-NP cells NNS I-NP are VBP B-VP mediated VBN I-VP by IN B-PP cyclic JJ B-NP adenosine NN I-NP monophosphate NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR minimally RB B-NP oxidized VBN I-NP LDL NN I-NP ( ( O MM-LDL NN B-NP ) ) O activated VBD B-VP endothelial JJ B-NP cells NNS I-NP to TO B-VP increase VB I-VP their PRP$ B-NP interaction NN I-NP with IN B-PP monocytes NNS B-NP but CC B-CONJP not RB I-CONJP neutrophils NNS B-NP COMMA COMMA O inducing VBG B-VP monocyte NN B-NP but CC B-CONJP not RB I-CONJP neutrophil NN B-NP binding NN B-NP and CC O synthesis NN B-NP of IN B-PP monocyte NN B-NP chemotactic JJ I-NP protein-1 NN I-NP and CC O monocyte NN B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O M-CSF NN B-NP ) ) O . . O In IN B-PP the DT B-NP present JJ I-NP studies NNS I-NP we PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP signaling NN I-NP pathways NNS I-NP by IN B-PP which WDT B-NP this DT B-NP monocyte-specific JJ I-NP response NN I-NP is VBZ B-VP induced VBN I-VP . . O Both CC O induction NN B-NP of IN B-PP monocyte NN B-NP binding NN I-NP and CC O mRNA NN B-NP levels NNS I-NP for IN B-PP M-CSF NN B-NP by IN B-PP MM-LDL NN B-NP were VBD B-VP not RB I-VP inhibited VBN I-VP in IN B-PP protein NN B-NP kinase NN I-NP C-depleted JJ I-NP endothelial JJ I-NP cells NNS I-NP . . O A DT B-NP number NN I-NP of IN B-PP our PRP$ B-NP studies NNS I-NP indicate VBP B-VP that IN B-SBAR cAMP NN B-NP is VBZ B-VP the DT B-NP second JJ I-NP messenger NN I-NP for IN B-PP the DT B-NP effects NNS I-NP of IN B-PP MM-LDL NN B-NP cited VBN B-VP above RB B-ADVP . . O Incubation NN B-NP of IN B-PP endothelial JJ B-NP cells NNS I-NP with IN B-PP MM-LDL NN B-NP caused VBD I-NP a DT O 173 CD B-NP % NN I-NP increase NN I-NP in IN B-PP intracellular JJ B-NP cAMP NN I-NP levels NNS I-NP . . O Agents NNS B-NP which WDT B-NP increased VBD B-VP cAMP NN B-NP levels NNS I-NP COMMA COMMA O including VBG B-PP cholera NN B-NP toxin NN I-NP COMMA COMMA O pertussis NN B-NP toxin NN I-NP COMMA COMMA O dibutyryl NN B-NP cAMP NN I-NP COMMA COMMA O and CC O isoproterenol NN B-NP mimicked VBD B-VP the DT B-NP actions NNS I-NP of IN B-PP MM-LDL NN B-NP . . O Agents NNS B-NP which WDT B-NP elevated VBD B-VP cAMP NN B-NP were VBD B-VP also RB I-VP shown VBN I-VP to TO I-VP activate VB I-VP NF NN B-NP kappa NN I-NP B NN I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP role NN I-NP for IN B-PP this DT B-NP transcription NN I-NP factor NN I-NP in IN B-PP activation NN B-NP of IN B-PP monocyte-endothelial JJ B-NP interactions NNS I-NP . . O Although IN B-SBAR endothelial JJ B-NP leukocyte NN I-NP adhesion NN I-NP molecule NN I-NP ( ( O ELAM NN B-NP ) ) O mRNA NN B-NP synthesis NN I-NP can MD B-VP be VB I-VP regulated VBN I-VP by IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP COMMA COMMA O ELAM NN B-NP was VBD B-VP not RB I-VP expressed VBN I-VP and CC O ELAM NN B-NP mRNA NN I-NP was VBD B-VP only RB I-VP slightly RB I-VP elevated JJ I-VP in IN B-PP response NN I-PP to TO I-PP MM-LDL NN B-NP . . O We PRP B-NP present VBP B-VP evidence NN B-NP that IN B-SBAR induction NN B-NP of IN B-PP neutrophil NN B-NP binding NN I-NP by IN B-PP LPS NN B-NP is VBZ B-VP actually RB I-VP suppressed VBN I-VP by IN B-PP agents NNS B-NP that WDT B-NP elevated VBD B-VP cAMP NN B-NP levels NNS I-NP . . O Antisense JJ B-NP oligonucleotides NNS I-NP to TO B-PP the DT B-NP p65 NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP block VBP B-VP CD11b NN B-NP expression NN I-NP and CC O alter VBP B-VP adhesion NN B-NP properties NNS I-NP of IN B-PP differentiated VBN B-NP HL-60 NN I-NP granulocytes NNS I-NP . . O NF-kappa NN B-NP B NN I-NP is VBZ B-VP a DT B-NP pleiotropic JJ I-NP regulator NN I-NP of IN B-PP a DT B-NP variety NN I-NP of IN B-PP genes NNS B-NP implicated VBN B-VP in IN B-PP the DT B-NP cellular JJ I-NP response NN I-NP to TO B-PP injury NN B-NP . . O This DT B-NP function NN I-NP has VBZ B-VP been VBN I-VP attributed VBN I-VP to TO B-PP the DT B-NP coordinated VBN I-NP binding NN I-NP of IN B-PP subunits NNS B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP to TO B-PP distinct JJ B-NP regions NNS I-NP of IN B-PP the DT B-NP promoter JJ I-NP elements NNS I-NP of IN B-PP numerous JJ B-NP genes NNS I-NP COMMA COMMA O including VBG B-PP cytokines NNS B-NP COMMA COMMA O growth NN B-NP factor NN I-NP receptors NNS I-NP COMMA COMMA O and CC O adhesion NN B-NP molecules NNS I-NP . . O Antisense JJ B-NP phosphorothioate JJ I-NP oligonucleotides NNS I-NP to TO B-PP the DT O p50 NN B-NP and CC O p65 NN B-NP subunits NNS B-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP were VBD B-VP used VBN I-VP to TO B-VP define VB I-VP the DT B-NP physiologic JJ I-NP role NN I-NP of IN B-PP this DT B-NP transcription NN I-NP factor NN I-NP in IN B-PP resting VBG B-NP and CC I-NP stimulated VBN I-NP granulocytes NNS I-NP . . O A DT B-NP reduction NN I-NP in IN B-PP the DT B-NP expression NN I-NP of IN B-PP p65 NN B-NP was VBD B-VP produced VBN I-VP by IN B-PP treatment NN B-NP with IN B-PP the DT B-NP phosphorothioate JJ I-NP antisense JJ I-NP oligodeoxynucleotide NN I-NP . . O This DT B-NP reduction NN I-NP was VBD B-VP accompanied VBN I-VP by IN B-PP rapid JJ B-NP changes NNS I-NP in IN B-PP the DT B-NP cellular JJ I-NP adhesion NN I-NP of IN B-PP dimethyl JJ B-NP sulfoxide-differentiated JJ I-NP HL-60 NN I-NP leukemia NN I-NP cells NNS I-NP stimulated VBN B-VP by IN B-PP 12-O-tetradecanoylphorbol NN B-NP 13-acetate NN I-NP ( ( O TPA NN B-NP ) ) O . . O These DT B-NP effects NNS I-NP were VBD B-VP characterized VBN I-VP by IN B-PP a DT B-NP marked JJ I-NP reduction NN I-NP in IN B-PP CD11b NN B-NP integrin JJ I-NP expression NN I-NP on IN B-PP the DT B-NP surface NN I-NP of IN B-PP treated VBN B-NP cells NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP p65 NN I-NP antisense JJ I-NP oligomer NN I-NP effectively RB B-ADVP abolished VBD B-VP an DT B-NP upregulation NN I-NP of IN B-PP CD11b NN B-NP that WDT B-NP was VBD B-VP produced VBN I-VP by IN B-PP formyl-met-leu-phe NN B-NP and CC O TPA NN B-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP p65 NN I-NP antisense JJ I-NP phosphorothioate JJ I-NP oligodeoxynucleotide NN I-NP had VBD B-VP no DT B-NP significant JJ I-NP effect NN I-NP on IN B-PP the DT B-NP production NN I-NP of IN B-PP reactive JJ B-NP oxygen NN I-NP intermediates NNS I-NP or CC B-PP on IN B-PP phagocytosis NNS B-NP by IN B-PP these DT B-NP cells NNS I-NP . . O These DT B-NP findings NNS I-NP indicate VBP B-VP that IN B-SBAR antisense JJ B-NP oligomers NNS I-NP to TO B-PP p65 NN B-NP can MD B-VP be VB I-VP used VBN I-VP to TO B-VP define VB I-VP the DT B-NP role NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP the DT B-NP activation NN I-NP pathways NNS I-NP of IN B-PP neutrophils NNS B-NP . . O Costimulation NN B-NP of IN B-PP cAMP NN B-NP and CC O protein NN B-NP kinase NN I-NP C NN I-NP pathways NNS B-NP inhibits VBZ B-VP the DT B-NP CD3-dependent JJ I-NP T NN I-NP cell NN I-NP activation NN I-NP and CC O leads VBZ B-VP to TO B-PP a DT B-NP persistent JJ I-NP expression NN I-NP of IN B-PP the DT B-NP AP-1 NN I-NP transcription NN I-NP factor NN I-NP . . O The DT B-NP effects NNS I-NP mediated VBN B-VP by IN B-PP a DT B-NP combined JJ I-NP stimulation NN I-NP of IN B-PP cAMP- NN B-NP and CC O protein NN B-ADJP kinase NN I-ADJP C NN I-ADJP ( ( I-ADJP PKC NN I-ADJP ) ) I-ADJP -dependent JJ I-ADJP pathways NNS B-NP have VBP B-VP been VBN I-VP investigated VBN I-VP in IN B-PP different JJ B-NP cellular JJ I-NP systems NNS I-NP COMMA COMMA O and CC O it PRP B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP that IN B-SBAR they PRP B-NP may MD B-VP complement VB I-VP each DT B-NP other JJ I-NP in IN B-PP activating VBG B-VP cell NN B-NP proliferation NN B-NP and CC O differentiation NN B-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR upon IN B-PP the DT B-NP stimulation NN I-NP of IN B-PP both DT B-NP pathways NNS I-NP T NN B-NP lymphocytes NNS I-NP became VBD B-VP refractory JJ B-ADJP to TO B-PP activation NN B-NP via IN B-PP the DT B-NP CD3\/T NN I-NP cell NN I-NP receptor NN I-NP ( ( I-NP TcR NN I-NP ) ) I-NP complex NN I-NP . . O T NN B-NP cells NNS I-NP preincubated VBN B-VP with IN B-PP phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O and CC O dibutyryl NN B-NP cAMP NN I-NP ( ( O Bt2cAMP NN B-NP ) ) O displayed VBD B-VP a DT B-NP deficient JJ I-NP proliferative JJ I-NP ability NN I-NP in IN B-PP response NN I-PP to TO I-PP anti-CD3 JJ B-NP mAb NN I-NP stimulation NN I-NP COMMA COMMA O whereas IN O lymphocytes NNS B-NP treated VBN B-VP individually RB B-ADVP with IN B-PP either CC O Bt2cAMP NN B-NP or CC O PMA NN B-NP responded VBD B-VP comparably RB B-ADVP to TO B-PP untreated JJ B-NP samples NNS I-NP . . O We PRP B-NP detected VBD B-VP an DT B-NP association NN I-NP between IN B-PP the DT B-NP reduced VBN B-NP mitogenic JJ I-NP response NN I-NP and CC O low JJ B-NP expression NN I-NP of IN B-PP both CC O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O and CC O the DT B-NP alpha NN I-NP chain NN I-NP ( ( O CD25 NN B-NP ) ) O of IN B-PP the DT B-NP IL-2 NN I-NP receptor NN I-NP ( ( O IL-2R NN B-NP ) ) O . . O Analysis NN B-NP of IN B-PP intracellular JJ B-NP Ca2+ NN I-NP mobilization NN I-NP suggested VBD B-VP that IN B-SBAR the DT B-NP CD3\/TcR-dependent JJ I-NP signal NN I-NP transduction NN I-NP was VBD B-VP impaired JJ I-VP in IN B-PP PMA\/Bt2cAMP-treated JJ B-NP cells NNS I-NP . . O Remarkably RB B-ADVP COMMA COMMA O we PRP B-NP observed VBD B-VP that IN B-SBAR these DT B-NP samples NNS I-NP displayed VBD B-VP a DT B-NP persistent JJ I-NP expression NN I-NP of IN B-PP the DT B-NP c-fos NN I-NP protooncogene NN I-NP COMMA COMMA O associated VBN B-VP to TO B-PP an DT B-NP increased VBN I-NP AP-1 NN I-NP DNA-binding JJ I-NP activity NN I-NP COMMA COMMA O whereas IN O no DT B-NP variations NNS I-NP of IN B-PP CREB NN B-NP or CC O NF-kB NN B-NP were VBD B-VP detected VBN I-VP . . O Neither CC O Bt2cAMP NN B-NP nor CC O PMA NN B-NP individually RB B-ADVP mediated VBD B-VP these DT B-NP sustained JJ I-NP effects NNS I-NP COMMA COMMA O which WDT B-NP therefore RB B-ADVP appear VBP B-VP as IN B-PP a DT B-NP consequence NN I-NP of IN B-PP the DT B-NP interplay NN I-NP between IN B-PP both DT B-NP metabolic JJ I-NP stimuli NNS I-NP . . O Altogether RB B-ADVP COMMA COMMA O the DT B-NP data NNS I-NP provide VBP B-VP the DT B-NP evidence NN I-NP that IN B-SBAR both DT B-NP pathways NNS I-NP complement VBP B-VP each DT B-NP other JJ I-NP in IN B-PP regulating VBG B-VP gene NN B-NP expression NN I-NP and CC O COMMA COMMA O conversely RB O COMMA COMMA O downregulate VBP B-NP the DT I-NP TcR NN I-NP transduction NN I-NP mechanisms NNS O Nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP COMMA COMMA O a DT B-NP mediator NN I-NP of IN B-PP lipopolysaccharide NN B-NP effects NNS I-NP . . O Exposure NN B-NP of IN B-PP certain JJ B-NP cell NN I-NP types NNS I-NP to TO B-PP bacterial JJ B-NP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O leads VBZ B-VP to TO B-PP activation NN B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O COMMA COMMA O an DT B-NP inducible JJ I-NP transcription NN I-NP factor NN I-NP . . O One CD B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP 's POS B-NP unique JJ I-NP properties NNS I-NP is VBZ B-VP its PRP$ B-NP posttranslational JJ I-NP activation NN I-NP via IN B-PP release NN B-NP of IN B-PP an DT B-NP inhibitory JJ I-NP subunit NN I-NP COMMA COMMA O called VBN B-VP inhibitor NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP ( ( O I NN B-NP kappa NN I-NP B NN I-NP ) ) O COMMA COMMA O from IN B-PP a DT B-NP sequestered JJ I-NP cytoplasmic JJ I-NP form NN I-NP . . O This DT B-NP event NN I-NP is VBZ B-VP also RB I-VP triggered VBN I-VP under IN B-PP various JJ B-NP other JJ I-NP conditions NNS I-NP of IN B-PP biomedical JJ B-NP importance NN I-NP . . O Other JJ B-NP bacterial JJ I-NP toxins NNS I-NP COMMA COMMA O tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF NN B-NP ) ) O COMMA COMMA O interleukin-1 NN B-NP ( ( O IL-1 NN B-NP ) ) O COMMA COMMA O T NN B-NP cell NN I-NP mitogens NNS I-NP COMMA COMMA O UV NN B-NP light NN I-NP COMMA COMMA O gamma NN B-NP rays NNS I-NP and CC O oxidative JJ B-NP stress NN I-NP were VBD B-VP reported VBN I-VP to TO I-VP induce VB I-VP NF-kappa NN B-NP B NN I-NP . . O The DT B-NP activated JJ I-NP form NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP rapidly RB I-VP taken VBN I-VP up RP B-PRT into IN B-PP nuclei NNS B-NP COMMA COMMA O initiates VBZ B-VP transcription NN B-NP from IN B-PP immediate JJ B-NP early JJ I-NP genes NNS I-NP in IN B-PP a DT B-NP wide JJ I-NP variety NN I-NP of IN B-PP cell NN B-NP types NNS I-NP . . O Most JJS B-NP of IN B-PP the DT B-NP target NN I-NP genes NNS I-NP for IN B-PP NF-kappa NN B-NP B NN I-NP are VBP B-VP of IN B-PP relevance NN B-NP for IN B-PP the DT B-NP immune JJ I-NP response NN I-NP and CC O can MD B-VP be VB I-VP grouped VBN I-VP into IN B-PP those DT B-NP encoding JJ B-VP cytokines NNS B-NP COMMA COMMA O cell NN B-NP surface NN I-NP receptors NNS I-NP COMMA COMMA O acute JJ B-NP phase NN I-NP proteins NNS I-NP and CC O viral JJ B-NP genomes NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP that DT B-NP of IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O . . O We PRP B-NP will MD B-VP discuss VB I-VP recent JJ B-NP experimental JJ I-NP evidences NNS I-NP suggesting VBG B-VP that IN B-SBAR LPS NN B-NP might MD B-VP share VB I-VP a DT B-NP pathway NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP with IN B-PP other JJ B-NP inducers NNS I-NP of IN B-PP the DT B-NP factor NN I-NP . . O This DT B-NP common JJ I-NP pathway NN I-NP may MD B-VP involve VB I-VP reactive JJ B-NP oxygen NN I-NP intermediates NNS I-NP ( ( O ROI NN B-NP ) ) O as IN B-PP messenger NN B-NP molecules NNS I-NP . . O Human JJ B-NP T NN I-NP cell NN I-NP transcription NN I-NP factor NN I-NP GATA-3 NN I-NP stimulates VBZ B-VP HIV-1 NN B-NP expression NN I-NP . . O A DT B-NP family NN I-NP of IN B-PP transcriptional JJ B-NP activating VBG I-NP proteins NNS I-NP COMMA COMMA O the DT B-NP GATA NN I-NP factors NNS I-NP COMMA COMMA O has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP bind VB I-VP to TO B-PP a DT B-NP consensus NN I-NP motif NN I-NP through IN B-PP a DT B-NP highly RB I-NP conserved VBN I-NP C4 NN I-NP zinc NN I-NP finger NN I-NP DNA NN I-NP binding NN I-NP domain NN I-NP . . O One CD B-NP member NN I-NP of IN B-PP this DT B-NP multigene JJ I-NP family NN I-NP COMMA COMMA O GATA-3 NN B-NP COMMA COMMA O is VBZ B-VP most RBS I-VP abundantly RB I-VP expressed VBN I-VP in IN B-PP T NN B-NP lymphocytes NNS I-NP COMMA COMMA O a DT B-NP cellular JJ I-NP target NN I-NP for IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O infection NN B-NP and CC O replication NN B-NP . . O In FW B-NP vitro FW I-NP DNase NN I-NP I CD I-NP footprinting NN I-NP analysis NN I-NP revealed VBD B-VP six CD B-NP hGATA-3 NN I-NP binding NN I-NP sites NNS I-NP in IN B-PP the DT B-NP U3 NN I-NP region NN I-NP ( ( O the DT B-NP transcriptional JJ I-NP regulatory JJ I-NP domain NN I-NP ) ) O of IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP . . O Cotransfection NN B-NP of IN B-PP an DT B-NP hGATA-3 NN I-NP expression NN I-NP plasmid NN I-NP with IN B-PP a DT B-NP reporter NN I-NP plasmid NN I-NP whose WP$ B-NP transcription NN I-NP is VBZ B-VP directed VBN I-VP by IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP resulted VBD B-VP in IN B-PP 6- CD B-NP to TO I-NP 10-fold JJ I-NP stimulation NN I-NP of IN B-PP LTR-mediated JJ B-NP transcription NN I-NP COMMA COMMA O whereas IN O site NN B-NP specific JJ I-NP mutation NN I-NP of IN B-PP these DT B-NP GATA NN I-NP sites NNS I-NP resulted VBD B-VP in IN B-PP virtual JJ B-NP abrogation NN I-NP of IN B-PP the DT B-NP activation NN I-NP by IN B-PP hGATA-3 NN B-NP . . O Further RB B-ADVP COMMA COMMA O deletion NN B-NP of IN B-PP the DT B-NP hGATA-3 NN I-NP transcriptional JJ I-NP activation NN I-NP domain NN I-NP abolished VBD B-VP GATA-dependent JJ B-NP HIV-1 NN I-NP trans-activation NN I-NP COMMA COMMA O showing VBG B-VP that IN B-SBAR the DT B-NP stimulation NN I-NP of IN B-PP viral JJ B-NP transcription NN I-NP observed VBN B-VP is VBZ B-VP a DT B-NP direct JJ I-NP effect NN I-NP of IN B-PP cotransfected VBN B-NP hGATA-3 NN I-NP . . O Introduction NN B-NP of IN B-PP the DT B-NP HIV-1 NN I-NP plasmids NNS I-NP in IN B-PP which WDT B-NP the DT B-NP GATA NN I-NP sites NNS I-NP have VBP B-VP been VBN I-VP mutated VBN I-VP into IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP also RB B-ADVP caused VBD B-VP a DT B-NP significant JJ I-NP reduction NN I-NP in IN B-PP LTR-mediated JJ B-NP transcription NN I-NP at IN B-PP both CC B-NP the DT I-NP basal JJ I-NP level NN I-NP and CC B-PP in IN B-PP ( ( O PHA- NN B-NP plus CC O PMA- NN B-NP ) ) B-NP stimulated JJ I-NP T NN I-NP cells NNS I-NP . . O These DT B-NP observations NNS I-NP suggest VBP B-VP that IN B-SBAR in IN B-PP addition NN I-PP to TO I-PP its PRP$ B-NP normal JJ I-NP role NN I-NP in IN B-PP T NN B-NP lymphocyte NN I-NP gene NN I-NP regulation NN I-NP COMMA COMMA O hGATA-3 NN B-NP may MD B-VP also RB I-VP play VB I-VP a DT B-NP significant JJ I-NP role NN I-NP in IN B-PP HIV-1 NN B-NP transcriptional JJ I-NP activation NN I-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP preexisting JJ I-NP and CC I-NP nuclear JJ I-NP forms NNS I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O The DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O 3 CD B-NP is VBZ B-VP an DT B-NP inducible JJ I-NP DNA-binding JJ I-NP protein NN I-NP that WDT B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP transcriptional JJ B-NP induction NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP during IN B-PP T NN B-NP cell NN I-NP activation NN I-NP . . O NF-AT NN B-NP is VBZ B-VP thought VBN I-VP to TO I-VP consist VB I-VP of IN B-PP two CD B-NP components NNS I-NP : : O a DT B-NP ubiquitous JJ I-NP COMMA COMMA I-NP inducible JJ I-NP nuclear JJ I-NP component NN I-NP that WDT B-NP we PRP B-NP have VBP B-VP identified VBN I-VP as IN B-PP Fos NN B-NP and CC O Jun NN B-NP proteins NNS B-NP COMMA COMMA O and CC O a DT B-NP preexisting VBG I-NP COMMA COMMA I-NP T NN I-NP cell-specific JJ I-NP component NN I-NP ( ( O NF-ATp NN B-NP ) ) O which WDT B-NP is VBZ B-VP the DT B-NP target NN I-NP for IN B-PP the DT B-NP immunosuppressive JJ I-NP agents NNS I-NP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O FK506 NN B-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR nuclear JJ B-NP extracts NNS I-NP from IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP form VBP B-VP two CD B-NP inducible JJ I-NP NF-AT NN I-NP complexes NNS I-NP with IN B-PP an DT B-NP oligonucleotide NN I-NP corresponding VBG B-VP to TO B-PP the DT B-NP distal JJ I-NP NF-AT NN I-NP site NN I-NP of IN B-PP the DT B-NP murine JJ I-NP IL-2 NN I-NP promoter NN I-NP COMMA COMMA O although IN B-SBAR hypotonic JJ B-NP extracts NNS I-NP of IN B-PP unstimulated JJ B-NP T NN I-NP cells NNS I-NP form VBP B-VP a DT B-NP single JJ I-NP complex NN I-NP containing VBG B-VP NF-ATp NN B-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP ability NN I-NP to TO B-VP detect VB I-VP NF-ATp NN B-NP in IN B-PP a DT B-NP gel NN I-NP shift NN I-NP assay NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP purification NN B-NP and CC O biochemical JJ B-NP studies NNS I-NP of IN B-PP this DT B-NP protein NN I-NP COMMA COMMA O is VBZ B-VP strikingly RB B-ADJP dependent JJ I-ADJP on IN B-PP the DT B-NP precise JJ I-NP sequence NN I-NP of IN B-PP the DT B-NP NF-AT NN I-NP oligonucleotide NN I-NP used VBN B-VP as IN B-PP the DT B-NP labeled JJ I-NP probe NN I-NP . . O Moreover RB B-ADVP we PRP B-NP present VBP B-VP evidence NN B-NP that IN B-SBAR the DT B-NP component NN I-NP that WDT B-NP forms VBZ B-VP the DT O faster-migrating JJ O ( ( O " `` O lower JJR B-ADJP " '' O ) ) O nuclear JJ B-NP NF-AT NN I-NP complex NN I-NP is VBZ B-VP derived VBN I-VP by IN B-PP a DT B-NP calcium-dependent JJ I-NP COMMA COMMA I-NP cyclosporin-sensitive JJ I-NP COMMA COMMA I-NP posttranslational JJ I-NP modification NN I-NP of IN B-PP NF-ATp NN B-NP COMMA COMMA O and CC O that IN B-SBAR Fos NN B-NP and CC O Jun NN B-NP proteins NNS B-NP stabilize VBP B-VP its PRP$ B-NP interaction NN I-NP with IN B-PP DNA NN B-NP . . O The DT B-NP results NNS I-NP are VBP B-VP discussed VBN I-VP in IN B-PP the DT B-NP context NN I-NP of IN B-PP a DT B-NP model NN I-NP relating VBG B-VP the DT B-NP two CD I-NP nuclear JJ I-NP NF-AT NN I-NP complexes NNS I-NP to TO B-PP NF-ATp NN B-NP . . O Enhancing NN B-NP effect NN I-NP of IN B-PP 17 CD B-NP beta-estradiol NN I-NP on IN B-PP human JJ B-NP NK NN I-NP cell NN I-NP activity NN I-NP . . O The DT B-NP in FW I-NP vitro FW I-NP effect NN I-NP of IN B-PP 17 CD B-NP beta-estradiol NN I-NP on IN B-PP NK NN B-NP activity NN I-NP was VBD B-VP studied VBN I-VP . . O The DT B-NP proliferation NN B-NP and CC O NK NN B-NP activity NN I-NP of IN B-PP YT-N17 NN B-NP ( ( O a DT B-NP human JJ I-NP NK-like JJ I-NP cell NN I-NP line NN I-NP ) ) O were VBD B-VP enhanced VBN I-VP by IN B-PP 17 CD B-NP beta-estradiol NN I-NP ( ( O E2 NN B-NP ) ) O COMMA COMMA O and CC O the DT B-NP enhancement NN I-NP was VBD B-VP blocked VBN I-VP by IN B-PP tamoxifen NN B-NP ( ( O Tx NN B-NP ) ) O COMMA COMMA O an DT B-NP antagonist NN I-NP of IN B-PP E2 NN B-NP . . O On IN B-PP the DT B-NP contrary NN I-NP COMMA COMMA O other JJ B-NP steroid NN I-NP hormones NNS I-NP such JJ B-PP as IN I-PP Tx NN B-NP COMMA COMMA O progesterone NN B-NP COMMA COMMA O and CC O testosterone NN B-NP had VBD B-VP no DT B-NP effect NN I-NP . . O YT-N17 NN B-NP contained VBD B-VP 11.8 CD B-NP fmol\/mg NN I-NP protein NN I-NP of IN B-PP estrogen NN B-NP receptor NN I-NP ( ( O mean NN B-NP of IN B-PP two CD B-NP independent JJ I-NP assays NNS I-NP ) ) O COMMA COMMA O a DT B-NP value NN I-NP which WDT B-NP was VBD B-VP 5-10-fold RB B-ADJP higher JJR I-ADJP than IN B-PP that DT B-NP of IN B-PP other JJ B-NP hematopoietic JJ I-NP cell NN I-NP lines NNS I-NP . . O An DT B-NP enhancement NN I-NP of IN B-PP NK NN B-NP activity NN I-NP by IN B-PP E2 NN B-NP was VBD B-VP also RB I-VP seen VBN I-VP in IN B-PP large JJ B-NP granular JJ I-NP lymphocytes NNS I-NP obtained VBN B-VP from IN B-PP normal JJ B-NP subjects NNS I-NP COMMA COMMA O and CC O it PRP B-NP was VBD B-VP again RB I-VP suppressed VBN I-VP by IN B-PP Tx NN B-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR E2 NN B-NP is VBZ B-VP one CD B-NP of IN B-PP the DT B-NP activating VBG I-NP factors NNS I-NP for IN B-PP NK\/LGL NN B-NP cells NNS I-NP . . O Cytokine NN B-NP modulation NN I-NP of IN B-PP HIV NN B-NP expression NN I-NP . . O Cytokines NNS B-NP COMMA COMMA O the DT B-NP peptide NN I-NP hormones NNS I-NP which WDT B-NP control VBP B-VP the DT B-NP homeostasis NN I-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP and CC O also RB O play VBP B-VP a DT B-NP fundamental JJ I-NP role NN I-NP in IN B-PP inflammatory JJ B-NP and CC I-NP immune JJ I-NP mediated JJ I-NP reactions NNS I-NP COMMA COMMA O have VBP B-VP been VBN I-VP involved VBN I-VP at IN B-PP multiple JJ B-NP levels NNS I-NP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP the DT B-NP acquired VBN I-NP immune JJ I-NP deficiency NN I-NP syndrome NN I-NP ( ( O AIDS NN B-NP ) ) O . . O Infection NN B-NP with IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP induce VB I-VP production NN B-NP of IN B-PP several JJ B-NP cytokines NNS I-NP both CC O in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP . . O Conversely RB B-ADVP COMMA COMMA O several JJ B-NP cytokines NNS I-NP modulate VBP B-VP the DT B-NP levels NNS I-NP of IN B-PP HIV NN B-NP expression NN I-NP in IN B-PP infected JJ B-NP cells NNS I-NP of IN B-PP both CC B-NP T NN I-NP lymphocytic JJ I-NP and CC I-NP mononuclear JJ I-NP phagocytic JJ I-NP lineage NN I-NP . . O Activated VBN B-NP mononuclear JJ I-NP cells NNS I-NP COMMA COMMA O particularly RB B-NP B NN I-NP cells NNS I-NP which WDT B-NP are VBP B-VP in IN B-PP a DT B-NP state NN I-NP of IN B-PP chronic JJ B-NP activation NN I-NP in IN B-PP HIV NN B-NP infected JJ I-NP individuals NNS I-NP COMMA COMMA O release VBP B-VP HIV-inductive JJ B-NP cytokines NNS I-NP and CC O thus RB O play VBP B-VP a DT B-NP potentially RB I-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP HIV NN B-NP infection NN I-NP . . O Tumor NN B-NP necrosis NN I-NP factor NN I-NP receptor NN I-NP expression NN I-NP and CC O signal NN B-NP transduction NN I-NP in IN B-PP HIV-1-infected JJ B-NP cells NNS I-NP . . O OBJECTIVE NN B-NP : : O To TO B-VP examine VB I-VP the DT B-NP inter-relationship NN I-NP between IN B-PP HIV-1 NN B-NP infection NN I-NP and CC O the DT B-NP cell NN I-NP surface NN I-NP receptors NNS I-NP for IN B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP ( ( I-NP TNF NN I-NP ) ) I-NP -alpha NN I-NP COMMA COMMA O an DT B-NP immunoregulatory JJ I-NP cytokine NN I-NP that WDT B-NP can MD B-VP enhance VB I-VP HIV-1 NN B-NP replication NN I-NP . . O DESIGN NN B-NP : : O Infected JJ B-NP promyelocytic JJ I-NP and CC I-NP promonocytic JJ I-NP cells NNS I-NP were VBD B-VP examined VBN I-VP because IN B-SBAR they PRP B-NP normally RB B-ADVP express VBP B-VP both DT B-NP types NNS I-NP of IN B-PP TNF NN B-NP receptors NNS I-NP . . O METHODS NNS B-NP : : O TNF NN B-NP receptor NN I-NP surface NN I-NP expression NN I-NP was VBD B-VP determined VBN I-VP by IN B-PP specific JJ B-NP monoclonal JJ I-NP antibody NN I-NP recognition NN I-NP and CC O flow NN B-NP cytometry NN I-NP COMMA COMMA O and CC O signal NN B-NP transduction NN I-NP was VBD B-VP detected VBN I-VP by IN B-PP gel NN B-NP shift NN I-NP analysis NN I-NP . . O HIV-1 NN B-NP activation NN B-NP and CC O expression NN B-NP was VBD B-VP quantitated VBN I-VP by IN B-PP reverse JJ B-NP transcriptase NN I-NP assay NN I-NP . . O RESULTS NNS B-NP : : O In IN B-PP the DT B-NP OM-10.1 NN I-NP promyelocytic JJ I-NP model NN I-NP of IN B-PP chronic JJ B-NP infection NN I-NP COMMA COMMA O TNF-alpha-induced JJ B-NP HIV-1 NN I-NP expression NN I-NP also RB B-ADVP resulted VBD B-VP in IN B-PP a DT B-NP substantial JJ I-NP increase NN I-NP in IN B-PP 75 CD B-NP kd NN I-NP TNF NN I-NP receptor NN I-NP ( ( O TR75 NN B-NP ) ) O expression NN B-NP although IN B-SBAR 55 CD B-NP kD NN I-NP TNF NN I-NP receptor NN I-NP ( ( O TR55 NN B-NP ) ) O levels NNS B-NP were VBD B-VP not RB I-VP dramatically RB I-VP altered VBN I-VP . . O A DT B-NP series NN I-NP of IN B-PP uninfected JJ B-NP parental JJ I-NP HL-60 NN I-NP subclones NNS I-NP all DT B-ADVP reduced VBD B-VP TR75 NN B-NP surface NN I-NP expression NN I-NP in IN B-PP response NN I-PP to TO I-PP TNF-alpha NN B-NP treatment NN I-NP . . O Enhanced VBN B-NP TR75 NN I-NP expression NN I-NP on IN B-PP OM-10.1 NN B-NP cells NNS I-NP followed VBD B-VP the DT B-NP same JJ I-NP TNF-alpha-dose NN I-NP dependency NN I-NP as IN B-PP that WDT B-NP observed VBN B-VP for IN B-PP HIV-1 NN B-NP production NN I-NP . . O An DT B-NP increase NN I-NP in IN B-PP TR75 NN B-NP expression NN I-NP was VBD B-VP also RB B-ADVP evident JJ B-ADJP during IN B-PP the DT B-NP peak NN I-NP of IN B-PP an DT B-NP acute JJ I-NP HIV-1 NN I-NP infection NN I-NP of IN B-PP HL-60 NN B-NP promyelocytes NNS I-NP . . O Although IN B-SBAR TR55 NN B-NP expression NN I-NP was VBD B-VP unaltered JJ B-ADJP during IN B-PP TNF-alpha-induced JJ B-NP HIV NN I-NP activation NN I-NP COMMA COMMA O this DT B-NP receptor NN I-NP was VBD B-VP still RB I-VP involved VBN I-VP in IN B-PP the DT B-NP viral JJ I-NP activation NN I-NP process NN I-NP . . O Antibody NN B-NP cross-linking NN I-NP of IN B-PP TR55 NN B-NP COMMA COMMA O in IN B-PP the DT I-PP absence NN I-PP of IN I-PP exogenous JJ B-NP TNF-alpha NN I-NP COMMA COMMA O induced VBN B-VP maximal JJ B-NP HIV-1 NN I-NP expression NN I-NP COMMA COMMA O an DT B-NP up-modulation NN I-NP of IN B-PP surface NN B-NP TR75 NN I-NP COMMA COMMA O and CC O nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP activity NN I-NP in IN B-PP OM-10.1 NN B-NP cultures NNS I-NP . . O Surprisingly RB B-ADVP COMMA COMMA O this DT B-NP was VBD B-VP the DT B-NP case NN I-NP even RB B-ADVP when WRB I-ADVP an DT B-NP antagonistic JJ I-NP anti-TR55 JJ I-NP antibody NN I-NP was VBD B-VP used VBN I-VP . . O Anti-TR55 JJ B-NP antibody NN I-NP cross-linking NN I-NP in IN B-PP chronically RB B-NP infected JJ I-NP U1 NN I-NP promonocytic JJ I-NP cultures NNS I-NP could MD B-VP only RB I-VP partially RB I-VP substitute VB I-VP for IN B-PP TNF-alpha-induced JJ B-NP HIV-1 NN I-NP expression NN I-NP . . O CONCLUSIONS NNS B-NP : : O Our PRP$ B-NP results NNS I-NP demonstrated VBD B-VP that IN B-SBAR HIV-1 NN B-NP infection NN I-NP can MD B-VP selectively RB I-VP influence VB I-VP the DT B-NP surface NN I-NP expression NN I-NP of IN B-PP TNF NN B-NP receptors NNS I-NP COMMA COMMA O potentially RB B-ADVP influencing VBG B-VP its PRP$ B-NP own JJ I-NP expression NN I-NP and CC O altering VBG B-VP normal JJ B-NP immunoregulatory JJ I-NP signal NN I-NP transduction NN I-NP . . O FK506 NN B-NP and CC O ciclosporin NN B-NP : : O molecular JJ B-NP probes NNS I-NP for IN B-PP studying VBG B-VP intracellular JJ B-NP signal NN I-NP transduction NN I-NP . . O The DT B-NP immunosuppressants NNS I-NP ciclosporin NN B-NP and CC O FK506 NN B-NP block VBP B-VP the DT B-NP Ca(2+)-dependent JJ I-NP signal-transduction NN I-NP pathway NN I-NP emanating VBG B-VP from IN B-PP the DT B-NP T-cell NN I-NP receptor NN I-NP COMMA COMMA O thereby RB B-ADVP inhibiting VBG B-VP the DT B-NP activation NN I-NP of IN B-PP helper NN B-NP T NN I-NP cells NNS I-NP . . O Using VBG B-VP these DT B-NP drugs NNS I-NP as IN B-PP probes NNS B-NP COMMA COMMA O chemists NNS B-NP and CC O biologists NNS B-NP have VBP B-VP uncovered VBN I-VP several JJ B-NP intracellular JJ I-NP signalling NN I-NP molecules NNS I-NP bridging VBG B-VP the DT B-NP generation NN I-NP of IN B-PP second-messenger NN B-NP Ca2+ NN I-NP ions NNS I-NP and CC O the DT B-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP IL-2 NN B-NP COMMA COMMA O among IN B-PP which WDT B-NP are VBP B-VP calmodulin NN B-NP COMMA COMMA O calcineurin NN B-NP and CC O the DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O . . O Hence RB B-ADVP COMMA COMMA O Ca2+ NN B-NP binds VBZ B-VP to TO B-PP calmodulin NN B-NP COMMA COMMA O leading VBG B-VP to TO B-PP the DT B-NP binding NN I-NP of IN B-PP calmodulin NN B-NP to TO B-PP calcineurin NN B-NP ; : O the DT B-NP activated VBN I-NP calcineurin NN I-NP COMMA COMMA O in IN B-PP turn NN B-NP COMMA COMMA O may MD B-VP dephosphorylate VB I-VP the DT B-NP cytoplasmic JJ I-NP subunit NN I-NP of IN B-PP NF-AT NN B-NP COMMA COMMA O resulting VBG B-VP in IN B-PP its PRP$ B-NP translocation NN I-NP from IN B-PP the DT B-NP cytoplasm NN I-NP into IN B-PP the DT B-NP nucleus NN I-NP to TO B-VP form VB I-VP a DT B-NP competent JJ I-NP transcriptional JJ I-NP activator NN I-NP . . O As IN B-SBAR described VBN B-VP by IN B-PP Jun NNP B-NP Liu NNP I-NP COMMA COMMA O these DT B-NP drugs NNS I-NP manifest VBP B-VP their PRP$ B-NP effects NNS I-NP in IN B-PP an DT B-NP unprecedented JJ I-NP fashion NN I-NP . . O They PRP B-NP do VBP B-VP not RB I-VP directly RB I-VP intercept VB I-VP intracellular JJ B-NP signalling NN I-NP molecules NNS I-NP . . O Instead RB B-ADVP COMMA COMMA O they PRP B-NP form VBP B-VP tight JJ B-NP complexes NNS I-NP with IN B-PP two CD B-NP different JJ I-NP classes NNS I-NP of IN B-PP abundant JJ B-NP cytosolic JJ I-NP receptors NNS I-NP called VBN B-VP immunophilins NNS B-NP upon IN B-PP entering VBG B-VP the DT B-NP cell NN I-NP COMMA COMMA O and CC O consequently RB B-VP inhibit VBP I-VP their PRP$ B-NP peptidyl JJ I-NP prolyl JJ I-NP cis-trans JJ I-NP isomerase NN I-NP activities NNS I-NP . . O The DT B-NP two CD I-NP structurally RB I-NP distinct JJ I-NP immunophilin-drug JJ I-NP complexes NNS I-NP bind VBP B-VP to TO B-PP COMMA COMMA O and CC O inhibit VBP B-VP COMMA COMMA O the DT B-NP phosphatase JJ I-NP activity NN I-NP of IN B-PP calcineurin NN B-NP . . O The DT B-NP impaired JJ I-NP transcription NN I-NP factor NN I-NP AP-1 NN I-NP DNA NN I-NP binding NN I-NP activity NN I-NP in IN B-PP lymphocytes NNS B-NP derived VBN B-VP from IN B-PP subjects NNS B-NP with IN B-PP some DT B-NP symptoms NNS I-NP of IN B-PP premature JJ B-NP aging NN I-NP . . O The DT B-NP study NN I-NP of IN B-PP human JJ B-NP disorders NNS I-NP known VBN B-VP as IN B-PP premature JJ B-NP aging NN I-NP syndromes NNS I-NP may MD B-VP provide VB I-VP insight NN B-NP into IN B-PP the DT B-NP mechanisms NNS I-NP of IN B-PP cellular JJ B-NP senescence NN I-NP . . O The DT B-NP main JJ I-NP feature NN I-NP of IN B-PP cellular JJ B-NP senescence NN I-NP in FW B-ADVP vitro FW I-ADVP is VBZ B-VP cessation NN B-NP of IN B-PP cell NN B-NP proliferation NN I-NP . . O Down NN B-NP syndrome NN I-NP ( ( O DS NN B-NP ) ) O and CC O neuronal JJ B-NP ceroid-lypofuscinosis NN I-NP ( ( O NCL NN B-NP ) ) O are VBP B-VP clinically RB I-VP characterized VBN I-VP by IN B-PP the DT B-NP premature JJ I-NP onset NN I-NP of IN B-PP numerous JJ B-NP features NNS I-NP normally RB B-VP associated VBN I-VP with IN B-PP human JJ B-NP aging NN I-NP . . O Phytohemagglutinin NN B-NP stimulated JJ B-NP lymphocytes NNS I-NP derived VBN B-VP from IN B-PP DS NN B-NP subjects NNS I-NP showed VBD B-VP a DT B-NP statistically RB I-NP significant JJ I-NP diminished VBN I-NP proliferation NN I-NP capacity NN I-NP in IN B-PP comparison NN I-PP with IN I-PP lymphocytes NNS B-NP derived VBN B-VP from IN B-PP NCL NN B-NP and CC O healthy JJ B-ADJP individuals NNS B-NP . . O We PRP B-NP demonstrated VBD B-VP COMMA COMMA O by IN B-PP applying VBG B-VP the DT B-NP electrophoretic JJ I-NP mobility NN I-NP shift NN I-NP assay NN I-NP COMMA COMMA O slightly RB B-NP impaired JJ I-NP AP-1 NN I-NP DNA NN I-NP binding NN I-NP activity NN I-NP in IN B-PP NCL NN B-NP lymphocytes NNS I-NP and CC O strong JJ B-NP in IN B-PP DS NN B-NP ones NNS I-NP . . O Our PRP$ B-NP results NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP same JJ I-NP molecular JJ I-NP mechanisms NNS I-NP of IN B-PP proliferation NN B-NP cessation NN I-NP could MD B-VP exist VB I-VP in IN B-PP fibroblasts NNS B-NP characterized VBN B-VP by IN B-PP replicative JJ B-NP senescence NN I-NP and CC B-PP in IN B-PP lymphocytes NNS B-NP derived VBN B-VP from IN B-PP individuals NNS B-NP with IN B-PP premature JJ B-NP aging NN I-NP syndromes NNS I-NP ( ( O Down NN B-NP ) ) O . . O Inhibition NN B-NP of IN B-PP HIV-1 NN B-NP latency NN I-NP reactivation NN I-NP by IN B-PP dehydroepiandrosterone NN B-NP ( ( O DHEA NN B-NP ) ) O and CC O an DT B-NP analog NN I-NP of IN B-PP DHEA NN B-NP . . O The DT B-NP initial JJ I-NP infection NN I-NP with IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O in IN B-PP most JJS B-NP individuals NNS I-NP usually RB B-ADVP results VBZ B-VP in IN B-PP the DT B-NP establishment NN I-NP of IN B-PP a DT B-NP latent JJ I-NP or CC I-NP chronic JJ I-NP infection NN I-NP before IN B-PP eventual JJ B-NP progression NN I-NP toward IN B-PP acquired VBN B-NP immunodeficiency NN I-NP syndrome NN I-NP . . O HIV-1 NN B-NP can MD B-VP also RB I-VP establish VB I-VP a DT B-NP latent JJ I-NP or CC I-NP persistent JJ I-NP infection NN I-NP in IN B-PP some DT B-NP T NN I-NP cell NN I-NP lines NNS I-NP that WDT B-NP show VBP B-VP minimal JJ B-NP constitutive JJ I-NP virus NN I-NP expression NN I-NP . . O However RB B-ADVP COMMA COMMA O activation NN B-NP of IN B-PP the DT B-NP T NN I-NP cell NN I-NP lines NNS I-NP leading VBG B-VP to TO B-PP enhanced VBN B-NP HIV-1 NN I-NP replication NN I-NP can MD B-VP be VB I-VP induced VBN I-VP by IN B-PP antigens NNS B-NP COMMA COMMA O mitogens NNS B-NP COMMA COMMA O and CC O cytokines NNS B-NP ( ( O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP { ( O TNF-alpha NN B-NP } ) O COMMA COMMA O interleukin NN B-NP 1 CD I-NP COMMA COMMA O and CC O interleukin-2 NN B-NP ) ) O . . O Various JJ B-NP gene NN I-NP products NNS I-NP from IN B-PP other JJ B-NP viruses NNS I-NP ( ( O HTLV-1 NN B-NP COMMA COMMA O HSV NN B-NP COMMA COMMA O EBV NN B-NP COMMA COMMA O CMV NN B-NP COMMA COMMA O HBV NN B-NP COMMA COMMA O and CC O HHV-6 NN B-NP ) ) O can MD B-VP also RB I-VP enhance VB I-VP HIV-1 NN B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP ( ( I-NP LTR NN I-NP ) ) I-NP -driven JJ I-NP reporter NN I-NP gene NN I-NP activity NN I-NP . . O On IN B-PP the DT I-PP basis NN I-PP of IN I-PP these DT B-NP observations NNS I-NP COMMA COMMA O it PRP B-NP has VBZ B-VP been VBN I-VP proposed VBN I-VP that IN B-SBAR reactivation NN B-NP of IN B-PP latent JJ B-NP HIV-1 NN I-NP harbored VBN B-VP in IN B-PP chronically RB B-NP infected JJ I-NP T NN B-NP lymphocytes NNS I-NP COMMA COMMA O monocytes NNS B-NP COMMA COMMA O or CC O macrophages NNS B-NP plays VBZ B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP AIDS NN B-NP . . O So RB B-ADVP far RB I-ADVP COMMA COMMA O there EX B-NP are VBP B-VP no DT B-NP drugs NNS B-NP or CC O therapy NN B-NP available JJ B-ADJP that WDT B-NP can MD B-VP provide VB I-VP protection NN B-NP against IN B-PP HIV-1 NN B-NP latency NN I-NP reactivation NN I-NP . . O ACH-2 NN B-NP COMMA COMMA O derived VBN B-VP from IN B-PP a DT B-NP human JJ I-NP T NN I-NP cell NN I-NP line NN I-NP ( ( O CEM NN B-NP ) ) O COMMA COMMA O is VBZ B-VP chronically RB B-ADJP infected VBN I-ADJP with IN B-PP HIV-1 NN O COMMA COMMA O with IN B-PP low JJ B-NP levels NNS I-NP of IN B-PP constitutive JJ B-NP virus NN I-NP expression NN I-NP . . O ACH-2 NN B-NP can MD B-VP be VB I-VP converted VBN I-VP to TO B-PP productive JJ B-NP infection NN I-NP by IN B-PP stimulation NN B-NP of IN B-PP the DT B-NP cells NNS I-NP with IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( O TPA NN B-NP ) ) O COMMA COMMA O mitogen NN B-NP or CC O cytokines NNS B-NP ( ( O TNF-alpha NN B-NP ) ) O COMMA COMMA O or CC O infection NN B-NP with IN B-PP HSV NN B-NP . . O Therefore RB B-ADVP the DT B-NP ACH-2 NN I-NP cell NN I-NP line NN I-NP is VBZ B-VP a DT B-NP good JJ I-NP candidate NN I-NP for IN B-PP studying VBG B-VP the DT B-NP effects NNS I-NP of IN B-PP drugs NNS B-NP on IN B-PP HIV-1 NN B-NP activation NN I-NP . . O Previously RB B-ADVP COMMA COMMA O we PRP B-NP have VBP B-VP reported VBN I-VP that IN B-SBAR DHEA NN B-NP and CC O synthetic JJ B-NP analogs NNS I-NP of IN B-PP DHEA NN B-NP can MD B-VP be VB I-VP modest JJ B-NP inhibitors NNS I-NP of IN B-PP HIV-1 NN B-NP IIIB NN I-NP replication NN I-NP in IN B-PP phytohemagglutinin-stimulated JJ B-NP peripheral JJ I-NP blood NN I-NP lymphocyte NN I-NP cultures NNS I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Visualization NN B-NP of IN B-PP the DT B-NP endogenous JJ I-NP NF-kappa NN I-NP B NN I-NP p50 NN I-NP subunit NN I-NP in IN B-PP the DT B-NP nucleus NN I-NP of IN B-PP follicular JJ B-NP dendritic JJ I-NP cells NNS I-NP in IN B-PP germinal JJ B-NP centers NNS I-NP . . O NF-kappa NN B-NP B NN I-NP COMMA COMMA O a DT O 50 CD O kDa\/65 CD O kDa NN O ( ( O p50\/p65 NN B-ADJP ) ) O heterodimer NN B-NP COMMA COMMA O is VBZ B-VP a DT B-NP ubiquitous JJ I-NP transcription NN I-NP factor NN I-NP involved VBN B-VP in IN B-PP the DT B-NP positive JJ I-NP regulation NN I-NP of IN B-PP various JJ B-NP immune JJ I-NP genes NNS I-NP . . O The DT B-NP aim NN I-NP of IN B-PP this DT B-NP study NN I-NP was VBD B-VP to TO B-VP determine VB I-VP whether IN B-SBAR NF-kappa NN B-NP B NN I-NP is VBZ B-VP related JJ B-ADJP to TO B-PP a DT B-NP particular JJ B-NP cell NN I-NP type NN I-NP and\/or CC O differentiation NN B-NP step NN I-NP during IN B-PP immunopoiesis NN B-NP . . O Using VBG B-VP in FW B-NP situ FW I-NP hybridization NN I-NP on IN B-PP sections NNS B-NP from IN B-PP non JJ B-NP HIV NN I-NP hyperplastic JJ I-NP lymph NN I-NP nodes NNS I-NP COMMA COMMA O we PRP B-NP found VBD B-VP that IN B-SBAR the DT B-NP gene NN I-NP of IN B-PP the DT B-NP 105 CD I-NP kDa NN I-NP precursor NN I-NP of IN B-PP p50 NN B-NP was VBD B-VP overexpressed VBN I-VP in IN B-PP the DT B-NP light JJ I-NP zone NN I-NP of IN B-PP germinal JJ B-NP centers NNS I-NP COMMA COMMA O with IN B-PP a DT B-NP network NN I-NP aspect NN I-NP COMMA COMMA O which WDT B-NP suggested VBD B-VP the DT B-NP involvement NN I-NP of IN B-PP follicular JJ B-NP dendritic JJ I-NP cells NNS I-NP ( ( O FDC NN B-NP ) ) O . . O By IN B-PP immunohistochemistry NN B-NP COMMA COMMA O p50 NN B-NP protein NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP the DT B-NP cytoplasm NN B-NP and CC O nucleus NN B-NP of IN B-PP FDC NN B-NP COMMA COMMA O confirming VBG B-VP the DT B-NP involvement NN I-NP of IN B-PP FDC NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O p50 NN B-NP protein NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP the DT B-NP cytoplasm NN I-NP of IN B-PP all DT B-NP lymphocytes NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O we PRP B-NP focused VBD B-VP our PRP$ B-NP study NN I-NP on IN B-PP isolated VBN B-NP FDC NN I-NP clusters NNS I-NP from IN B-PP normal JJ B-NP tonsils NNS I-NP . . O As IN B-SBAR showed VBN B-VP on IN B-PP tissue NN B-NP sections NNS I-NP COMMA COMMA O we PRP B-NP detected VBD B-VP the DT B-NP p50 NN I-NP in IN B-PP both CC O cytoplasm NN B-NP and CC O nucleus NN B-NP of IN B-PP FDC NN B-NP . . O Nuclei NNS B-NP of IN B-PP lymphocytes NNS B-NP from IN B-PP FDC NN B-NP clusters NNS I-NP were VBD B-VP negative JJ B-ADJP . . O We PRP B-NP next RB B-ADVP studied VBD B-VP p65 NN B-NP and CC O c-Rel NN B-NP protein NN I-NP expression NN B-NP in IN B-PP FDC NN B-NP clusters NNS I-NP . . O p65 NN B-NP was VBD B-VP detected VBN I-VP in IN B-PP the DT B-NP cytoplasm NN I-NP of IN B-PP FDC NN B-NP COMMA COMMA O whereas IN O nuclei NNS B-NP were VBD B-VP negative JJ B-ADJP . . O Furthermore RB B-ADVP COMMA COMMA O p65 NN B-NP was VBD B-VP detected VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP some DT B-NP lymphocytes NNS I-NP . . O c-Rel NN B-NP protein NN I-NP was VBD B-VP detected VBN I-VP only RB B-PP in IN I-PP the DT B-NP cytoplasm NN I-NP of IN B-PP lymphocytes NNS B-NP and CC B-PP not RB B-PP in IN I-PP the DT B-NP nucleus NN B-NP and CC O cytoplasm NN B-NP of IN B-PP FDC NN B-NP . . O Our PRP$ B-NP results NNS I-NP indicated VBD B-VP that IN B-SBAR COMMA COMMA O in IN B-PP the DT I-PP context NN I-PP of IN I-PP T NN B-NP cell-dependent JJ I-NP B NN I-NP cell NN I-NP immunopoiesis NN I-NP occurring VBG B-VP in IN B-PP FDC NN B-NP clusters NNS I-NP COMMA COMMA O p50 NN B-NP is VBZ B-VP mainly RB B-ADVP related JJ B-ADJP to TO B-PP FDC NN B-NP with IN B-PP a DT B-NP massive JJ I-NP overexpression NN I-NP in IN B-PP the DT B-NP nuclei NNS I-NP COMMA COMMA O whereas IN O p65 NN B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP a DT B-NP scattered VBN I-NP manner NN I-NP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP lymphocytes NNS B-NP and CC O c-Rel NN B-NP protein NN I-NP exclusively RB B-ADVP in IN B-PP the DT B-NP cytoplasm NN I-NP of IN B-PP lymphocytes NNS B-NP from IN B-PP FDC NN B-NP clusters NNS I-NP . . O These DT B-NP results NNS I-NP suggested VBD B-VP that IN B-SBAR the DT B-NP two CD I-NP subunits NNS I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O the DT B-NP c-Rel NN I-NP protein NN I-NP have VBP B-VP different JJ B-NP roles NNS I-NP in IN B-PP different JJ B-NP cell NN I-NP types NNS I-NP during IN B-PP B NN B-NP cell NN I-NP immunopoiesis NN I-NP . . O Involvement NN B-NP of IN B-PP transcription NN B-NP factor NN I-NP YB-1 NN I-NP in IN B-PP human JJ B-NP T-cell NN I-NP lymphotropic JJ I-NP virus NN I-NP type NN I-NP I CD I-NP basal JJ I-NP gene NN I-NP expression NN I-NP . . O Sequences NNS B-NP which WDT B-NP control VBP B-VP basal JJ O human JJ B-NP T-cell NN I-NP lymphotropic NN I-NP virus NN I-NP type NN I-NP I CD I-NP ( ( O HTLV-I NN B-NP ) ) O transcription NN B-NP likely RB B-ADVP play VB B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP initiation NN B-NP and CC O maintenance NN B-NP of IN B-PP virus NN B-NP replication NN I-NP . . O We PRP B-NP previously RB B-ADVP identified VBD B-VP and CC O analyzed VBD B-VP a DT B-NP 45-nucleotide JJ I-NP sequence NN I-NP ( ( O downstream JJ B-NP regulatory JJ I-NP element NN I-NP 1 CD I-NP { ( O DRE NN B-NP 1 CD I-NP } ) O ) ) O COMMA COMMA O +195 CD B-NP to TO O +240 CD B-NP COMMA COMMA O at IN B-PP the DT B-NP boundary NN I-NP of IN B-PP the DT B-NP R\/U5 NN I-NP region NN I-NP of IN B-PP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP which WDT B-NP is VBZ B-VP required VBN I-VP for IN B-PP HTLV-I NN B-NP basal JJ I-NP transcription NN I-NP . . O We PRP B-NP identified VBD B-VP a DT B-NP protein NN I-NP COMMA COMMA O p37 NN B-NP COMMA COMMA O which WDT B-NP specifically RB B-ADVP bound VBD B-VP to TO B-PP DRE NN B-NP 1 CD I-NP . . O An DT B-NP affinity NN I-NP column NN I-NP fraction NN I-NP COMMA COMMA O containing VBG B-VP p37 NN B-NP COMMA COMMA O stimulated VBD B-VP HTLV-I NN B-NP transcription NN I-NP approximately RB B-ADVP 12-fold RB I-ADVP in FW B-ADVP vitro FW I-ADVP . . O We PRP B-NP now RB B-ADVP report VBP B-VP the DT B-NP identification NN I-NP of IN B-PP a DT B-NP cDNA NN I-NP clone NN I-NP ( ( O 15B-7 NN B-NP ) ) O COMMA COMMA O from IN B-PP a DT B-NP Jurkat NN I-NP expression NN I-NP library NN I-NP COMMA COMMA O that WDT B-NP binds VBZ B-VP specifically RB B-ADVP to TO B-PP the DT B-NP DRE NN I-NP 1 CD I-NP regulatory JJ I-NP sequence NN I-NP . . O Binding NN B-NP of IN B-PP the DT B-NP cDNA NN I-NP fusion NN I-NP protein NN I-NP COMMA COMMA O similarly RB B-ADVP to TO B-PP the DT B-NP results NNS I-NP obtained VBN B-VP with IN B-PP purified VBN B-NP Jurkat NN I-NP protein NN I-NP COMMA COMMA O was VBD B-VP decreased VBN I-VP by IN B-PP introduction NN B-NP of IN B-PP site-specific JJ B-NP mutations NNS I-NP in IN B-PP the DT B-NP DRE NN I-NP 1 CD I-NP regulatory JJ I-NP sequence NN I-NP . . O In FW B-NP vitro FW I-NP transcription NN B-NP and CC O translation NN B-NP of IN B-PP 15B-7 NN B-NP cDNA NN I-NP produced VBD B-VP a DT B-NP fusion NN I-NP protein NN I-NP which WDT B-NP bound VBD B-VP specifically RB B-ADVP to TO B-PP the DT O HTLV-I NN O +195 CD B-NP to TO O +240 CD B-NP oligonucleotide NN B-NP . . O The DT B-NP partial JJ I-NP cDNA NN I-NP encodes VBZ B-VP a DT B-NP protein NN I-NP which WDT B-NP is VBZ B-VP homologous JJ B-ADJP to TO B-PP the DT B-NP C-terminal JJ I-NP 196 CD I-NP amino NN I-NP acids NNS I-NP of IN B-PP the DT B-NP 36-kDa JJ I-NP transcription NN I-NP factor NN I-NP COMMA COMMA O YB-1 NN B-NP . . O Cotransfection NN B-NP of IN B-PP a DT B-NP YB-1 NN I-NP expression NN I-NP plasmid NN I-NP increases VBZ B-VP HTLV-I NN B-NP basal JJ I-NP transcription NN I-NP approximately RB B-ADVP 14-fold RB I-ADVP in IN B-PP Jurkat NN B-NP T NN I-NP lymphocytes NNS I-NP . . O On IN B-PP the DT I-PP basis NN I-PP of IN I-PP the DT B-NP molecular JJ I-NP weight NN I-NP COMMA COMMA O DNA-binding JJ B-NP characteristics NNS I-NP COMMA COMMA O and CC O in FW B-NP vivo FW I-NP transactivation NN I-NP activity NN I-NP COMMA COMMA O we PRP B-NP suggest VBP B-VP that IN B-SBAR the DT B-NP previously RB I-NP identified VBN I-NP DRE NN I-NP 1-binding JJ I-NP protein NN I-NP COMMA COMMA O p37 NN B-NP COMMA COMMA O is VBZ B-VP YB-1 NN B-NP . . O Chlorinated VBN B-NP dibenzo-p-dioxins NNS B-NP and CC O dibenzofurans NNS B-NP and CC O the DT B-NP human JJ I-NP immune JJ I-NP system NN I-NP . . O 1 LS B-LST . . O Blood NN B-NP cell NN I-NP receptors NNS I-NP in IN B-PP volunteers NNS B-NP with IN B-PP moderately RB B-NP increased VBN I-NP body NN I-NP burdens NNS I-NP . . O Using VBG B-VP monoclonal JJ B-NP antibodies NNS I-NP ( ( O mAbs NNS B-NP ) ) O and CC O flow NN B-NP cytometry NN I-NP COMMA COMMA O we PRP B-NP studied VBD B-VP a DT B-NP variety NN I-NP of IN B-PP surface NN B-NP receptors NNS I-NP on IN B-PP lymphocyte NN B-NP subpopulations NNS I-NP of IN B-PP workers NNS B-NP with IN B-PP moderately RB B-NP increased VBN I-NP body NN I-NP burdens NNS I-NP of IN B-PP 2COMMA3COMMA7COMMA8-tetrachlorodibenzo-p-dioxin NN B-NP ( ( O TCDD NN B-NP ) ) O and CC B-PP of IN B-PP other JJ B-NP polychlorinated VBN B-NP dibenzo-p-dioxins NNS B-NP and CC O dibenzofurans NNS B-NP ( ( O PCDD\/PCDF NN B-NP ) ) O COMMA COMMA O expressed VBN B-VP here RB B-ADVP as IN B-PP International-Toxicity NN B-NP Equivalencies NN I-NP ( ( O I-TE NN B-NP ) ) O . . O The DT B-NP hypothesis NN I-NP to TO B-VP be VB I-VP tested VBN I-VP was VBD B-VP whether IN B-SBAR or CC O not RB O humans NNS B-NP exhibit VBP B-VP a DT B-NP similar JJ I-NP susceptibility NN I-NP to TO B-PP PCDDs\/PCDFs NNS B-NP with IN B-PP respect NN I-PP to TO I-PP the DT B-NP surface NN I-NP receptors NNS I-NP found VBN B-VP previously RB I-VP to TO I-VP respond VB I-VP to TO B-PP small JJ B-NP doses NNS I-NP of IN B-PP 2COMMA3COMMA7COMMA8-tetrachlorodibenzo-p-dioxin NN B-NP ( ( O TCDD NN B-NP ) ) O in IN B-PP Callithrix FW B-NP jacchus FW I-NP . . O These DT B-NP are VBP B-VP : : O helper-inducer JJ B-NP ( ( O memory NN B-NP ) ) O T NN B-NP cells NNS I-NP ( ( O CD4+CD45R0+CD45RA-CD29highCD11a+ JJ B-NP ) ) O COMMA COMMA O CD20+ JJ B-NP B NN I-NP cells NNS I-NP COMMA COMMA O and CC O cytotoxic JJ B-NP T NN I-NP cells NNS I-NP ( ( O CD8+CD56+\/CD57+ JJ B-NP ) ) O . . O Furthermore RB B-ADVP COMMA COMMA O 68 CD B-NP triple-labellings NNS I-NP with IN B-PP mAbs NNS B-NP were VBD B-VP performed VBN I-VP on IN B-PP the DT B-NP cells NNS I-NP of IN B-PP each DT B-NP volunteer NN I-NP to TO B-VP possibly RB I-VP generate VB I-VP further JJ B-NP hypotheses NNS I-NP . . O It PRP B-NP was VBD B-VP evaluated VBN I-VP whether IN B-SBAR any DT B-NP of IN B-PP the DT B-NP variables NNS I-NP might MD B-VP be VB I-VP used VBN I-VP as IN B-PP a DT B-NP biomarker NN I-NP of IN B-PP effects NNS B-NP for IN B-PP this DT B-NP class NN I-NP of IN B-PP compounds NNS B-NP . . O There EX B-NP were VBD B-VP two CD B-NP main JJ I-NP goals NNS I-NP : : O ( ( B-LST 1 LS I-LST ) ) O to TO B-VP evaluate VB I-VP whether IN B-SBAR workers NNS B-NP with IN B-PP a DT B-NP moderately RB I-NP increased VBN I-NP PCDD\/PCDF-body NN I-NP burden NN I-NP { ( O 25-140 CD B-NP ppt NN I-NP TCDD NN I-NP or CC O 104-522 CD B-NP ppt NN I-NP I-TE NN I-NP in IN B-PP blood NN B-NP fat NN I-NP } ) O exhibit VBP B-VP changes NNS B-NP in IN B-PP the DT B-NP surface NN I-NP receptors NNS I-NP of IN B-PP white JJ B-NP blood NN I-NP cells NNS I-NP COMMA COMMA O as IN B-SBAR observed VBN B-VP in IN B-PP previous JJ B-NP studies NNS I-NP in IN B-PP non-human JJ B-NP primates NNS I-NP COMMA COMMA O and CC O ( ( B-LST 2 LS I-LST ) ) O to TO B-VP clarify VB I-VP whether IN B-SBAR persons NNS B-NP at IN B-PP the DT B-NP upper JJ I-NP range NN I-NP { ( O 10-23 CD B-NP ppt NN I-NP TCDD NN I-NP or CC O 30-90 CD B-NP ppt NN I-NP I-TE NN I-NP in IN B-PP blood NN B-NP fat NN I-NP } ) O of IN B-PP the DT B-NP body NN I-NP burden NN I-NP reference NN I-NP values NNS I-NP of IN B-PP a DT O not RB B-ADVP particularly RB I-ADVP exposed VBN B-NP population NN I-NP show VBP B-VP detectable JJ B-NP deviations NNS I-NP in IN B-PP these DT B-NP immunological JJ I-NP variables NNS I-NP COMMA COMMA O when WRB B-ADVP compared VBN B-VP with IN B-PP persons NNS B-NP at IN B-PP the DT B-NP lower JJR I-NP and CC I-NP medium NN I-NP range NN I-NP { ( O 1-3 CD B-NP ppt NN I-NP TCDD NN I-NP or CC O 9-29 CD B-NP ppt NN I-NP I-TE NN I-NP } ) O of IN B-PP these DT B-NP body NN I-NP burden NN I-NP reference NN I-NP values NNS I-NP . . O Regression NN B-NP analysis NN I-NP of IN B-PP our PRP$ B-NP data NNS I-NP revealed VBD B-VP slight JJ B-NP trends NNS I-NP for IN B-PP some DT B-NP of IN B-PP the DT B-NP biomarkers NNS I-NP ( ( O e.g. FW B-ADVP CD45R0+ JJ B-NP ) ) O . . O With IN B-PP one CD B-NP exception NN I-NP COMMA COMMA O these DT B-NP were VBD B-VP all DT B-ADVP increases NNS B-NP . . O None NN B-NP of IN B-PP the DT B-NP alterations NNS I-NP observed VBN B-VP are VBP B-VP of IN B-PP medical JJ B-NP relevance NN I-NP . . O The DT B-NP slight JJ I-NP increase NN I-NP in IN B-PP the DT B-NP percentage NN I-NP of IN B-PP CD4+CD45R0+ JJ B-NP cells NNS I-NP remained VBD B-VP significant JJ B-ADJP even RB B-PP after IN I-PP covariant JJ B-NP analysis NN I-NP taking VBG B-VP age-related JJ B-NP changes NNS I-NP into IN B-PP account NN B-NP . . O Altogether RB B-ADVP COMMA COMMA O the DT B-NP data NNS I-NP do VBP B-VP not RB I-VP provide VB I-VP any DT B-NP evidence NN I-NP to TO B-VP support VB I-VP an DT B-NP assumption NN I-NP that IN B-SBAR moderately RB B-NP increased VBN I-NP body NN I-NP burdens NNS I-NP of IN B-PP PCDDs\/PCDFs NNS B-NP in IN B-PP adults NNS B-NP induce VBP B-VP decreases NNS B-NP in IN B-PP the DT B-NP cellular JJ I-NP components NNS I-NP of IN B-PP the DT B-NP human JJ I-NP immune JJ I-NP system NN I-NP . . O Adult JJ B-NP humans NNS I-NP certainly RB B-ADVP are VBP B-VP less RBR B-ADJP susceptible JJ I-ADJP to TO B-PP this DT B-NP action NN I-NP of IN B-PP PCDDs\/PCDFs NNS B-NP than IN B-PP adolescent JJ B-NP Callithrix FW I-NP jacchus FW I-NP . . O The DT B-NP lymphotoxin NN I-NP promoter NN I-NP is VBZ B-VP stimulated VBN I-VP by IN B-PP HTLV-I NN B-NP tax NN I-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP human JJ B-NP T-cell NN I-NP lines NNS I-NP . . O The DT B-NP HTLV-I NN I-NP transcriptional JJ I-NP activator NN I-NP tax NN I-NP was VBD B-VP used VBN I-VP to TO B-VP gain VB I-VP insight NN B-NP into IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP lymphotoxin NN B-NP ( ( O LT NN B-NP ; : O TNF-beta NN B-NP ) ) O gene NN B-NP induction NN I-NP . . O Tax-expressing JJ B-NP cell NN I-NP lines NNS I-NP produce VBP B-VP LT NN B-NP biologic JJ I-NP activity NN I-NP . . O An DT O LT NN B-NP promoter NN I-NP ( ( O LT-293 NN B-NP ) ) O CAT NN B-NP construct NN I-NP that WDT B-NP contained VBD B-VP an DT B-NP NF-kappa NN I-NP B NN I-NP site NN I-NP was VBD B-VP active JJ B-ADJP in IN B-PP the DT B-NP LT-producing JJ I-NP C81-66-45 NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O which WDT B-NP contains VBZ B-VP defective JJ B-NP HTLV-I NN I-NP but CC O expresses VBZ B-VP tax NN B-NP . . O The DT B-NP observation NN I-NP that IN B-SBAR a DT B-NP mutated VBN I-NP LT-kappa NN I-NP B NN I-NP construct NN I-NP ( ( O M1-CAT NN B-NP ) ) O was VBD B-VP inactive JJ B-ADJP in IN B-PP C81-66-45 NN B-NP COMMA COMMA O confirmed VBD B-VP the DT B-NP importance NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP LT NN B-NP gene NN I-NP expression NN I-NP . . O Tax NN B-NP was VBD B-VP transfected VBN I-VP into IN B-PP HTLV-I-negative JJ B-NP human JJ I-NP T-cell NN I-NP lines NNS I-NP . . O Jurkat NN B-NP T NN I-NP cells NNS I-NP stably RB B-VP expressing VBG I-VP tax NN B-NP contained VBD B-VP elevated JJ B-NP levels NNS I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP that WDT B-NP directly RB B-VP bound VBD I-VP to TO B-PP the DT B-NP LT-kappa NN I-NP B NN I-NP site NN I-NP . . O Tax NN B-NP co-transfected VBN B-VP with IN B-PP reporter NN B-NP constructs NNS I-NP into IN B-PP Jurkat NN B-NP cells NNS I-NP maximally RB B-VP activated VBD I-VP HTLV-I-LTR-CAT NN B-NP and CC O kappa NN B-NP B-fos-CAT NN I-NP and CC O also RB O activated VBD B-VP LT-293 NN B-NP to TO B-PP a DT B-NP lesser JJR I-NP extent NN I-NP . . O In IN B-PP JM NN B-NP T NN I-NP cells NNS I-NP COMMA COMMA O tax NN B-NP induced JJ B-VP LT-293 NN B-NP activity NN I-NP by IN B-PP two- CD B-NP to TO O four-fold JJ B-NP COMMA COMMA O though IN B-SBAR there EX B-NP was VBD B-VP no DT B-NP induction NN I-NP of IN B-PP M1-CAT NN B-NP . . O The DT B-NP increase NN I-NP in IN B-PP LT-293 NN B-NP CAT NN I-NP activity NN I-NP mirrored VBD B-VP the DT B-NP increase NN I-NP in IN B-PP LT NN B-NP biologic JJ I-NP activity NN I-NP seen VBN B-VP under IN B-PP these DT B-NP conditions NNS I-NP . . O These DT B-NP studies NNS I-NP COMMA COMMA O the DT B-NP first JJ I-NP to TO B-VP demonstrate VB I-VP induction NN B-NP of IN B-PP LT NN B-NP promoter NN I-NP activity NN I-NP over IN B-PP basal JJ B-NP levels NNS I-NP COMMA COMMA O indicate VBP B-VP that IN B-SBAR HTLV-I NN B-NP tax NN I-NP causes VBZ B-VP low-level JJ B-NP activation NN I-NP of IN B-PP both CC O endogenous JJ B-NP LT NN I-NP and CC O the DT B-NP LT NN I-NP promoter NN I-NP COMMA COMMA O at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP through IN B-PP activation NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O Transient JJ B-NP pseudohypoaldosteronism NN I-NP in IN B-PP obstructive JJ B-NP renal JJ I-NP disease NN I-NP with IN B-PP transient JJ B-NP reduction NN I-NP of IN B-PP lymphocytic JJ B-NP aldosterone NN I-NP receptors NNS I-NP . . O Results NNS B-NP in IN B-PP two CD B-NP affected JJ I-NP infants NNS I-NP . . O We PRP B-NP report VBP B-VP two CD B-NP patients NNS I-NP with IN B-PP transient JJ B-NP pseudohypoaldosteronism NN I-NP due JJ B-PP to TO I-PP obstructive JJ B-NP renal JJ I-NP disease NN I-NP . . O Both DT B-NP patients NNS I-NP presented VBD B-VP with IN B-PP a DT B-NP salt-losing JJ I-NP episode NN I-NP simulating VBG I-NP adrenal JJ I-NP insufficiency NN I-NP . . O In IN B-PP one CD B-NP patient NN I-NP COMMA COMMA O transient JJ B-NP reduction NN I-NP of IN B-PP aldosterone NN B-NP receptors NNS I-NP could MD B-VP be VB I-VP documented VBN I-VP COMMA COMMA O while IN B-SBAR in IN B-PP the DT B-NP second JJ I-NP patient NN I-NP the DT B-NP clinical JJ I-NP and CC I-NP biochemical JJ I-NP parameters NNS I-NP were VBD B-VP consistent JJ B-ADJP with IN B-PP transient JJ B-NP pseudohypoaldosteronism NN I-NP . . O The DT B-NP macrophage NN I-NP transcription NN I-NP factor NN I-NP PU.1 NN I-NP directs VBZ B-VP tissue-specific JJ B-NP expression NN I-NP of IN B-PP the DT B-NP macrophage NN I-NP colony-stimulating JJ I-NP factor NN I-NP receptor NN I-NP . . O The DT O macrophage NN B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O M-CSF NN B-NP ) ) O receptor NN B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP a DT B-NP tissue-specific JJ I-NP fashion NN I-NP from IN B-PP two CD B-NP distinct JJ I-NP promoters NNS I-NP in IN B-PP monocytes\/macrophages NNS B-NP and CC O the DT B-NP placenta NN I-NP . . O In IN B-SBAR order NN O to TO O further RB B-ADVP understand VB B-VP the DT B-NP transcription NN I-NP factors NNS I-NP which WDT B-NP play VBP B-VP a DT B-NP role NN I-NP in IN B-PP the DT B-NP commitment NN I-NP of IN B-PP multipotential JJ B-NP progenitors NNS I-NP to TO B-PP the DT B-NP monocyte\/macrophage NN I-NP lineage NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP initiated VBN I-VP an DT B-NP investigation NN I-NP of IN B-PP the DT B-NP factors NNS I-NP which WDT B-NP activate VBP B-VP the DT B-NP M-CSF NN I-NP receptor NN I-NP very RB B-ADVP early RB I-ADVP during IN B-PP the DT B-NP monocyte NN I-NP differentiation NN I-NP process NN I-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP human JJ I-NP monocytic JJ I-NP M-CSF NN I-NP receptor NN I-NP promoter NN I-NP directs VBZ B-VP reporter NN B-NP gene NN I-NP activity NN I-NP in IN B-PP a DT B-NP tissue-specific JJ I-NP fashion NN I-NP . . O Since IN B-SBAR one CD B-NP of IN B-PP the DT B-NP few JJ I-NP transcription NN I-NP factors NNS I-NP which WDT B-NP have VBP B-VP been VBN I-VP implicated VBN I-VP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP monocyte NN B-NP genes NNS I-NP is VBZ B-VP the DT O macrophage- NN B-NP and CC O B-cell-specific JJ B-ADJP PU.1 NN B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O we PRP B-NP investigated VBD B-VP whether IN B-SBAR PU.1 NN B-NP binds VBZ B-VP and CC O activates VBZ B-VP the DT B-NP M-CSF NN I-NP receptor NN I-NP promoter NN I-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR both CC O in FW B-NP vitro-translated VBN I-NP PU.1 NN I-NP and CC O PU.1 NN B-NP from IN B-PP nuclear JJ B-NP extracts NNS I-NP bind VBP B-VP to TO B-PP a DT B-NP specific JJ I-NP site NN I-NP in IN B-PP the DT B-NP M-CSF NN I-NP receptor NN I-NP promoter NN I-NP just RB B-ADVP upstream JJ I-ADVP from IN B-PP the DT B-NP major JJ I-NP transcription NN I-NP initiation NN I-NP site NN I-NP . . O Mutations NNS B-NP in IN B-PP this DT B-NP site NN I-NP which WDT B-NP eliminate VB B-VP PU.1 NN B-NP binding NN I-NP decrease VBP B-VP M-CSF NN B-NP receptor NN I-NP promoter NN I-NP activity NN I-NP significantly RB B-ADVP in IN B-PP macrophage JJ B-NP cell NN I-NP lines NNS I-NP only RB B-ADVP . . O Furthermore RB B-ADVP COMMA COMMA O PU.1 NN B-NP transactivates VBZ B-VP the DT B-NP M-CSF NN I-NP receptor NN I-NP promoter NN I-NP in IN B-PP nonmacrophage JJ B-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR PU.1 NN B-NP plays VBZ B-VP a DT B-NP major JJ I-NP role NN I-NP in IN B-PP macrophage NN B-NP gene NN I-NP regulation NN B-NP and CC O development NN B-NP by IN B-PP directing VBG B-VP the DT B-NP expression NN I-NP of IN B-PP a DT B-NP receptor NN I-NP for IN B-PP a DT B-NP key JJ I-NP macrophage NN I-NP growth NN I-NP factor NN I-NP . . O Increased VBN B-NP natural JJ I-NP killer NN I-NP cell NN I-NP activity NN I-NP correlates VBZ B-VP with IN B-PP low JJ B-NP or CC I-NP negative JJ I-NP expression NN I-NP of IN B-PP the DT B-NP HER-2\/neu NN I-NP oncogene NN I-NP in IN B-PP patients NNS B-NP with IN B-PP breast NN B-NP cancer NN I-NP . . O BACKGROUND NN B-NP . . O Increased VBN B-NP expression NN I-NP of IN B-PP the DT B-NP HER-2\/neu NN I-NP oncogene NN I-NP in IN B-PP breast NN B-NP cancer NN I-NP correlates VBZ B-VP with IN B-PP decreased VBN B-NP estrogen NN I-NP receptor NN I-NP concentration NN I-NP and CC O seems VBZ B-VP to TO I-VP be VB I-VP an DT B-NP important JJ I-NP prognostic JJ I-NP factor NN I-NP . . O The DT B-NP authors NNS I-NP investigated VBD B-VP whether IN B-SBAR there EX B-NP is VBZ B-VP a DT B-NP correlation NN I-NP between IN B-PP HER-2\/neu NN B-NP expression NN I-NP and CC O immunologic JJ B-NP parameters NNS I-NP representing VBG B-VP tumor NN B-NP defense NN I-NP in IN B-PP patients NNS B-NP with IN B-PP breast NN B-NP cancer NN I-NP . . O METHOD NN B-NP . . O A DT B-NP Western JJ I-NP blot NN I-NP analysis NN I-NP was VBD B-VP used VBN I-VP to TO B-VP investigate VB I-VP HER-2\/neu NN B-NP expression NN I-NP COMMA COMMA O whereas IN O a DT B-NP chromium-release NN I-NP assay NN I-NP using VBG B-VP the DT B-NP K562 NN I-NP cell NN I-NP line NN I-NP as IN B-PP target NN B-NP was VBD B-VP used VBN I-VP to TO B-VP measure VB I-VP natural JJ B-NP killer NN I-NP ( ( O NK NN B-NP ) ) O cell NN B-NP activity NN I-NP . . O RESULTS NNS B-NP . . O In IN B-PP patients NNS B-NP with IN B-PP breast NN B-NP cancer NN I-NP COMMA COMMA O NK NN B-NP cell NN I-NP activity NN I-NP was VBD B-VP significantly RB B-ADJP higher JJR I-ADJP compared VBN B-PP with IN B-PP patients NNS B-NP with IN B-PP benign JJ B-NP tumors NNS I-NP ( ( O P NN B-NP = JJ B-VP 0.006 CD B-NP ) ) O or CC O healthy JJ B-NP control NN I-NP subjects NNS I-NP ( ( O P NN B-NP = JJ B-VP 0.002 CD B-NP ) ) O . . O Moreover RB B-ADVP COMMA COMMA O 23.3 CD B-NP % NN I-NP of IN B-PP patients NNS B-NP with IN B-PP breast NN B-NP cancer NN I-NP showed VBD B-VP an DT B-NP overexpression NN I-NP of IN B-PP HER-2\/neu NN B-NP protein NN I-NP . . O Within IN B-PP this DT B-NP group NN I-NP of IN B-PP patients NNS B-NP COMMA COMMA O NK NN B-NP cell NN I-NP activity NN I-NP was VBD B-VP significantly RB B-ADJP lower JJR I-ADJP ( ( O 45.6 CD B-NP +\/- CC I-NP 16.1 CD I-NP % NN I-NP ) ) O compared VBN B-PP with IN B-PP the DT B-NP group NN I-NP with IN B-PP no DT B-NP HER-2\/neu NN I-NP overexpression NN I-NP ( ( O 57.3 CD B-NP +\/- CC I-NP 11.0 CD I-NP % NN I-NP ) ) O . . O NK NN B-NP cell NN I-NP activity NN I-NP did VBD B-VP not RB I-VP increase VB I-VP in IN B-PP patients NNS B-NP with IN B-PP HER-2\/neu NN B-NP overexpression NN I-NP . . O Thus RB B-ADVP COMMA COMMA O there EX B-NP was VBD B-VP a DT B-NP statistically RB I-NP significant JJ I-NP correlation NN I-NP of IN B-PP cytolytic JJ B-NP effector NN I-NP cell NN I-NP function NN I-NP with IN B-PP HER-2\/neu NN B-NP expression NN I-NP of IN B-PP the DT B-NP tumor NN I-NP ( ( O P NN B-NP = JJ B-VP 0.003 CD B-NP ) ) O COMMA COMMA O and CC O HER-2\/neu NN B-NP overexpression NN I-NP correlated VBD B-VP with IN B-PP a DT B-NP negative JJ I-NP estrogen NN I-NP receptor NN I-NP status NN I-NP ( ( O P NN B-NP = JJ B-VP 0.005 CD B-NP ) ) O . . O CONCLUSION NN B-NP . . O These DT B-NP data NNS I-NP add VBP B-VP further JJ B-NP evidence NN I-NP to TO B-PP previous JJ B-NP observations NNS I-NP from IN B-PP the DT B-NP authors NNS I-NP ' POS B-NP laboratory NN O that IN B-NP certain JJ I-NP tumor NN I-NP characteristics NNS B-VP may MD I-VP be VB I-VP associated VBN B-PP with IN B-NP reactions NNS O of IN B-NP the DT I-NP host NN O with IN B-NP breast NN I-NP cancer NN O Induction NN B-NP of IN B-PP tyrosine NN B-NP phosphorylation NN I-NP and CC O T-cell NN B-NP activation NN I-NP by IN B-PP vanadate NN B-NP peroxide NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP protein NN B-NP tyrosine NN I-NP phosphatases NNS I-NP . . O Rapid JJ B-NP tyrosine NN I-NP phosphorylation NN I-NP of IN B-PP key JJ B-NP cellular JJ I-NP proteins NNS I-NP is VBZ B-VP a DT B-NP crucial JJ I-NP event NN I-NP in IN B-PP the DT B-NP transduction NN I-NP of IN B-PP activation NN B-NP signals NNS I-NP to TO B-PP T-lymphocytes NNS B-NP . . O The DT B-NP regulatory JJ I-NP role NN I-NP of IN B-PP protein NN B-NP tyrosine NN I-NP phosphatases NNS I-NP ( ( O PTPases NNS B-NP ) ) O in IN B-PP this DT B-NP process NN I-NP was VBD B-VP explored VBN I-VP by IN B-PP studying VBG B-VP the DT B-NP effects NNS I-NP of IN B-PP a DT B-NP powerful JJ I-NP PTPase NN I-NP inhibitor NN I-NP COMMA COMMA O vanadate NN B-NP peroxide NN I-NP ( ( O pervanadate NN B-NP ) ) O COMMA COMMA O on IN B-PP the DT B-NP activation NN I-NP cascade NN I-NP of IN B-PP Jurkat NN B-NP human JJ I-NP leukaemic JJ I-NP T-cells NNS I-NP . . O Pervanadate NN B-NP induced VBD B-VP activation NN B-NP of IN B-PP the DT B-NP tyrosine NN I-NP kinases NNS I-NP lck NN B-NP and CC O fyn NN B-NP ( ( O 4- CD B-NP and CC I-NP 3-fold JJ I-NP respectively RB B-ADVP ) ) O and CC O a DT B-NP dramatic JJ I-NP increase NN I-NP in IN B-PP tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP cellular JJ B-NP proteins NNS I-NP COMMA COMMA O notably RB B-NP phospholipase NN I-NP C NN I-NP gamma NN I-NP 1 CD I-NP . . O After IN B-PP this DT B-NP event NN I-NP COMMA COMMA O we PRP B-NP observed VBD B-VP a DT B-NP rise NN I-NP in IN B-PP intracellular JJ B-NP Ca2+ NN I-NP concentration NN I-NP COMMA COMMA O corresponding VBG B-VP to TO B-PP an DT B-NP influx NN I-NP . . O This DT B-NP effect NN I-NP required VBD B-VP surface NN B-NP expression NN I-NP of IN B-PP the DT B-NP CD45 NN I-NP PTPase NN I-NP and CC O was VBD B-VP not RB I-VP observed VBN I-VP in IN B-PP CD45-deficient JJ B-NP variants NNS I-NP of IN B-PP Jurkat NN B-NP cells NNS I-NP . . O In IN B-PP the DT B-NP CD45-negative JJ I-NP variant NN I-NP COMMA COMMA O the DT B-NP effect NN I-NP of IN B-PP pervanadate NN B-NP on IN B-PP tyrosine NN B-NP phosphorylation NN I-NP was VBD B-VP globally RB I-VP decreased VBN I-VP and CC O some DT B-NP phosphorylated VBN I-NP substrates NNS I-NP were VBD B-VP specifically RB B-ADVP missing JJ B-ADJP . . O Pervanadate NN B-NP also RB B-ADVP stimulated VBD B-VP transcription NN B-NP of IN B-PP the DT B-NP c-fos NN I-NP gene NN I-NP and CC O accumulation NN B-NP of IN B-PP its PRP$ B-NP mRNA NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP several JJ B-NP other JJ I-NP hallmarks NNS I-NP of IN B-PP T-lymphocyte NN B-NP activation NN I-NP such JJ B-PP as IN I-PP surface NN B-NP expression NN I-NP of IN B-PP the DT B-NP CD69 NN I-NP antigen NN I-NP and CC O the DT B-NP interleukin NN I-NP 2 CD I-NP receptor NN I-NP alpha-chain NN I-NP ( ( O CD25 NN B-NP ) ) O . . O Pervanadate NN B-NP synergized VBD B-VP with IN B-PP signals NNS B-NP delivered VBN B-VP by IN B-PP T-cell NN B-NP antigen NN I-NP receptor NN I-NP engagement NN I-NP or CC B-PP by IN B-PP a DT B-NP phorbol NN I-NP ester NN I-NP to TO B-VP induce VB I-VP interleukin NN B-NP 2 CD I-NP production NN I-NP . . O Pervanadate NN B-NP activated VBD B-VP NF-kappa NN B-NP B NN I-NP COMMA COMMA O as IN B-SBAR shown VBN B-VP by IN B-PP an DT B-NP increase NN I-NP in IN B-PP DNA-binding JJ B-NP activity NN I-NP of IN B-PP this DT B-NP transcription NN I-NP factor NN I-NP . . O We PRP B-NP thus RB B-ADVP conclude VBP B-VP that IN B-SBAR PTPases NNS B-NP play VBP B-VP a DT B-NP crucial JJ I-NP role NN I-NP in IN B-PP the DT B-NP negative JJ I-NP regulation NN I-NP of IN B-PP signal NN B-NP transduction NN I-NP culminating VBG B-VP in IN B-PP T-lymphocyte NN B-NP activation NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O induction NN B-NP of IN B-PP tyrosine NN B-NP phosphorylation NN I-NP appears VBZ B-VP sufficient JJ B-ADJP per FW I-ADJP se FW I-ADJP to TO B-VP initiate VB I-VP a DT B-NP complete JJ I-NP activation NN I-NP programme NN I-NP . . O Steroid-resistant JJ B-NP asthma NN I-NP . . O Cellular JJ B-NP mechanisms NNS I-NP contributing VBG B-VP to TO B-PP inadequate JJ B-NP response NN I-NP to TO B-PP glucocorticoid NN B-NP therapy NN I-NP . . O The DT B-NP current JJ I-NP study NN I-NP examined VBD B-VP whether IN B-SBAR alterations NNS B-NP in IN B-PP glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O binding NN B-NP contribute VBP B-VP to TO B-PP poor JJ B-NP response NN I-NP to TO B-PP glucocorticoid NN B-NP therapy NN I-NP in IN B-PP asthma NN B-NP . . O 29 CD B-NP asthma NN I-NP patients NNS I-NP with IN B-PP forced VBN B-NP expiratory JJ I-NP volume NN I-NP in IN B-PP 1 CD B-NP s NN I-NP ( ( O FEV1 NN B-NP ) ) O < JJR B-NP 70 CD I-NP % NN I-NP predicted VBN B-VP were VBD B-VP studied VBN I-VP . . O Patients NNS B-NP were VBD B-VP classified VBN I-VP as IN B-PP steroid NN B-ADJP sensitive JJ I-ADJP ( ( O SS JJ B-ADJP ) ) O if IN B-SBAR their PRP$ B-NP morning NN I-NP FEV1 NN I-NP increased VBD B-VP > RBR B-NP 30 CD I-NP % NN I-NP after IN B-PP a DT B-NP 1-wk JJ I-NP course NN I-NP of IN B-PP oral JJ B-NP prednisone NN I-NP 20 CD B-NP mg NN I-NP twice RB B-ADVP daily RB I-ADVP and CC O steroid NN B-ADJP resistant JJ I-ADJP ( ( O SR JJ B-ADJP ) ) O if IN B-SBAR they PRP B-NP failed VBD B-VP to TO I-VP increase VB I-VP > RBR B-NP 15 CD I-NP % NN I-NP . . O PBMC NN B-NP obtained VBN B-VP from IN B-PP these DT B-NP two CD I-NP groups NNS I-NP COMMA COMMA O 17 CD B-NP SR JJ I-NP and CC O 12 CD B-NP SS JJ I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP 12 CD B-NP normal JJ I-NP controls NNS I-NP were VBD B-VP analyzed VBN I-VP . . O SR JJ B-NP patients NNS I-NP had VBD B-VP two CD B-NP distinguishable JJ I-NP GR NN I-NP binding NN I-NP abnormalities NNS I-NP : : O 15 CD B-NP of IN B-PP the DT B-NP 17 CD I-NP SR JJ I-NP patients NNS I-NP demonstrated VBD B-VP a DT B-NP significantly RB I-NP reduced VBN I-NP GR NN I-NP binding NN I-NP affinity NN I-NP COMMA COMMA O as IN B-SBAR compared VBN B-VP with IN B-PP SS JJ B-NP patients NNS I-NP ( ( O P NN B-NP = JJ B-VP 0.0001 CD B-NP ) ) O and CC O normal JJ B-NP controls NNS I-NP ( ( O P NN B-NP = JJ B-VP 0.0001 CD B-NP ) ) O . . O This DT B-NP defect NN I-NP was VBD B-VP localized JJ I-VP to TO B-PP T NN B-NP cells NNS I-NP and CC O reverted VBD B-VP to TO B-PP normal JJ B-NP after IN B-PP 48 CD B-NP h NN I-NP in IN B-PP culture NN B-NP media NNS I-NP . . O However RB B-ADVP COMMA COMMA O incubation NN B-NP with IN B-PP a DT B-NP combination NN I-NP of IN B-PP IL-2 NN B-NP and CC O IL-4 NN B-NP sustained VBD B-VP this DT B-NP abnormality NN I-NP . . O The DT B-NP other JJ I-NP two CD I-NP SR JJ I-NP patients NNS I-NP had VBD B-VP an DT B-NP abnormally RB I-NP low JJ I-NP GR NN I-NP number NN I-NP with IN B-PP normal JJ B-NP binding NN I-NP affinity NN I-NP that WDT B-NP was VBD B-VP not RB O limited VBN B-ADJP to TO B-PP T NN B-NP cells NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O GR NN B-NP number NN I-NP failed VBD B-VP to TO I-VP normalize VB I-VP after IN B-PP incubation NN B-NP in IN B-PP media NNS B-NP alone RB B-ADVP or CC O IL-2 NN B-NP and CC O IL-4 NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O SR JJ B-NP asthma NN I-NP may MD B-VP be VB I-VP due JJ B-PP to TO I-PP more JJR B-NP than IN I-NP one CD I-NP abnormality NN I-NP COMMA COMMA O the DT B-NP majority NN I-NP related JJ B-ADJP to TO B-PP a DT B-NP reversible JJ I-NP cytokine-induced JJ I-NP reduction NN I-NP in IN B-PP GR NN B-NP binding NN I-NP affinity NN I-NP and CC O the DT B-NP second JJ I-NP related JJ B-ADJP to TO B-PP an DT B-NP irreversible JJ I-NP reduction NN I-NP in IN B-PP GR NN B-NP number NN I-NP . . O These DT B-NP findings NNS I-NP may MD B-VP have VB I-VP important JJ B-NP implications NNS I-NP for IN B-PP the DT B-NP design NN I-NP of IN B-PP alternative JJ B-NP treatment NN I-NP approaches NNS I-NP for IN B-PP recalcitrant JJ B-NP asthma NN I-NP . . O Rhabdomyosarcomas NNS B-NP do VBP B-VP not RB I-VP contain VB I-VP mutations NNS B-NP in IN B-PP the DT B-NP DNA NN I-NP binding NN I-NP domains NNS I-NP of IN B-PP myogenic JJ B-NP transcription NN I-NP factors NNS I-NP . . O Skeletal JJ B-NP myogenesis NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP a DT B-NP group NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP ( ( O MyoD NN B-NP COMMA COMMA O myogenin NN B-NP COMMA COMMA O myf5 NN B-NP COMMA COMMA O and CC O myf6 NN B-NP ) ) O that WDT B-NP are VBP B-VP " `` B-NP basic JJ I-NP helix-loop-helix JJ I-NP " '' I-NP proteins NNS I-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT B-NP promoters NNS I-NP of IN B-PP muscle-specific JJ B-NP genes NNS I-NP and CC O promote VBP B-VP their PRP$ B-NP expression NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR after IN B-PP a DT B-NP mutation NN I-NP of IN B-PP Leu122 NN B-NP to TO B-PP Arg NN B-NP the DT B-NP DNA NN I-NP binding NN I-NP basic JJ I-NP domain NN I-NP of IN B-PP MyoD NN B-NP confers VBZ B-VP c-myc-like JJ B-NP functional JJ I-NP characteristics NNS I-NP to TO B-PP the DT B-NP protein NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP used VBD B-VP single-strand JJ B-NP conformation NN I-NP polymorphism NN I-NP analysis NN I-NP to TO B-VP determine VB I-VP whether IN B-SBAR such JJ B-NP mutations NNS I-NP occur VBP B-VP naturally RB B-ADVP in IN B-PP rhabdomyosarcomas NNS B-NP . . O We PRP B-NP have VBP B-VP found VBN I-VP that IN B-SBAR the DT B-NP basic JJ I-NP domains NNS I-NP of IN B-PP all PDT B-NP the DT I-NP myogenic JJ I-NP factors NNS I-NP remain VBP B-VP unaltered JJ B-ADJP in IN B-PP rhabdomyosarcomas NNS B-NP . . O Selection NN B-NP against IN B-PP such JJ B-NP mutations NNS I-NP may MD B-VP be VB I-VP the DT B-NP result NN I-NP of IN B-PP functional JJ B-NP redundancy NN I-NP of IN B-PP these DT B-NP myogenic JJ I-NP transcription NN I-NP factors NNS I-NP . . O Increased VBN B-NP proliferation NN B-NP COMMA COMMA O cytotoxicity NN B-NP COMMA COMMA O and CC O gene NN B-NP expression NN I-NP after IN B-PP stimulation NN B-NP of IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP lymphocytes NNS I-NP through IN B-PP a DT B-NP surface NN I-NP ganglioside NN I-NP ( ( O GD3 NN B-NP ) ) O { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP J NNP B-NP Immunol NNP I-NP 1994 CD B-NP Jul NNP I-NP 15 CD I-NP ; : O 153 CD B-NP ( ( I-NP 2 CD I-NP ) ) O : : O 910 CD B-NP } ) O Previous JJ B-NP studies NNS I-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR gangliosides NNS B-NP have VBP B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP cell NN B-NP signaling NN B-NP and CC O recognition NN B-NP . . O However RB B-ADVP COMMA COMMA O their PRP$ B-NP specific JJ I-NP function NN I-NP in IN B-PP these DT B-NP processes NNS I-NP has VBZ B-VP not RB I-VP been VBN I-VP clearly RB I-VP defined VBN I-VP . . O A DT B-NP mAb NN I-NP COMMA COMMA O R24 NN B-NP COMMA COMMA O that WDT B-NP reacts VBZ B-VP specifically RB B-ADVP with IN B-PP a DT B-NP cell NN I-NP surface NN I-NP ganglioside NN I-NP ( ( O GD3 NN B-NP ) ) O has VBZ B-VP been VBN I-VP demonstrated VBN I-VP to TO I-VP stimulate VB I-VP proliferation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP derived VBN B-VP from IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP mechanisms NNS I-NP by IN B-PP which WDT B-NP the DT B-NP R24 NN I-NP mAb NN I-NP affects VBZ B-VP T NN B-NP cell NN I-NP functions NNS I-NP . . O We PRP B-NP have VBP B-VP observed VBN I-VP that IN B-SBAR the DT B-NP R24 NN I-NP mAb NN I-NP stimulates VBZ B-VP GD3+ JJ B-NP T NN I-NP cell NN I-NP proliferation NN B-NP COMMA COMMA O cytotoxicity NN B-NP COMMA COMMA O and CC O surface NN B-NP marker NN I-NP expression NN I-NP of IN B-PP IL-2R NN B-NP alpha-chain NN I-NP COMMA COMMA O IL-2R NN B-NP beta-chain NN I-NP COMMA COMMA O HLA-DR NN B-NP COMMA COMMA O CD11a NN B-NP COMMA COMMA O and CC O CD11c NN B-NP . . O Additionally RB B-ADVP COMMA COMMA O IFN-gamma NN B-NP activity NN I-NP but CC B-CONJP not RB I-CONJP IL-1 NN B-NP COMMA COMMA O IL-2 NN B-NP COMMA COMMA O or CC O IL-4 NN B-NP activity NN B-NP was VBD B-VP present JJ B-ADJP in IN B-PP culture NN B-NP supernatants NNS I-NP 72 CD B-NP h NN I-NP after IN B-PP R24 NN B-NP stimulation NN I-NP . . O In IN B-PP some DT B-NP donors NNS I-NP COMMA COMMA O increased VBN O IL-6 NN B-NP and CC O TNF-alpha NN B-NP activity NN B-NP also RB B-ADVP was VBD B-VP detected VBN I-VP after IN B-PP R24 NN B-NP treatment NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O R24 NN B-NP treatment NN I-NP resulted VBD B-VP in IN B-PP translocation NN B-NP of IN B-PP c-rel NN B-NP COMMA COMMA O but CC O little JJ B-NP or CC I-NP no DT I-NP NF NN I-NP kappa NN I-NP B NN I-NP p50 NN B-NP or CC O p65 NN B-NP COMMA COMMA O from IN B-PP the DT B-NP cytoplasm NN I-NP to TO B-PP the DT B-NP nucleus NN I-NP and CC O an DT B-NP increase NN I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP binding NN I-NP complexes NNS I-NP containing VBG B-VP c-rel NN B-NP and CC O p50 NN B-NP . . O This DT B-NP treatment NN I-NP also RB B-ADVP caused VBD B-VP increased VBN B-NP tyrosine NN I-NP phosphorylation NN I-NP of IN B-PP specific JJ B-NP protein NN I-NP substrates NNS I-NP . . O R24-stimulated JJ B-NP increases NNS I-NP in IN B-PP proliferation NN B-NP COMMA COMMA O cytotoxicity NN B-NP COMMA COMMA O and CC O cell NN B-NP surface NN I-NP protein NN I-NP expression NN I-NP could MD B-VP be VB I-VP blocked VBN I-VP by IN B-PP cyclosporin NN B-NP and CC O staurosporin NN B-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR cyclophilin\/calcineurin NN B-NP and CC O protein NN B-NP kinase NN I-NP C NN I-NP may MD B-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP R24 NN I-NP signaling NN I-NP pathway NN I-NP . . O Additionally RB B-ADVP COMMA COMMA O herbimycin NN B-NP A NN I-NP COMMA COMMA O a DT B-NP tyrosine NN I-NP kinase NN I-NP inhibitor NN I-NP COMMA COMMA O blocked VBD B-VP the DT B-NP R24-stimulated JJ I-NP increase NN I-NP in IN B-PP proliferation NN B-NP but CC B-CONJP not RB I-CONJP cytotoxicity NN B-NP at IN B-PP concentrations NNS B-NP consistent JJ B-ADJP with IN B-PP specificity NN B-NP for IN B-PP tyrosine NN B-NP kinases NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR multiple JJ B-NP biochemical JJ I-NP pathways NNS I-NP are VBP B-VP involved VBN I-VP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP by IN B-PP R24 NN B-NP . . O The DT B-NP SCL NN I-NP protein NN I-NP displays VBZ B-VP cell-specific JJ B-NP heterogeneity NN I-NP in IN B-PP size NN B-NP . . O SCL NN B-NP protein NN I-NP production NN I-NP was VBD B-VP examined VBN I-VP in IN B-PP a DT B-NP variety NN I-NP of IN B-PP hemopoietic JJ B-NP cell NN I-NP lines NNS I-NP by IN B-PP immunoblotting VBG B-NP using VBG B-VP specific JJ B-NP polyclonal JJ I-NP antisera NNS I-NP . . O SCL NN B-NP protein NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP erythroid JJ O COMMA COMMA O megakaryocyte NN B-NP COMMA COMMA O mast NN B-NP and CC O early JJ B-ADJP myeloid JJ I-ADJP cell NN B-NP lines NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP several JJ B-NP lymphoid JJ I-NP leukemia NN I-NP cell NN I-NP lines NNS I-NP which WDT B-NP are VBP B-VP known VBN I-VP to TO I-VP harbor VB I-VP SCL NN B-NP gene NN I-NP rearrangements NNS I-NP . . O In IN B-PP most JJS B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O proteins NNS B-NP of IN B-PP molecular JJ B-NP weight NN I-NP 49 CD B-NP and CC I-NP 44 CD I-NP kDa NN I-NP were VBD B-VP found VBN I-VP COMMA COMMA O however RB B-ADVP two CD B-NP myeloid JJ I-NP cell NN I-NP lines NNS I-NP expressed VBD B-VP only RB B-NP lower JJR I-NP molecular JJ I-NP weight NN I-NP species NNS I-NP of IN B-PP 24 CD B-NP and CC I-NP 22 CD I-NP kDa NN I-NP . . O This DT B-NP size NN I-NP discrepancy NN I-NP appeared VBD B-VP to TO I-VP be VB I-VP due JJ B-PP to TO I-PP cell-specific JJ B-NP translational JJ I-NP regulation NN I-NP COMMA COMMA O since IN B-SBAR overexpression NN B-NP of IN B-PP a DT B-NP retrovirally RB I-NP transfected VBN I-NP SCL NN I-NP gene NN I-NP yielded VBD B-VP the DT B-NP higher JJR I-NP molecular JJ I-NP weight NN I-NP forms NNS I-NP in IN B-PP most JJS B-NP cell NN I-NP lines NNS I-NP ( ( O GP+E-86 NN B-NP COMMA COMMA O AT2.5 NN B-NP COMMA COMMA O M1 NN B-NP ) ) O but CC O only RB B-NP the DT I-NP 22 CD I-NP kDa NN I-NP form NN I-NP in IN B-PP the DT B-NP myeloid JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O WEHI-3B\/D+ NN B-NP . . O Overexpression NN B-NP of IN B-PP full-length JJ B-NP SCL NN I-NP protein NN I-NP in IN B-PP the DT B-NP lymphoid JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O SupT1 NN B-NP and CC O Raji NN B-NP COMMA COMMA O did VBD B-VP not RB I-VP alter VB I-VP cell NN B-NP phenotype NN I-NP and CC O there EX B-NP was VBD B-VP no DT B-NP evidence NN I-NP for IN B-PP autoregulation NN B-NP of IN B-PP SCL NN B-NP transcription NN I-NP . . O The DT B-NP restricted JJ I-NP pattern NN I-NP of IN B-PP SCL NN B-NP protein NN I-NP synthesis NN I-NP is VBZ B-VP consistent JJ B-ADJP with IN B-PP the DT B-NP restricted JJ I-NP expression NN I-NP of IN B-PP SCL NN B-NP mRNA NN I-NP documented VBN B-VP previously RB B-ADVP . . O In IN B-PP addition NN B-NP COMMA COMMA O the DT B-NP present JJ I-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR SCL NN B-NP protein NN I-NP size NN I-NP was VBD B-VP determined VBN I-VP by IN B-PP regulation NN B-NP of IN B-PP translation NN B-NP in IN B-PP a DT B-NP cell-specific JJ I-NP manner NN I-NP . . O Activation NN B-NP of IN B-PP the DT B-NP granulocyte-macrophage JJ I-NP colony-stimulating JJ I-NP factor NN I-NP promoter NN I-NP in IN B-PP T NN B-NP cells NNS I-NP requires VBZ B-VP cooperative JJ B-NP binding NN I-NP of IN B-PP Elf-1 NN B-NP and CC O AP-1 NN B-NP transcription NN B-NP factors NNS I-NP . . O The DT O granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O gene NN B-NP has VBZ B-VP been VBN I-VP studied VBN I-VP extensively RB B-ADVP as IN B-PP a DT B-NP model NN I-NP system NN I-NP of IN B-PP transcriptional JJ B-NP induction NN I-NP during IN B-PP T-lymphocyte NN B-NP activation NN I-NP . . O The DT B-NP GM-CSF NN I-NP gene NN I-NP is VBZ B-VP not RB I-VP expressed VBN I-VP in IN B-PP resting VBG B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP but CC O is VBZ B-VP rapidly RB I-VP induced VBN I-VP at IN B-PP the DT B-NP transcriptional JJ I-NP level NN I-NP following VBG B-PP activation NN B-NP through IN B-PP the DT B-NP cell NN I-NP surface NN I-NP T-cell NN I-NP receptor NN I-NP . . O A DT B-NP highly RB I-NP conserved VBN I-NP 19-bp JJ I-NP element NN I-NP located JJ B-ADJP immediately RB I-ADJP 5' JJ B-NP of IN B-PP the DT B-NP human JJ I-NP GM-CSF NN I-NP TATA NN I-NP box NN I-NP ( ( O bp NN B-NP -34 CD B-NP to TO B-PP -52 CD B-NP ) ) O COMMA COMMA O herein RB B-VP called VBN I-VP purine NN B-NP box NN I-NP 1 CD I-NP ( ( O PB1 NN B-NP ) ) O COMMA COMMA O has VBZ B-VP been VBN I-VP shown VBN I-VP to TO B-VP bind VB I-VP a DT B-NP T-cell NN I-NP nuclear JJ I-NP protein NN I-NP complex NN I-NP and CC O to TO B-VP be VB I-VP required VBN I-VP for IN B-PP transcriptional JJ B-NP induction NN I-NP of IN B-PP the DT B-NP GM-CSF NN I-NP gene NN I-NP following VBG B-PP T-cell NN B-NP activation NN I-NP . . O The DT B-NP PB1 NN I-NP sequence NN I-NP motif NN I-NP is VBZ B-VP highly RB B-ADJP conserved VBN I-ADJP in IN B-PP both CC B-NP human JJ I-NP and CC I-NP murine JJ I-NP GM-CSF NN I-NP genes NNS I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP PB1 NN I-NP element NN I-NP alone RB B-ADVP confers VBZ B-VP inducibility NN B-NP on IN B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP following VBG B-PP transfection NN B-NP into IN B-PP human JJ B-NP Jurkat NN I-NP T NN I-NP cells NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O we PRP B-NP identify VBP B-VP a DT B-NP major JJ I-NP PB1 NN I-NP nuclear JJ I-NP protein-binding JJ I-NP complex NN I-NP that WDT B-NP is VBZ B-VP not RB O present JJ B-ADJP in IN B-PP resting VBG B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP but CC O is VBZ B-VP rapidly RB I-VP induced VBN I-VP following VBG B-PP T-cell NN B-NP activation NN I-NP . . O Sequence NN B-NP analysis NN I-NP revealed VBD B-VP that IN B-SBAR PB1 NN B-NP is VBZ B-VP composed VBN I-VP of IN B-PP adjacent JJ B-NP binding VBG I-NP sites NNS I-NP for IN B-PP Ets NN B-NP and CC O AP-1 NN B-NP transcription NN I-NP factors NNS I-NP . . O In FW B-NP vitro FW I-NP mutagenesis NN I-NP experiments NNS I-NP demonstrated VBD B-VP that IN B-SBAR both CC B-NP the DT I-NP Ets NNS B-NP and CC O AP-1 NN B-NP sites NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP binding NN B-NP of IN B-PP the DT B-NP inducible JJ I-NP PB1 NN I-NP nuclear JJ I-NP protein NN I-NP complex NN I-NP and CC B-PP for IN B-PP the DT B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP this DT B-NP element NN I-NP and CC O the DT B-NP GM-CSF NN I-NP promoter NN I-NP in IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP Tax NN I-NP associates VBZ B-VP with IN B-PP and CC O is VBZ B-VP negatively RB I-VP regulated VBN I-VP by IN B-PP the DT B-NP NF-kappa NN I-NP B2 NN I-NP p100 NN I-NP gene NN I-NP product NN I-NP : : O implications NNS B-NP for IN B-PP viral JJ B-NP latency NN I-NP . . O Human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP I CD I-NP ( ( O HTLV-I NN B-NP ) ) O is VBZ B-VP the DT B-NP etiologic JJ I-NP agent NN I-NP of IN B-PP the DT B-NP adult JJ I-NP T-cell NN I-NP leukemia NN I-NP COMMA COMMA O an DT O aggressive JJ O and CC O often RB B-ADVP fatal JJ B-NP malignancy NN I-NP of IN B-PP activated VBN B-NP human JJ I-NP CD4 NN I-NP T NN I-NP cells NNS I-NP . . O HTLV-I NN B-NP encodes VBZ B-VP an DT B-NP essential JJ I-NP 40-kDa JJ I-NP protein NN I-NP termed VBN B-VP Tax NN B-NP that WDT B-NP not RB B-CONJP only RB I-CONJP transactivates VBZ B-VP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP of IN B-PP this DT B-NP retrovirus NN I-NP but CC B-CONJP also RB I-CONJP induces VBZ B-VP an DT B-NP array NN I-NP of IN B-PP cellular JJ B-NP genes NNS I-NP . . O Tax-mediated JJ B-NP transformation NN I-NP of IN B-PP T NN B-NP cells NNS I-NP likely RB B-ADVP involves VBZ B-VP the DT B-NP deregulated VBN I-NP expression NN I-NP of IN B-PP various JJ B-NP cellular JJ I-NP genes NNS I-NP that WDT B-NP normally RB B-ADVP regulate VBP B-VP lymphocyte NN B-NP growth NN I-NP produced VBN B-VP by IN B-PP altered JJ B-NP activity NN I-NP of IN B-PP various JJ B-NP endogenous JJ I-NP host NN I-NP transcription NN I-NP factors NNS I-NP . . O In IN B-PP particular JJ B-NP COMMA COMMA O Tax NN B-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP modulating VBG B-VP the DT B-NP expression NN B-NP or CC O activity NN B-NP of IN B-PP various JJ B-NP host NN I-NP transcription NN I-NP factors NNS I-NP COMMA COMMA O including VBG B-PP members NNS B-NP of IN B-PP the DT O NF-kappa NN B-NP B\/Rel NN I-NP and CC O CREB\/ATF NN B-NP families NNS B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP the DT B-NP cellular JJ I-NP factors NNS I-NP HEB-1 NN B-NP and CC O p67SRF NN B-NP . . O An DT B-NP additional JJ I-NP distinguishing JJ I-NP characteristic NN I-NP of IN B-PP HTLV-I NN B-NP infection NN I-NP is VBZ B-VP the DT B-NP profound JJ I-NP state NN I-NP of IN B-PP viral JJ B-NP latency NN I-NP that WDT B-NP is VBZ B-VP present JJ B-ADJP in IN B-PP circulating VBG B-NP primary JJ I-NP leukemic JJ I-NP T NN I-NP cells NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR HTLV-I NN B-NP Tax NN I-NP can MD B-VP physically RB I-VP associate VB I-VP with IN B-PP p100 NN B-NP COMMA COMMA O the DT B-NP product NN I-NP of IN B-PP the DT B-NP Rel-related JJ I-NP NF-kappa NN I-NP B2 NN I-NP gene NN I-NP COMMA COMMA O both CC O in IN B-PP transfected VBN B-NP cells NNS I-NP and CC B-PP in IN B-PP HTLV-I-infected JJ B-NP leukemic JJ I-NP T-cell NN I-NP lines NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP physical JJ I-NP interaction NN I-NP of IN B-PP Tax NN B-NP with IN B-PP p100 NN B-NP leads VBZ B-VP to TO B-PP the DT B-NP inhibition NN I-NP of IN B-PP Tax-induced JJ B-NP activation NN I-NP of IN B-PP the DT O HTLV-I NN B-NP and CC O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP long JJ B-NP terminal JJ I-NP repeats NNS I-NP COMMA COMMA O reflecting VBG B-VP p100-mediated JJ B-NP cytoplasmic JJ I-NP sequestration NN I-NP of IN B-PP the DT O normally RB B-ADVP nuclearly RB B-NP expressed VBN I-NP Tax NN I-NP protein NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O a DT B-NP mutant NN I-NP of IN B-PP Tax NN B-NP that WDT B-NP selectively RB B-ADVP fails VBZ B-VP to TO I-VP activate VB I-VP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP expression NN I-NP does VBZ B-VP not RB I-VP associate VB I-VP with IN B-PP p100 NN B-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Regulation NN B-NP of IN B-PP the DT B-NP BZLF1 NN I-NP promoter NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP by IN B-PP second JJ B-NP messengers NNS I-NP in IN B-PP anti-immunoglobulin-treated JJ B-NP B NN I-NP cells NNS I-NP . . O Initiation NN B-NP of IN B-PP the DT O Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O lytic JJ B-NP cycle NN I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP BZLF1 NN I-NP gene NN I-NP . . O The DT B-NP BZLF1 NN I-NP gene NN I-NP promoter NN I-NP ( ( O Zp NN B-NP ) ) O was VBD B-VP activated VBN I-VP by IN B-PP crosslinking NN B-NP of IN B-PP cell NN B-NP surface NN I-NP immunoglobulin NN B-NP ( ( O Ig NN B-NP ) ) O with IN B-PP anti-Ig JJ B-NP antibody NN I-NP in IN B-PP B NN B-NP cells NNS I-NP COMMA COMMA O even RB B-PP in IN I-PP the DT I-PP absence NN I-PP of IN I-PP other JJ B-NP viral JJ I-NP genes NNS I-NP . . O We PRP B-NP identified VBD B-VP several JJ B-NP anti-Ig JJ I-NP response NN I-NP elements NNS I-NP within IN B-PP Zp NN B-NP COMMA COMMA O which WDT B-NP were VBD B-VP originally RB I-VP defined VBN I-VP as IN B-PP 12-O-tetradecanoylphorbol-13-acetate NN B-NP ( ( O TPA NN B-NP ) ) O response NN B-NP elements NNS I-NP ( ( O ZI NN B-NP repeats NNS I-NP and CC O ZII NN B-NP COMMA COMMA O an DT B-NP AP-1-like JJ I-NP domain NN I-NP ) ) O . . O Since IN B-SBAR anti-Ig JJ B-NP crosslinking NN I-NP leads VBZ B-VP to TO B-PP activation NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O and CC O an DT B-NP increase NN I-NP in IN B-PP intracellular JJ B-NP calcium NN I-NP level NN I-NP COMMA COMMA O Zp NN B-NP was VBD B-VP tested VBN I-VP for IN B-PP the DT B-NP response NN I-NP to TO B-PP these DT B-NP cellular JJ I-NP factors NNS I-NP . . O Treatment NN B-NP with IN B-PP calcium NN B-NP ionophore NN I-NP A23187 NN I-NP increased VBD B-VP Zp NN B-NP activity NN I-NP . . O When WRB B-ADVP the DT B-NP calcium NN I-NP ionophore NN I-NP was VBD B-VP used VBN I-VP in IN B-PP conjunction NN I-PP with IN I-PP TPA NN B-NP COMMA COMMA O a DT B-NP PKC NN I-NP activator NN I-NP COMMA COMMA O the DT B-NP Zp NN I-NP induction NN I-NP was VBD B-VP synergistically RB I-VP enhanced VBN I-VP . . O Retinoic JJ B-NP acid NN I-NP downmodulates VBZ B-VP erythroid JJ B-NP differentiation NN I-NP and CC O GATA1 NN B-NP expression NN I-NP in IN B-PP purified VBN B-NP adult-progenitor JJ I-NP culture NN I-NP . . O All-trans JJ B-NP retinoic JJ B-NP acid NN I-NP ( ( O RA NN B-NP ) ) O is VBZ B-VP an DT B-NP important JJ I-NP morphogen NN I-NP in IN B-PP vertebrate NN B-NP development NN I-NP COMMA COMMA O a DT B-NP normal JJ I-NP constituent NN I-NP in IN B-PP human JJ B-NP adult JJ I-NP blood NN I-NP and CC O is VBZ B-VP also RB I-VP involved VBN I-VP in IN B-PP the DT B-NP control NN I-NP of IN B-PP cell NN B-NP growth NN B-NP and CC O differentiation NN B-NP in IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP . . O We PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP effects NNS I-NP of IN B-PP RA NN B-NP on IN B-PP normal JJ B-NP hematopoiesis NN I-NP by IN B-PP using VBG B-VP early JJ B-NP hematopoietic JJ B-NP progenitor NN I-NP cells NNS I-NP ( ( O HPC NN B-NP ) ) O stringently RB B-VP purified VBN I-VP from IN B-PP adult JJ B-NP peripheral JJ I-NP blood NN I-NP . . O In IN B-PP clonogenetic JJ O fetal JJ O calf NN O serum-supplemented JJ O ( ( O FCS+ JJ B-ADJP ) ) O or CC O -nonsupplemented JJ O ( ( O FCS- JJ B-ADJP ) ) O culture NN B-NP treated VBN B-VP with IN B-PP saturating JJ B-NP levels NNS I-NP of IN B-PP interleukin-3 NN B-NP ( ( O IL-3 NN B-NP ) ) O granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O and CC O erythropoietin NN B-NP ( ( O Ep NN B-NP ) ) O ( ( O combined VBN B-PP with IN B-PP c-kit NN B-NP ligand NN I-NP in IN B-PP FCS(-)-culture JJ B-NP conditions NNS I-NP ) ) O COMMA COMMA O RA NN B-NP induces VBZ B-VP a DT B-NP dramatic JJ I-NP dose-dependent JJ I-NP shift NN I-NP from IN B-PP erythroid JJ B-NP to TO B-PP granulomonocytic JJ B-NP colony NN B-NP formation NN I-NP COMMA COMMA O the DT B-NP latter JJ I-NP colonies NNS I-NP being VBG B-VP essentially RB I-VP represented VBN I-VP by IN B-PP granulocytic JJ B-NP clones NNS I-NP . . O This DT B-NP shift NN I-NP is VBZ B-VP apparently RB I-VP not RB I-VP caused VBN I-VP by IN B-PP a DT B-NP recruitment NN I-NP phenomenon NN I-NP COMMA COMMA O because IN B-SBAR in IN B-PP FCS+ JJ B-NP culture NN I-NP COMMA COMMA O the DT B-NP total JJ I-NP number NN I-NP of IN B-PP colonies NNS B-NP is VBZ B-VP not RB I-VP significantly RB I-VP modified VBN I-VP by IN B-PP RA NN B-NP addition NN I-NP . . O In IN B-PP FCS- JJ B-NP liquid-suspension NN I-NP culture NN I-NP supplemented VBN B-VP with IN B-PP saturating JJ B-NP Ep NN I-NP level NN I-NP and CC O low-dose JJ B-NP IL-3\/GM-CSF NN I-NP COMMA COMMA O adult JJ B-NP HPC NN I-NP undergo VBP B-VP unilineage JJ B-NP erythropoietic JJ I-NP differentiation NN I-NP : : O Here RB B-ADVP again RB B-ADVP COMMA COMMA O treatment NN B-NP with IN B-PP high-dose JJ B-NP RA NN I-NP induces VBZ B-VP a DT B-NP shift NN I-NP from IN B-PP the DT B-NP erythroid JJ I-NP to TO I-NP granulocytic JJ I-NP differentiation NN I-NP pathway NN I-NP . . O Studies NNS B-NP on IN B-PP RA NN O time-response JJ O or CC O pulse NN B-NP treatment NN B-NP in IN B-PP semisolid JJ B-NP or CC I-NP liquid JJ I-NP culture NN I-NP show VBP B-VP that IN B-SBAR early JJ B-NP RA NN I-NP addition NN I-NP is VBZ B-VP most RBS B-ADJP effective JJ I-ADJP COMMA COMMA O thus RB B-ADVP indicating VBG B-VP that IN B-SBAR early JJ B-NP but CC I-NP not RB I-NP late JJ I-NP HPC NN I-NP are VBP B-VP sensitive JJ B-ADJP to TO B-PP its PRP$ B-NP action NN I-NP . . O We PRP B-NP then RB B-ADVP analyzed VBD B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP master NN I-NP GATA1 NN I-NP gene NN I-NP COMMA COMMA O which WDT B-NP encodes VBZ B-VP a DT B-NP finger NN I-NP transcription NN I-NP factor NN I-NP required VBN B-VP for IN B-PP normal JJ B-NP erythroid JJ I-NP development NN I-NP ; : O addition NN B-NP of IN B-PP RA NN B-NP to TO B-PP HPC NN B-NP stimulated VBN B-VP into IN B-PP unilineage JJ B-NP erythropoietic JJ I-NP differentiation NN I-NP in IN B-PP liquid JJ B-NP culture NN I-NP caused VBD B-VP a DT B-NP virtually RB I-NP complete JJ I-NP inhibition NN I-NP of IN B-PP GATA1 NN B-NP mRNA NN I-NP induction NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR RA NN B-NP directly RB B-ADVP inhibits VBZ B-VP the DT B-NP erythroid JJ I-NP differentiation NN I-NP program NN I-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP early JJ B-NP adult JJ I-NP HPC NN I-NP COMMA COMMA O and CC O may MD B-VP lead VB I-VP to TO B-PP a DT B-NP shift NN I-NP from IN B-PP the DT B-NP erythroid JJ I-NP to TO I-NP granulocytic JJ I-NP differentiation NN I-NP pathway NN I-NP . . O This DT B-NP phenomenon NN I-NP is VBZ B-VP correlated VBN I-VP with IN B-PP inhibition NN B-NP of IN B-PP GATA1 NN B-NP induction NN I-NP in IN B-PP the DT B-NP early JJ I-NP stages NNS I-NP of IN B-PP erythropoietic JJ B-NP differentiation NN I-NP . . O Effects NNS B-NP of IN B-PP CD45 NN B-NP on IN B-PP NF-kappa NN B-NP B NN I-NP . . O Implications NNS B-NP for IN B-PP replication NN B-NP of IN B-PP HIV-1 NN B-NP . . O Increased VBN B-NP levels NNS I-NP of IN B-PP replication NN B-NP of IN B-PP the DT B-NP HIV NN I-NP type NN I-NP 1 CD I-NP are VBP B-VP observed VBN I-VP after IN B-PP the DT B-NP activation NN I-NP of IN B-PP infected JJ B-NP T NN I-NP cells NNS I-NP through IN B-PP the DT B-NP TCR NN I-NP . . O However RB B-ADVP COMMA COMMA O anti-CD45 JJ B-NP antibodies NNS I-NP inhibit VBP B-VP these DT B-NP effects NNS I-NP in IN B-PP cells NNS B-NP from IN B-PP infected JJ B-NP individuals NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP examined VBD B-VP interrelationships NNS B-NP between IN B-PP CD45 NN B-NP and CC O HIV-1 NN B-NP further RB B-ADVP . . O We PRP B-NP measured VBD B-VP effects NNS B-NP on IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP in IN B-PP T NN B-NP cell NN I-NP lines NNS I-NP that WDT B-NP were VBD B-VP stimulated VBN I-VP with IN B-PP antibodies NNS B-NP against IN B-PP CD45 NN B-NP and CC B-PP in IN B-PP those DT B-NP that WDT B-NP lacked VBD B-VP the DT B-NP expression NN I-NP of IN B-PP CD45 NN B-NP on IN B-PP their PRP$ B-NP surfaces NNS I-NP . . O First RB B-ADVP COMMA COMMA O anti-CD45 JJ B-NP antibodies NNS I-NP did VBD B-VP not RB I-VP affect VB I-VP basal JJ B-NP but CC O decreased VBD B-VP activated JJ B-NP levels NNS B-NP of IN B-PP expression NN B-NP from IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP . . O Second RB B-ADVP COMMA COMMA O T NN B-NP cells NNS I-NP COMMA COMMA O which WDT B-NP lack VBP B-VP CD45 NN B-NP and CC O can MD B-VP not RB I-VP signal VB I-VP via IN B-PP the DT B-NP TCR NN I-NP COMMA COMMA O supported VBD B-VP higher JJR B-NP levels NNS I-NP of IN B-PP viral JJ B-NP replication NN I-NP and CC O gene NN B-NP expression NN I-NP . . O This DT B-NP was VBD B-VP due JJ B-PP to TO I-PP the DT B-NP presence NN I-NP of IN B-PP active JJ B-NP NF-kappa NN I-NP B NN I-NP complexes NNS I-NP in IN B-PP the DT B-NP nucleus NN I-NP of IN B-PP CD45- JJ B-NP T NN I-NP cells NNS I-NP . . O Additionally RB B-ADVP COMMA COMMA O infected JJ B-NP T NN I-NP cells NNS I-NP displayed VBD B-VP lower JJR B-NP levels NNS I-NP of IN B-PP CD45 NN B-NP on IN B-PP their PRP$ B-NP surfaces NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O CD45 NN B-NP plays VBZ B-VP an DT B-NP active JJ I-NP role NN I-NP in IN B-PP the DT B-NP physiology NN I-NP of IN B-PP T NN B-NP cells NNS I-NP and CC B-PP in IN B-PP the DT B-NP replication NN I-NP of IN B-PP HIV-1 NN B-NP . . O Induction NN B-NP of IN B-PP phosphatidylinositol NN B-NP turnover NN I-NP and CC O EGR-1 NN B-NP mRNA NN I-NP expression NN I-NP by IN B-PP crosslinking VBG B-NP of IN B-PP surface NN B-NP IgM NN B-NP and CC O IgD NN B-NP in IN B-PP the DT B-NP human JJ I-NP B NN I-NP cell NN I-NP line NN I-NP B104 NN I-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR a DT B-NP human JJ I-NP B NN I-NP lymphoma NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O B104 NN B-NP COMMA COMMA O expressed VBD B-VP surface NN B-NP IgM NN I-NP ( ( O sIgM NN B-NP ) ) O and CC O surface NN B-NP IgD NN I-NP ( ( O sIgD NN B-NP ) ) O COMMA COMMA O and CC O that IN B-SBAR crosslinking VBG B-NP of IN B-PP sIgM NN B-NP and CC O sIgD NN B-NP by IN B-PP anti-IgM JJ B-NP antibody NN B-NP ( ( O Ab NN B-NP ) ) O and CC O anti-IgD JJ B-NP Ab NN I-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O induced VBD B-VP Ca2+ NN B-NP influx NN I-NP to TO B-PP almost RB B-NP the DT I-NP same JJ I-NP degree NN I-NP COMMA COMMA O whereas IN O only RB B-NP sIgM-crosslinking NN I-NP caused VBD B-VP B104 NN B-NP cell NN I-NP death NN I-NP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP investigated VBD B-VP the DT B-NP accumulation NN I-NP of IN B-PP cyclic JJ B-NP AMP NN I-NP ( ( O cAMP NN B-NP ) ) O COMMA COMMA O the DT B-NP hydrolysis NN I-NP of IN B-PP inositol NN B-NP phosphates NNS I-NP COMMA COMMA O protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O activity NN B-NP and CC O the DT B-NP induction NN I-NP of IN B-PP Egr-1 NN B-NP and CC O c-fos NN B-NP mRNA NN B-NP expression NN I-NP by IN B-PP sIgM- NN B-NP and CC O sIgD-crosslinking NN B-NP to TO B-VP examine VB I-VP differences NNS B-NP in IN B-PP the DT B-NP signals NNS I-NP mediated VBN B-VP through IN B-PP sIgM NN B-NP and CC O sIgD NN B-NP in IN B-PP B104 NN B-NP cells NNS I-NP . . O Both CC O sIgM- NN B-NP and CC O sIgD-crosslinking NN B-NP with IN B-PP antibodies NNS B-NP induced VBD B-VP elevation NN B-NP of IN B-PP cAMP NN B-NP levels NNS I-NP COMMA COMMA O phosphatidylinositol NN B-NP turnover NN I-NP COMMA COMMA O PKC NN B-NP activation NN I-NP and CC O expression NN B-NP of IN B-PP Egr-1 NN B-NP and CC O c-fos NN B-NP mRNA NN B-NP COMMA COMMA O although IN B-SBAR sIgM-crosslinking NN B-NP was VBD B-VP more RBR B-ADJP effective JJ I-ADJP than IN B-PP sIgD-crosslinking NN B-NP COMMA COMMA O presumably RB B-ADVP due JJ B-PP to TO I-PP the DT B-NP higher JJR I-NP expression NN I-NP of IN B-PP sIgM NN B-NP than IN B-PP of IN B-PP sIgD NN B-NP . . O Egr-1 NN B-NP mRNA NN I-NP expression NN I-NP induced VBN B-VP by IN B-PP sIgM- NN B-NP and CC O sIgD-crosslinking NN B-NP was VBD B-VP inhibited VBN I-VP by IN B-PP H7 NN B-NP COMMA COMMA O erbstatin NN B-NP and CC O genistein NN B-NP COMMA COMMA B-PP but CC I-PP not RB B-PP by IN I-PP HA1004 NN B-NP . . O Erbstatin NN B-NP and CC O genistein NN B-NP inhibited VBD B-VP the DT B-NP sIg-crosslinking-induced JJ I-NP Egr-1 NN I-NP mRNA NN I-NP expression NN I-NP in IN B-PP a DT B-NP dose-dependent JJ I-NP manner NN I-NP parallel JJ B-ADJP to TO B-PP that WDT B-NP observed VBN B-VP in IN B-PP the DT B-NP inhibition NN I-NP of IN B-PP sIg-crosslinking-induced JJ B-NP protein NN I-NP tyrosine NN I-NP phosphorylation NN I-NP . . O Phorbol NN B-NP myristate NN I-NP acetate NN I-NP induced VBD B-VP Egr-1 NN B-NP mRNA NN I-NP expression NN I-NP but CC O forskolin NN B-NP and CC O dibutyryl NN B-NP cyclic JJ I-NP AMP NN I-NP did VBD B-VP not RB O . . O These DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP Egr-1 NN I-NP mRNA NN I-NP activating NN I-NP signals NNS I-NP through IN B-PP sIgM NN B-NP and CC O sIgD NN B-NP are VBP B-VP protein NN B-NP tyrosine NN I-NP kinase- NN I-NP and CC O PKC-dependent JJ B-ADJP COMMA COMMA O but CC O protein NN B-ADJP kinase NN I-ADJP A-independent JJ I-ADJP . . O Cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O FK506 NN B-NP rescued VBD B-VP B104 NN B-NP cells NNS I-NP from IN B-PP death NN B-NP induced VBN B-VP by IN B-PP anti-IgM JJ B-NP Ab NN I-NP COMMA COMMA O but CC O did VBD B-VP not RB I-VP affect VB I-VP the DT B-NP expression NN I-NP of IN B-PP Egr-1 NN B-NP and CC O c-fos NN B-NP mRNA NN B-NP COMMA COMMA O showing VBG B-VP that IN B-SBAR CsA NN B-NP and CC O FK506 NN B-NP affect VBP B-VP signal NN B-NP transducers NNS I-NP differently RB B-ADVP from IN B-PP or CC O downstream RB B-ADVP to TO B-PP these DT B-NP molecules NNS I-NP . . O The DT B-NP difference NN I-NP in IN B-PP signals NNS B-NP transduced VBN B-VP through IN B-PP sIgM NN B-NP and CC O sIgD NN B-NP in IN B-PP B104 NN B-NP cells NNS I-NP is VBZ B-VP discussed VBN I-VP . . O G(Anh)MTetra NN B-NP COMMA COMMA O a DT B-NP natural JJ I-NP bacterial JJ I-NP cell NN I-NP wall NN I-NP breakdown NN I-NP product NN I-NP COMMA COMMA O induces VBZ B-VP interleukin-1 NN B-NP beta NN I-NP and CC O interleukin-6 NN B-NP expression NN B-NP in IN B-PP human JJ B-NP monocytes NNS I-NP . . O A DT B-NP study NN I-NP of IN B-PP the DT B-NP molecular JJ I-NP mechanisms NNS I-NP involved VBN B-VP in IN B-PP inflammatory JJ B-NP cytokine NN I-NP expression NN I-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP J NNP B-NP Biol NNP I-NP Chem NNP I-NP 1994 CD B-NP Jun NNP I-NP 17 CD I-NP ; : O 269 CD B-NP ( ( I-NP 24 CD I-NP ) ) O : : O 16983 CD B-NP } ) O It PRP B-NP is VBZ B-VP believed VBN I-VP that IN B-SBAR induction NN B-NP of IN B-PP cytokine NN B-NP expression NN I-NP by IN B-PP bacterial JJ B-NP cell NN I-NP wall NN I-NP components NNS I-NP plays VBZ B-VP a DT B-NP role NN I-NP in IN B-PP the DT B-NP development NN B-NP and CC O course NN B-NP of IN B-PP sepsis NN B-NP . . O However RB B-ADVP COMMA COMMA O most JJS B-NP attention NN I-NP has VBZ B-VP been VBN I-VP focused VBN I-VP on IN B-PP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O . . O We PRP B-NP studied VBD B-VP the DT B-NP ability NN I-NP of IN B-PP N-acetylglucosaminyl-1COMMA6-anhydro-N-acetylmuramyl-L-alanyl-D-isoglutamyl-m-diaminopimelyl-D-alanine NN B-NP ( ( O G(Anh)MTetra NN B-NP ) ) O COMMA COMMA O a DT B-NP naturally RB I-NP occurring VBG I-NP breakdown NN I-NP product NN I-NP of IN B-PP peptidoglycan NN B-NP that WDT B-NP is VBZ B-VP produced VBN I-VP by IN B-PP soluble JJ B-NP lytic JJ I-NP transglycosylase NN I-NP of IN B-PP Escherichia FW B-NP coli FW I-NP COMMA COMMA O to TO B-VP induce VB I-VP cytokine NN B-NP expression NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP . . O G(Anh)MTetra NN B-NP was VBD B-VP found VBN I-VP to TO I-VP strongly RB I-VP induce VB I-VP interleukin NN B-NP ( ( I-NP IL NN I-NP ) ) I-NP -1 CD I-NP beta NN I-NP and CC O IL-6 NN B-NP mRNA NN B-NP expression NN I-NP after IN B-PP 2 CD B-NP h NN I-NP and CC O IL-1 NN B-NP beta NN I-NP and CC O IL-6 NN B-NP protein NN B-NP secretion NN I-NP after IN B-PP 48 CD B-NP h NN I-NP of IN B-PP activation NN B-NP . . O The DT B-NP increase NN I-NP in IN B-PP mRNA NN B-NP accumulation NN I-NP was VBD B-VP at IN B-ADVP least JJS I-ADVP partly RB B-ADVP due JJ B-PP to TO I-PP an DT B-NP increase NN I-NP in IN B-PP the DT B-NP transcription NN I-NP rates NNS I-NP of IN B-PP the DT B-NP respective JJ I-NP genes NNS I-NP and CC O was VBD B-VP accompanied VBN I-VP by IN B-PP a DT B-NP strong JJ I-NP induction NN I-NP of IN B-PP nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP and CC O activator NN B-NP protein-1 NN I-NP transcription NN I-NP factor NN I-NP expression NN B-NP . . O Experiments NNS B-NP using VBG B-VP inhibitors NNS B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP COMMA COMMA O protein NN B-NP kinase NN I-NP A NN I-NP COMMA COMMA O and CC O tyrosine NN B-NP kinase-dependent JJ I-NP pathways NNS I-NP revealed VBD B-VP that IN B-SBAR G(Anh)MTetra-induced JJ O IL-1 NN B-NP beta NN I-NP and CC O IL-6 NN B-NP mRNA NN B-NP expression NN I-NP involves VBZ B-VP activation NN B-NP of IN B-PP an DT B-NP H7-inhibitable JJ I-NP pathway NN I-NP . . O By IN B-PP using VBG B-VP the DT B-NP protein NN I-NP synthesis NN I-NP inhibitor NN I-NP cycloheximide NN I-NP COMMA COMMA O it PRP B-NP was VBD B-VP shown VBN I-VP that IN B-SBAR G(Anh)MTetra-induced JJ B-NP IL-6 NN I-NP mRNA NN I-NP expression NN I-NP depends VBZ B-VP on IN B-PP the DT B-NP synthesis NN I-NP of IN B-PP new JJ B-NP protein NN I-NP COMMA COMMA O whereas IN O G(Anh)MTetra-induced JJ B-NP IL-1 NN I-NP beta NN I-NP mRNA NN I-NP accumulation NN I-NP does VBZ B-VP not RB O . . O When WRB B-ADVP responses NNS B-NP to TO B-PP G(Anh)MTetra NN B-NP were VBD B-VP compared VBN I-VP with IN B-PP those DT B-NP to TO B-PP LPS NN B-NP and CC O muramyldipeptide NN B-NP ( ( O MDP NN B-NP ) ) O COMMA COMMA O it PRP B-NP was VBD B-VP found VBN I-VP that IN B-SBAR the DT B-NP optimal JJ I-NP response NN I-NP to TO B-PP G(Anh)MTetra NN B-NP induction NN I-NP was VBD B-VP similar JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP LPS NN B-NP but CC O significantly RB B-ADJP higher JJR I-ADJP than IN B-PP the DT B-NP response NN I-NP to TO B-PP MDP NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O maximal JJ O G(Anh)MTetra-induced JJ O IL-1 NN B-NP beta NN I-NP and CC O IL-6 NN B-NP mRNA NN B-NP expression NN I-NP could MD B-VP be VB I-VP enhanced VBN I-VP by IN B-PP co-stimulation NN B-NP with IN B-PP LPS NN B-NP or CC O MDP NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR different JJ B-NP receptors NNS B-NP and\/or CC O transduction NN B-NP pathways NNS I-NP were VBD B-VP involved VBN I-VP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR G(Anh)MTetra NN B-NP induces VBZ B-VP IL-1 NN B-NP beta NN I-NP and CC O IL-6 NN B-NP expression NN B-NP in IN B-PP human JJ B-NP monocytes NNS I-NP suggesting VBG B-VP a DT B-NP possible JJ I-NP role NN I-NP for IN B-PP G(Anh)MTetra NN B-NP in IN B-PP the DT B-NP release NN I-NP of IN B-PP cytokines NNS B-NP during IN B-PP sepsis NN B-NP . . O Human JJ B-NP interferon NN I-NP regulatory JJ I-NP factor NN I-NP 2 CD I-NP gene NN I-NP . . O Intron-exon JJ B-NP organization NN I-NP and CC O functional JJ B-NP analysis NN I-NP of IN B-PP 5'-flanking JJ B-NP region NN I-NP . . O Interferon NN B-NP regulatory JJ I-NP factor NN I-NP 2 CD I-NP ( ( O IRF-2 NN B-NP ) ) O is VBZ B-VP a DT B-NP transcriptional JJ I-NP regulatory JJ I-NP protein NN I-NP that WDT B-NP terminates VBZ B-VP interferon NN B-NP beta NN I-NP expression NN I-NP initiated VBN B-VP by IN B-PP interferon NN B-NP regulatory JJ I-NP factor NN I-NP 1 CD I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP isolated VBD B-VP the DT B-NP genomic JJ I-NP DNA NN I-NP for IN B-PP human JJ B-NP IRF-2 NN I-NP gene NN I-NP COMMA COMMA O determined VBD B-VP the DT B-NP intron-exon JJ I-NP structure NN I-NP of IN B-PP the DT B-NP human JJ I-NP IRF-2 NN I-NP gene NN I-NP COMMA COMMA O mapped VBD B-VP the DT B-NP major JJ I-NP transcription NN I-NP initiation NN I-NP site NN I-NP COMMA COMMA O identified VBD B-VP a DT B-NP number NN I-NP of IN B-PP potential JJ B-NP regulatory JJ I-NP elements NNS I-NP in IN B-PP the DT B-NP 5'-flanking JJ I-NP region NN I-NP COMMA COMMA O and CC O localized VBD B-VP the DT B-NP IRF-2 NN I-NP gene NN I-NP on IN B-PP human JJ B-NP chromosome NN I-NP 4 CD I-NP . . O The DT B-NP IRF-2 NN I-NP promoter NN I-NP region NN I-NP contains VBZ B-VP a DT B-NP CpG NN I-NP island NN I-NP COMMA COMMA O with IN B-PP several JJ B-NP GC NN I-NP boxes NNS I-NP COMMA COMMA O a DT B-NP putative JJ I-NP NF-kappa NN I-NP B-binding JJ I-NP site NN I-NP COMMA COMMA O and CC O a DT B-NP CAAT NN I-NP box NN I-NP COMMA COMMA O but CC O no DT B-NP TATA NN I-NP box NN I-NP . . O When WRB B-ADVP the DT B-NP promoter NN I-NP region NN I-NP was VBD B-VP linked VBN I-VP with IN B-PP a DT B-NP heterologous JJ I-NP reporter NN I-NP gene NN I-NP COMMA COMMA O we PRP B-NP found VBD B-VP that IN B-SBAR the DT B-NP promoter NN I-NP region NN I-NP is VBZ B-VP inducible JJ B-ADJP by IN B-PP both CC O interferons NNS B-NP ( ( O interferon-alpha NN B-NP and CC O -gamma NN B-NP ) ) O and CC O interferon NN B-NP regulatory JJ I-NP factor NN I-NP 1 CD I-NP . . O The DT B-NP region NN I-NP which WDT B-NP induced VBD B-VP these DT B-NP inductions NNS I-NP was VBD B-VP identified VBN I-VP as IN B-PP being VBG B-VP confined VBN I-VP to TO B-PP 40 CD B-NP nucleotides NNS I-NP 5' JJ B-NP to TO B-PP the DT B-NP major JJ I-NP transcriptional JJ I-NP initiation NN I-NP site NN I-NP by IN B-PP testing VBG B-VP a DT B-NP series NN I-NP of IN B-PP clones NNS B-NP with IN B-PP truncated VBN B-NP promoter NN I-NP of IN B-PP IRF-2 NN B-NP . . O This DT B-NP region NN I-NP contains VBZ B-VP elements NNS B-NP which WDT B-NP are VBP B-VP shared VBN I-VP with IN B-PP the DT B-NP transcriptional JJ I-NP enhancers NNS I-NP of IN B-PP other JJ B-NP genes NNS I-NP including VBG B-PP interferon NN B-NP regulatory JJ I-NP factor NN I-NP 1 CD I-NP COMMA COMMA O interferon NN B-NP beta NN I-NP COMMA COMMA O and CC O interferon-inducible JJ B-NP genes NNS I-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR interferon NN B-NP regulatory JJ I-NP factor NN I-NP 1 CD I-NP not RB B-CONJP only RB I-CONJP triggers VBZ B-VP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP interferon NN I-NP signal NN I-NP transduction NN I-NP pathway NN I-NP COMMA COMMA O but CC B-CONJP also RB I-CONJP may MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP limiting VBG B-VP the DT B-NP duration NN I-NP of IN B-PP this DT B-NP response NN I-NP by IN B-PP activating VBG B-VP the DT B-NP transcription NN I-NP of IN B-PP IRF-2 NN B-NP . . O rel NN B-NP Is VBZ B-VP rapidly RB I-VP tyrosine-phosphorylated JJ I-VP following VBG B-PP granulocyte-colony JJ B-NP stimulating NN I-NP factor NN I-NP treatment NN I-NP of IN B-PP human JJ B-NP neutrophils NNS I-NP . . O Stimulation NN B-NP of IN B-PP neutrophils NNS B-NP with IN B-PP granulocyte-colony JJ B-NP stimulating NN I-NP factor NN I-NP ( ( O G-CSF NN B-NP ) ) O results VBZ B-VP in IN B-PP an DT B-NP enhanced VBN I-NP respiratory JJ I-NP burst NN I-NP COMMA COMMA O prolonged JJ B-NP survival NN I-NP COMMA COMMA O and CC O increased VBN B-NP tumor NN I-NP cell NN I-NP killing NN I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP G-CSF NN B-NP are VBP B-VP mediated VBN I-VP by IN B-PP binding VBG B-NP to TO B-PP specific JJ O COMMA COMMA O high JJ B-NP affinity NN I-NP receptors NNS B-NP . . O G-CSF NN B-NP receptors NNS I-NP lack VBP B-VP intrinsic JJ B-NP tyrosine NN I-NP kinase NN I-NP activity NN I-NP COMMA COMMA O but CC O activation NN B-NP of IN B-PP the DT B-NP receptor NN I-NP results VBZ B-VP in IN B-PP the DT B-NP rapid JJ I-NP induction NN I-NP of IN B-PP tyrosine NN B-NP kinase NN I-NP activity NN I-NP . . O Antiphosphotyrosine JJ B-NP immunoblots NNS I-NP of IN B-PP whole JJ B-NP cell NN I-NP lysates NNS I-NP prepared VBN B-VP from IN B-PP neutrophils NNS B-NP show VBP B-VP that IN B-SBAR the DT B-NP G-CSF NN I-NP rapidly RB B-ADVP induces VBZ B-VP prominent JJ B-NP tyrosine NN I-NP phosphorylation NN I-NP of IN B-PP a DT B-NP protein NN I-NP of IN B-PP a DT B-NP relative JJ I-NP molecular JJ I-NP mass NN I-NP of IN B-PP 80 CD B-NP kDa NN I-NP . . O Using VBG B-VP monospecific JJ B-NP antibodies NNS I-NP COMMA COMMA O the DT B-NP 80-kDa JJ I-NP tyrosine-phosphorylated JJ I-NP protein NN I-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP p80c-rel NN B-NP COMMA COMMA O a DT B-NP proto-oncogene NN I-NP belonging VBG B-VP to TO B-PP a DT B-NP family NN I-NP of IN B-PP transcriptional JJ B-NP regulators NNS I-NP which WDT B-NP include VBP B-VP NF-kB NN B-NP . . O The DT B-NP induction NN I-NP of IN B-PP tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP p80c-rel NN B-NP was VBD B-VP unique JJ B-ADJP to TO B-PP G-CSF NN B-NP in IN B-SBAR that IN I-SBAR granulocyte-macrophage JJ B-NP colony NN I-NP stimulating NN I-NP factor NN I-NP which WDT B-NP also RB B-ADVP stimulates VBZ B-VP neutrophils NNS B-NP and CC O induces VBZ B-VP tyrosine NN B-NP phosphorylation NN I-NP does VBZ B-VP not RB I-VP result VB I-VP in IN B-PP tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP p80c-rel NN B-NP . . O The DT B-NP consequences NNS I-NP of IN B-PP p80c-rel NN B-NP tyrosine NN I-NP phosphorylation NN I-NP are VBP B-VP not RB I-VP yet RB I-VP known VBN I-VP ; : O however RB B-ADVP COMMA COMMA O tyrosine-phosphorylated JJ B-NP p80c-rel NN I-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP binding VBG B-VP to TO B-PP DNA NN B-NP COMMA COMMA O and CC O G-CSF NN B-NP stimulation NN I-NP results VBZ B-VP in IN B-PP an DT B-NP increase NN I-NP in IN B-PP the DT B-NP amount NN I-NP of IN B-PP p80c-rel NN B-NP which WDT B-NP binds VBZ B-VP to TO B-PP DNA NN B-NP . . O These DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR one CD B-NP of IN B-PP the DT B-NP first JJ I-NP biochemical JJ I-NP events NNS I-NP which WDT B-NP occurs VBZ B-VP in IN B-PP neutrophils NNS B-NP following VBG B-PP G-CSF NN B-NP stimulation NN I-NP COMMA COMMA O activation NN B-NP of IN B-PP a DT B-NP tyrosine NN I-NP kinase NN I-NP COMMA COMMA O leads VBZ B-VP directly RB B-ADVP to TO B-PP the DT B-NP tyrosine NN I-NP phosphorylation NN I-NP of IN B-PP p80c-rel NN B-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP tyrosine NN I-NP kinase NN I-NP activated VBN B-VP by IN B-PP G-CSF NN B-NP appears VBZ B-VP to TO I-VP directly RB I-VP transduce VB I-VP a DT B-NP signal NN I-NP to TO B-PP a DT B-NP protein NN I-NP which WDT B-NP functions VBZ B-VP as IN B-PP a DT B-NP transcriptional JJ I-NP regulator NN I-NP . . O Autoregulation NN B-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transactivator NN I-NP RelA NN B-NP ( ( O p65 NN B-NP ) ) O by IN B-PP multiple JJ B-NP cytoplasmic JJ I-NP inhibitors NNS I-NP containing VBG B-VP ankyrin NN B-NP motifs NNS I-NP . . O RelA NN B-NP ( ( O p65 NN B-NP ) ) O functions VBZ B-VP as IN B-PP the DT B-NP critical JJ I-NP transactivating VBG I-NP component NN I-NP of IN B-PP the DT B-NP heterodimeric JJ I-NP p50-p65 NN I-NP NF-kappa NN I-NP B NN I-NP complex NN I-NP and CC O contains VBZ B-VP a DT B-NP high-affinity JJ I-NP binding VBG I-NP site NN I-NP for IN B-PP its PRP$ B-NP cytoplasmic JJ I-NP inhibitor NN I-NP COMMA COMMA O I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP . . O After IN B-PP cellular JJ B-NP activation NN I-NP COMMA COMMA O I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP is VBZ B-VP rapidly RB I-VP degraded VBN I-VP in IN B-PP concert NN I-PP with IN I-PP the DT B-NP induced VBN I-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O The DT B-NP present JJ I-NP study NN I-NP demonstrates VBZ B-VP that IN B-SBAR tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha-induced JJ I-NP degradation NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP is VBZ B-VP preceded VBN I-VP by IN B-PP its PRP$ B-NP rapid JJ I-NP phosphorylation NN I-NP in FW B-ADVP vivo FW I-ADVP . . O However RB B-ADVP COMMA COMMA O these DT B-NP effects NNS I-NP on IN B-PP I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP result VBP B-VP in IN B-PP nuclear JJ B-NP mobilization NN I-NP of IN B-PP only RB B-NP a DT I-NP fraction NN I-NP of IN B-PP the DT B-NP entire JJ I-NP cytoplasmic JJ I-NP pool NN I-NP of IN B-PP RelA NN B-NP . . O Subsequent JJ B-NP studies NNS I-NP have VBP B-VP revealed VBN I-VP that IN B-SBAR ( ( B-LST i LS I-LST ) ) O cytoplasmic JJ B-NP RelA NN I-NP is VBZ B-VP stably RB I-VP associated VBN I-VP not RB B-CONJP only RB I-CONJP with IN B-PP I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP but CC B-CONJP also RB I-CONJP with IN B-PP other JJ B-NP ankyrin NN I-NP motif-rich JJ I-NP proteins NNS I-NP including VBG B-PP the DT B-NP products NNS I-NP of IN B-PP the DT O NF-kappa NN B-NP B2 NN I-NP ( ( O p100 NN B-NP ) ) O and CC O NF-kappa NN B-NP B1 NN I-NP ( ( O p105 NN B-NP ) ) O genes NNS B-NP ; : O ( ( B-LST ii LS I-LST ) ) O in IN B-PP contrast NN I-PP to TO I-PP RelA-I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP COMMA COMMA O RelA-p100 NN B-NP cytoplasmic JJ I-NP complexes NNS I-NP are VBP B-VP not RB I-VP dissociated VBN I-VP following VBG B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP activation NN I-NP ; : O ( ( B-LST iii LS I-LST ) ) O p100 NN B-NP functions VBZ B-VP as IN B-PP a DT B-NP potent JJ I-NP inhibitor NN I-NP of IN B-PP RelA-mediated JJ B-NP transcription NN I-NP in FW B-ADVP vivo FW I-ADVP ; : O ( ( B-LST iv LS I-LST ) ) O the DT B-NP interaction NN I-NP of IN B-PP RelA NN B-NP and CC O p100 NN B-NP involves VBZ B-VP the DT B-NP conserved VBN I-NP Rel NN I-NP homology NN I-NP domain NN I-NP of IN B-PP both DT B-NP proteins NNS I-NP but CC B-CONJP not RB I-CONJP the DT B-NP nuclear JJ I-NP localization NN I-NP signal NN I-NP of IN B-PP RelA NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP required VBN I-VP for IN B-PP I NN B-NP kappa NN I-NP B NN I-NP alpha NN I-NP binding NN I-NP ; : O ( ( B-LST v LS I-LST ) ) O p100 NN B-NP inhibition NN I-NP of IN B-PP RelA NN B-NP function NN I-NP requires VBZ B-VP the DT B-NP C-terminal JJ I-NP ankyrin NN I-NP motif NN I-NP domain NN I-NP COMMA COMMA O which WDT B-NP mediates VBZ B-VP cytoplasmic JJ B-NP retention NN I-NP of IN B-PP RelA NN B-NP ; : O and CC O ( ( B-LST vi LS I-LST ) ) O as IN B-SBAR observed VBN B-VP with IN B-PP I PRP B-NP kappa NN I-NP B NN I-NP alpha NN I-NP COMMA COMMA O nuclear JJ B-NP RelA NN I-NP stimulates VBZ B-VP p100 NN O mRNA NN B-NP and CC O protein NN B-NP expression NN B-NP . . O These DT B-NP findings NNS I-NP thus RB B-ADVP reveal VBP B-VP the DT B-NP presence NN I-NP of IN B-PP a DT B-NP second JJ I-NP inducible JJ I-NP autoregulated JJ I-NP inhibitory JJ I-NP pathway NN I-NP that WDT B-NP helps VBZ B-VP ensure VB I-VP the DT B-NP rapid JJ I-NP but CC I-NP transient JJ I-NP action NN I-NP of IN B-PP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP . . O Calcineurin NN B-NP acts VBZ B-VP in IN B-PP synergy NN B-NP with IN B-PP PMA NN B-NP to TO B-VP inactivate VB I-VP I NN B-NP kappa NN I-NP B\/MAD3 NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O The DT O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O promoter NN B-NP consists VBZ B-VP of IN B-PP several JJ O independent JJ O T NN B-NP cell NN I-NP receptor NN I-NP ( ( O TcR NN B-NP ) ) O responsive JJ B-NP elements NNS I-NP . . O The DT B-NP induction NN I-NP of IN B-PP promoters NNS B-NP dependent JJ B-ADJP on IN B-PP these DT B-NP elements NNS I-NP is VBZ B-VP inhibitable JJ B-ADJP by IN B-PP the DT B-NP immunosuppressants NNS I-NP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O tacrolimus NN B-NP ( ( O FK-506 NN B-NP ) ) O . . O Calcineurin NN B-NP COMMA COMMA O a DT B-NP Ca2+\/calmodulin-dependent JJ I-NP protein NN I-NP phosphatase NN I-NP COMMA COMMA O is VBZ B-VP the DT B-NP FK-506- NN I-NP and CC I-NP CsA-sensitive JJ I-NP enzyme NN I-NP required VBN B-VP for IN B-PP TcR NN B-NP mediated JJ I-NP activation NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP . . O We PRP B-NP report VBP B-VP that IN B-SBAR a DT B-NP constitutively RB I-NP active JJ I-NP form NN I-NP of IN B-PP calcineurin NN B-NP partially RB B-VP substitutes VBZ I-VP for IN B-PP the DT B-NP Ca2+ NN I-NP co-stimulus NN I-NP required VBN B-VP to TO B-VP activate VB I-VP the DT B-NP IL-2 NN I-NP promoter NN I-NP elements NNS I-NP IL-2A NN B-NP ( ( O which WDT B-NP binds VBZ B-VP the DT B-NP factors NNS I-NP OAP NN B-NP and CC O Oct-1 NN B-NP ) ) O and CC O IL-2E NN B-NP ( ( O which WDT B-NP binds VBZ B-VP NF-AT NN B-NP ) ) O COMMA COMMA O and CC O completely RB B-VP substitutes VBZ I-VP for IN B-PP the DT B-NP Ca2+ NN I-NP co-stimulus NN I-NP required VBN B-VP to TO B-VP stimulate VB I-VP an DT B-NP NF-kappa NN I-NP B-dependent JJ I-NP element NN I-NP . . O Calcineurin NN B-NP stimulates VBZ B-VP the DT B-NP NF-kappa NN I-NP B NN I-NP element NN I-NP by IN B-PP enhancing VBG B-VP inactivation NN B-NP of IN B-PP I NN B-NP kappa NN I-NP B\/MAD3 NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O thereby RB B-VP increasing VBG I-VP the DT B-NP amount NN I-NP of IN B-PP nuclear JJ B-NP NF-kappa NN I-NP B NN I-NP DNA NN I-NP binding NN I-NP activity NN I-NP . . O These DT B-NP data NNS I-NP provide VBP B-VP the DT B-NP first JJ I-NP demonstration NN I-NP in FW B-ADVP vivo FW I-ADVP that IN B-SBAR activation NN B-NP of IN B-PP a DT B-NP protein NN I-NP phosphatase NN I-NP can MD B-VP inactivate VB I-VP I NN B-NP kappa NN I-NP B NN I-NP COMMA COMMA O and CC O suggest VBP B-VP one CD B-NP possible JJ I-NP explanation NN I-NP for IN B-PP mechanism-based JJ B-NP toxicities NNS I-NP associated VBN B-VP with IN B-PP FK-506 NN B-NP and CC O CsA NN B-NP by IN B-PP demonstrating VBG B-VP that IN B-SBAR these DT B-NP drugs NNS I-NP can MD B-VP inhibit VB I-VP the DT B-NP calcineurin-dependent JJ I-NP activation NN I-NP of IN B-PP a DT B-NP virtually RB I-NP ubiquitous JJ I-NP transcription NN I-NP factor NN I-NP . . O Direct JJ B-NP exposure NN I-NP to TO B-PP 2COMMA3COMMA7COMMA8-tetrachlorodibenzo-p-dioxin NN B-NP ( ( O TCDD NN B-NP ) ) O increases VBZ B-VP infectivity NN B-NP of IN B-PP human JJ B-NP erythrocytes NNS I-NP to TO B-PP a DT B-NP malarial JJ I-NP parasite NN I-NP . . O Direct JJ B-NP exposure NN I-NP to TO B-PP 10 CD B-NP nM NN I-NP 2COMMA3COMMA7COMMA8-TCDD NN I-NP caused VBD B-VP a DT B-NP 75 CD I-NP % NN I-NP increase NN I-NP and CC O a DT B-NP 2-fold JJ I-NP increase NN I-NP in IN B-PP the DT B-NP infectivity NN I-NP of IN B-PP isolated VBN B-NP human JJ I-NP erythrocytes NNS I-NP to TO B-PP P. FW B-NP falciparum FW I-NP after IN B-PP 48 CD B-NP hours NNS I-NP when WRB B-ADVP the DT B-NP parasites NNS I-NP were VBD B-VP in IN B-PP an DT B-NP unsynchronized JJ I-NP or CC I-NP synchronized JJ I-NP state NN I-NP of IN B-PP growth NN B-NP COMMA COMMA O respectively RB B-ADVP . . O Treatment NN B-NP of IN B-PP human JJ B-NP erythrocytes NNS I-NP with IN B-PP 10 CD B-NP microM NN I-NP sodium NN B-NP orthovanadate NN I-NP ( ( O NaOV NN B-NP ) ) O COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP plasma NN B-NP membrane NN I-NP Ca-ATPase NN I-NP and CC O phosphotyrosine NN B-NP phosphatase NN I-NP COMMA COMMA O decreased VBD B-VP parasitemia NN B-NP by IN B-PP 30 CD B-NP % NN I-NP . . O Co-treatment NN B-NP of IN B-PP RBCs NNS B-NP with IN B-PP TCDD NN B-NP and CC O NaOV NN B-NP completely RB B-ADVP blocked VBD B-VP the DT B-NP TCDD-induced JJ I-NP increase NN I-NP in IN B-PP parasitemia NN B-NP . . O Because IN B-SBAR erythrocytes NNS B-NP are VBP B-VP anucleated JJ I-VP COMMA COMMA O these DT B-NP results NNS I-NP are VBP B-VP discussed VBN I-VP as IN B-PP evidence NN B-NP for IN B-PP biochemical JJ B-NP changes NNS I-NP by IN B-PP TCDD NN B-NP without IN B-PP requiring VBG B-VP the DT B-NP activation NN I-NP of IN B-PP gene NN B-NP products NNS I-NP . . O Comparative JJ B-NP mapping NN I-NP of IN B-PP SRY NN B-NP in IN B-PP the DT B-NP great JJ I-NP apes NNS I-NP . . O Cytogenetic JJ B-NP studies NNS I-NP of IN B-PP the DT B-NP primate JJ I-NP Y NN I-NP chromosomes NNS I-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR extensive JJ B-NP rearrangements NNS I-NP have VBP B-VP occurred VBN I-VP during IN B-PP evolution NN B-NP of IN B-PP the DT B-NP great JJ I-NP apes NNS I-NP . . O We PRP B-NP have VBP B-VP used VBN I-VP in FW B-NP situ FW I-NP hybridization NN I-NP to TO B-VP define VB I-VP these DT B-NP rearrangements NNS I-NP at IN B-PP the DT B-NP molecular JJ I-NP level NN I-NP . . O pHU-14 NN B-NP COMMA COMMA O a DT B-NP probe NN I-NP including VBG B-PP sequences NNS B-NP from IN B-PP the DT B-NP sex NN I-NP determining JJ I-NP gene NN I-NP SRY NN I-NP COMMA COMMA O hybridizes VBZ B-VP close RB B-ADVP to TO B-PP the DT B-NP early JJ I-NP replicating VBG I-NP pseudoautosomal JJ I-NP segment NN I-NP in IN B-PP a DT B-NP telomeric JJ I-NP or CC I-NP subtelomeric JJ I-NP position NN I-NP of IN B-PP the DT B-NP Y NN I-NP chromosomes NNS I-NP of IN B-PP all DT B-NP great JJ I-NP apes NNS I-NP . . O The DT B-NP low JJ I-NP copy NN I-NP repeat NN I-NP detected VBN B-VP by IN B-PP the DT B-NP probe NN I-NP Fr35-II NN I-NP is VBZ B-VP obviously RB I-VP included VBN I-VP in IN B-PP Y NN B-NP chromosomal NN I-NP rearrangements NNS I-NP during IN B-PP hominid NN B-NP evolution NN I-NP . . O These DT B-NP results NNS I-NP COMMA COMMA O combined VBN B-VP with IN B-PP previous JJ B-NP studies NNS I-NP COMMA COMMA O suggest VBP B-VP that IN B-SBAR the DT B-NP Y NN I-NP chromosome NN I-NP in IN B-PP great JJ B-NP apes NNS I-NP has VBZ B-VP a DT B-NP conserved VBN I-NP region NN I-NP including VBG B-PP the DT B-NP pseudoautosomal JJ I-NP region NN I-NP and CC O the DT B-NP testis-determining JJ I-NP region NN I-NP . . O The DT B-NP rest NN I-NP of IN B-PP the DT B-NP Y NN I-NP chromosome NN I-NP has VBZ B-VP undergone VBN I-VP several JJ B-NP rearrangements NNS I-NP in IN B-PP the DT B-NP different JJ I-NP great JJ I-NP apes NNS I-NP . . O Detection NN B-NP of IN B-PP minimal JJ B-NP residual JJ I-NP disease NN I-NP in IN B-PP a DT B-NP patient NN I-NP with IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP by IN B-PP RT-PCR NN B-NP : : O necessity NN B-NP of IN B-PP chemotherapy NN B-NP following VBG B-PP ATRA NN B-NP therapy NN I-NP . . O We PRP B-NP examined VBD B-VP bone NN B-NP marrow NN I-NP cells NNS I-NP by IN B-PP reverse JJ B-NP transcriptase-polymerase NN I-NP chain NN I-NP reaction NN I-NP ( ( O RT-PCR NN B-NP ) ) O to TO B-VP detect VB I-VP residual JJ B-NP PML\/RAR NN I-NP alpha NN I-NP mRNA-containing JJ I-NP cells NNS I-NP following VBG B-PP treatment NN B-NP with IN B-PP all-trans JJ B-NP retinoic JJ I-NP acid NN I-NP ( ( O ATRA NN B-NP ) ) O and CC O cytotoxic JJ B-NP chemotherapy NN I-NP in IN B-PP a DT B-NP patient NN I-NP with IN B-PP APL NN B-NP . . O This DT B-NP RT-PCR NN I-NP assay NN I-NP can MD B-VP detect VB I-VP one CD B-NP leukemic JJ I-NP cell NN I-NP in IN B-PP 10(2) CD B-NP normal JJ I-NP cells NNS I-NP in FW B-ADVP vitro FW I-ADVP . . O We PRP B-NP show VBP B-VP that IN B-SBAR PML\/RAR NN B-NP alpha NN I-NP mRNA NN I-NP was VBD B-VP still RB B-ADVP detectable JJ B-ADJP despite IN B-PP clinical JJ B-NP remission NN I-NP following VBG B-PP ATRA NN B-NP treatment NN I-NP COMMA COMMA O but CC O undetectable JJ B-ADJP following VBG B-PP consolidation NN B-NP with IN B-PP chemotherapy NN B-NP . . O These DT B-NP data NNS I-NP show VBP B-VP that IN B-SBAR this DT B-NP technique NN I-NP is VBZ B-VP useful JJ B-ADJP for IN B-PP the DT B-NP identification NN I-NP of IN B-PP minimal JJ B-NP residual JJ I-NP disease NN I-NP in NN O patients NNS B-NP with IN B-PP APL NN B-NP and CC O that IN B-SBAR cytotoxic JJ B-NP chemotherapy NN I-NP following VBG B-PP ATRA NN B-NP therapy NN I-NP is VBZ B-VP required VBN I-VP for IN B-PP the DT B-NP elimination NN I-NP of IN B-PP APL NN B-NP cells NNS I-NP . . O Genes NNS B-NP encoding VBG B-VP general JJ B-NP initiation NN I-NP factors NNS I-NP for IN B-PP RNA NN B-NP polymerase NN I-NP II CD I-NP transcription NN I-NP are VBP B-VP dispersed VBN I-VP in IN B-PP the DT B-NP human JJ I-NP genome NN I-NP . . O General JJ B-NP transcription NN I-NP factors NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP accurate JJ B-NP initiation NN I-NP of IN B-PP transcription NN B-NP by IN B-PP RNA NN B-NP polymerase NN I-NP II CD I-NP . . O Human JJ B-NP cDNAs NNS I-NP encoding VBG B-VP subunits NNS B-NP of IN B-PP these DT B-NP factors NNS I-NP have VBP B-VP been VBN I-VP cloned VBN I-VP and CC O sequenced VBN B-VP . . O Using VBG B-VP fluorescence NN B-NP in FW I-NP situ FW I-NP hybridization NN I-NP ( ( O FISH NN B-NP ) ) O COMMA COMMA O we PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP genes NNS I-NP encoding VBG B-VP the DT B-NP TATA-box NN I-NP binding NN I-NP protein NN I-NP ( ( O TBP NN B-NP ) ) O COMMA COMMA O TFIIB NN B-NP COMMA COMMA O TFIIE NN B-NP alpha NN I-NP COMMA COMMA O TFIIE NN B-NP beta NN I-NP COMMA COMMA O RAP30 NN B-NP COMMA COMMA O RAP74 NN B-NP and CC O the DT B-NP 62 CD I-NP kDa NN I-NP subunit NN I-NP COMMA COMMA O of IN B-PP TFIIH NN B-NP are VBP B-VP located JJ B-ADJP at IN B-PP the DT B-NP human JJ I-NP chromosomal JJ I-NP bands NNS I-NP 6q26-27 NN B-NP COMMA COMMA O 1p21-22 NN B-NP COMMA COMMA O 3q21-24 NN B-NP COMMA COMMA O 8p12 NN B-NP COMMA COMMA O 13q14 NN B-NP COMMA COMMA O 19p13.3 NN B-NP and CC O 11p14-15.1 NN B-NP COMMA COMMA O respectively RB B-ADVP . . O This DT B-NP dispersed JJ I-NP localization NN I-NP of IN B-PP a DT B-NP group NN I-NP of IN B-PP functionally RB B-NP related JJ I-NP gene NN I-NP provides VBZ B-VP insights NNS B-NP into IN B-PP the DT B-NP molecular JJ I-NP mechanism NN I-NP of IN B-PP human JJ B-NP genome NN I-NP evolution NN I-NP and CC O their PRP$ B-NP possible JJ I-NP involvement NN I-NP in IN B-PP human JJ B-NP diseases NNS I-NP . . O Patterns NN B-NP of IN B-PP Pan NN B-NP expression NN I-NP and CC O role NN B-NP of IN B-PP Pan NN B-NP proteins NNS I-NP in IN B-PP endocrine NN B-NP cell NN I-NP type-specific JJ I-NP complex JJ I-NP formation NN I-NP . . O The DT B-NP Pan NN I-NP gene NN I-NP encodes VBZ B-VP at IN B-NP least JJS I-NP two CD I-NP distinct JJ I-NP transcripts NNS I-NP COMMA COMMA O Pan-1 NN B-NP and CC O Pan-2 NN B-NP ( ( O also RB B-VP known VBN I-VP as IN B-PP E47 NN B-NP and CC O E12 NN B-NP COMMA COMMA O respectively RB B-ADVP ) ) O COMMA COMMA O by IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP alternative JJ B-NP RNA NN I-NP splicing NN I-NP . . O Northern JJ B-NP blot NN I-NP analyses NNS I-NP performed VBN B-VP on IN B-PP rat NN B-NP and CC O mouse NN B-NP tissues NNS B-NP have VBP B-VP detected VBN I-VP ubiquitously RB B-NP expressed VBN I-NP Pan NN I-NP transcripts NNS I-NP COMMA COMMA O but CC O the DT B-NP abundance NN B-NP COMMA COMMA O distribution NN B-NP COMMA COMMA O and CC O form NN B-NP of IN B-PP Pan NN B-NP proteins NNS I-NP have VBP B-VP not RB I-VP been VBN I-VP clearly RB I-VP defined VBN I-VP . . O Studies NNS B-NP of IN B-PP cell NN B-NP lines NNS I-NP representing VBG B-VP endocrine NN O COMMA COMMA O fibroblast NN B-NP COMMA COMMA O and CC O lymphoid JJ B-ADJP lineages NNS B-NP using VBG B-VP polyclonal JJ B-NP antisera NNS I-NP to TO B-VP detect VB I-VP E2A NN B-NP proteins NNS I-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR significant JJ B-NP E2A NN I-NP protein NN I-NP expression NN I-NP is VBZ B-VP restricted JJ I-VP to TO B-PP B-lymphocytes NNS B-NP . . O We PRP B-NP have VBP B-VP developed VBN I-VP a DT B-NP monoclonal JJ I-NP antibody NN I-NP COMMA COMMA O Yae NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP specific JJ B-ADJP for IN B-PP Pan\/E2A NN B-NP proteins NNS I-NP COMMA COMMA O and CC O have VBP B-VP used VBN I-VP the DT B-NP Yae NN I-NP antibody NN I-NP to TO B-VP examine VB I-VP a DT B-NP variety NN I-NP of IN B-PP endocrine JJ B-NP and CC I-NP nonendocrine JJ I-NP cell NN I-NP lineages NNS I-NP for IN B-PP differences NNS B-NP in IN B-PP Pan\/E2A NN B-NP protein NN I-NP expression NN I-NP COMMA COMMA O subcellular JJ B-NP localization NN I-NP COMMA COMMA O and CC O heteromeric JJ B-NP complex JJ I-NP formation NN I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP previous JJ B-NP results NNS I-NP obtained VBN B-VP using VBG B-VP polyclonal JJ B-NP antiseras NN I-NP to TO B-VP detect VB I-VP Pan\/E2A NN B-NP proteins NNS I-NP COMMA COMMA O we PRP B-NP report VBP B-VP comparable JJ B-NP levels NNS I-NP of IN B-PP Pan NN B-NP proteins NNS I-NP in IN B-PP GH\/PRL- NN B-NP and CC O insulin-producing JJ B-ADJP COMMA COMMA O B- NN B-NP and CC O T-lymphocyte NN B-NP cells NNS B-NP . . O IEF-1 NN B-NP COMMA COMMA O a DT B-NP pancreatic JJ I-NP beta-cell NN I-NP type-specific JJ I-NP complex NN I-NP believed VBN B-VP to TO I-VP regulate VB I-VP insulin NN B-NP expression NN I-NP COMMA COMMA O is VBZ B-VP demonstrated VBN I-VP to TO I-VP consist VB I-VP of IN B-PP at IN B-NP least JJS I-NP two CD I-NP distinct JJ I-NP species NNS I-NP COMMA COMMA O one CD B-NP of IN B-PP which WDT B-NP does VBZ B-VP not RB I-VP contain VB I-VP Pan NN B-NP molecules NNS I-NP . . O Although IN B-SBAR it PRP B-NP has VBZ B-VP been VBN I-VP postulated VBN I-VP that IN B-SBAR pituitary JJ B-NP endocrine JJ I-NP cells NNS I-NP and CC O pancreatic JJ B-NP endocrine NN I-NP beta-cells NNS I-NP share VBP B-VP identical JJ B-NP Pan\/E2A NN I-NP complexes NNS I-NP COMMA COMMA O native-Western JJ B-NP analyses NNS I-NP of IN B-PP pituitary JJ B-NP and CC I-NP endocrine JJ I-NP beta-cells NNS I-NP detect VBP B-VP Pan NN B-NP proteins NNS I-NP in IN B-PP distinct JJ B-NP cell NN I-NP type-specific JJ I-NP complexes NNS I-NP . . O Interferon NN B-NP alpha NN I-NP selectively RB B-ADVP affects VBZ B-VP expression NN B-NP of IN B-PP the DT B-NP human JJ I-NP myeloid JJ I-NP cell NN I-NP nuclear JJ I-NP differentiation NN I-NP antigen NN I-NP in IN B-PP late JJ B-NP stage NN I-NP cells NNS I-NP in IN B-PP the DT B-NP monocytic JJ I-NP but CC B-CONJP not RB I-CONJP the DT B-NP granulocytic JJ I-NP lineage NN B-NP . . O The DT B-NP human JJ I-NP myeloid JJ B-NP cell NN I-NP nuclear JJ I-NP differentiation NN I-NP antigen NN I-NP ( ( O MNDA NN B-NP ) ) O is VBZ B-VP expressed VBN I-VP constitutively RB B-ADVP in IN B-PP cells NNS B-NP of IN B-PP the DT B-NP myeloid JJ I-NP lineage NN I-NP COMMA COMMA O appearing VBG B-VP in IN B-PP myeloblast JJ B-NP cells NNS I-NP in IN B-PP some DT B-NP cases NNS I-NP of IN B-PP acute JJ B-NP myeloid JJ I-NP leukemia NN I-NP and CC O consistently RB B-VP being VBG I-VP detected VBN I-VP in IN B-PP promyelocyte JJ B-NP stage NN I-NP cells NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP all DT B-NP later JJR I-NP stage NN I-NP cells NNS I-NP including VBG B-PP peripheral JJ B-NP blood NN I-NP monocytes NNS I-NP and CC O granulocytes NNS B-NP . . O The DT B-NP human JJ I-NP myeloid JJ I-NP leukemia NN I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O HL-60 NN B-NP COMMA COMMA O U937 NN B-NP COMMA COMMA O and CC O THP-1 NN B-NP COMMA COMMA O express VBP B-VP similar JJ B-NP levels NNS I-NP of IN B-PP immunochemically RB B-NP detectable JJ I-NP MNDA NN I-NP . . O Although IN B-SBAR COMMA COMMA O the DT B-NP level NN I-NP of IN B-PP MNDA NN B-NP mRNA NN I-NP in IN B-PP primary JJ B-NP monocytes NNS I-NP is VBZ B-VP very RB B-ADJP low JJ I-ADJP it PRP B-NP was VBD B-VP up-regulated VBN I-VP at IN B-PP 6 CD B-NP h NN I-NP following VBG B-PP the DT B-NP addition NN I-NP of IN B-PP interferon NN B-NP alpha NN I-NP . . O The DT B-NP effect NN I-NP of IN B-PP interferon NN B-NP alpha NN I-NP on IN B-PP the DT B-NP MNDA NN I-NP mRNA NN I-NP is VBZ B-VP also RB I-VP observed VBN I-VP in IN B-PP the DT B-NP cell NN I-NP lines NNS I-NP HL-60 NN B-NP COMMA COMMA O U937 NN B-NP COMMA COMMA O and CC O THP-1 NN B-NP . . O The DT B-NP MNDA NN I-NP mRNA NN I-NP level NN I-NP in IN B-PP primary JJ B-NP granulocytes NNS I-NP was VBD B-VP unaffected JJ I-VP by IN B-PP addition NN B-NP of IN B-PP interferon NN B-NP alpha NN I-NP and CC O other JJ B-NP agents NNS I-NP including VBG B-PP interferon NN B-NP gamma NN I-NP COMMA COMMA O endotoxin NN B-NP COMMA COMMA O poly(I).poly(C) NN B-NP COMMA COMMA O and CC O FMLP NN B-NP . . O The DT B-NP MNDA NN I-NP mRNA NN I-NP level NN I-NP in IN B-PP the DT B-NP myeloid JJ I-NP cell NN I-NP lines NNS I-NP was VBD B-VP also RB I-VP unaffected JJ I-VP by IN B-PP the DT B-NP latter JJ I-NP four CD I-NP agents NNS I-NP . . O Induction NN B-NP of IN B-PP differentiation NN B-NP in IN B-PP the DT B-NP myeloid JJ I-NP cell NN I-NP lines NNS I-NP with IN B-PP phorbol NN B-NP ester NN I-NP induces VBZ B-VP monocyte NN B-NP differentiation NN I-NP which WDT B-NP was VBD B-VP accompanied VBN I-VP by IN B-PP a DT B-NP decrease NN I-NP in IN B-PP MNDA NN B-NP mRNA NN I-NP level NN I-NP . . O This DT B-NP reduced JJ I-NP level NN I-NP of IN B-PP mRNA NN B-NP could MD B-VP then RB I-VP be VB I-VP elevated JJ I-VP with IN B-PP subsequent JJ B-NP interferon NN I-NP alpha NN I-NP treatment NN I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP phorbol NN B-NP ester NN I-NP on IN B-PP MNDA NN B-NP mRNA NN I-NP appeared VBD B-VP to TO I-VP be VB I-VP associated VBN I-VP with IN B-PP induced VBN B-NP differentiation NN I-NP since IN B-SBAR inhibiting VBG B-VP cell NN B-NP proliferation NN I-NP did VBD B-VP not RB I-VP alter VB I-VP the DT B-NP level NN I-NP of IN B-PP MNDA NN B-NP mRNA NN I-NP and CC O cell NN B-NP cycle NN I-NP variation NN I-NP in IN B-PP MNDA NN B-NP mRNA NN I-NP levels NNS I-NP were VBD B-VP not RB I-VP observed VBN I-VP . . O The DT B-NP ability NN I-NP of IN B-PP interferon NN B-NP alpha NN I-NP to TO B-VP up-regulate VB I-VP MNDA NN B-NP mRNA NN I-NP in IN B-PP phorbol NN B-NP ester NN I-NP treated JJ B-NP myeloid JJ I-NP cell NN I-NP lines NNS I-NP is VBZ B-VP consistent JJ B-ADJP with IN B-PP the DT B-NP observations NNS I-NP made VBN B-VP in IN B-PP primary JJ B-NP monocytes NNS I-NP . . O ( ( O ABSTRACT NN B-NP TRUNCATED VBN B-VP AT IN B-PP 250 CD B-NP WORDS NNS I-NP ) ) O Calcineurin NN B-NP potentiates VBZ B-VP activation NN B-NP of IN B-PP the DT B-NP granulocyte-macrophage JJ I-NP colony-stimulating JJ I-NP factor NN I-NP gene NN I-NP in IN B-PP T NN B-NP cells NNS I-NP : : O involvement NN B-NP of IN B-PP the DT B-NP conserved VBN I-NP lymphokine NN I-NP element NN I-NP 0 CD I-NP . . O Granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O and CC O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O are VBP B-VP produced VBN I-VP by IN B-PP stimulation NN B-NP with IN B-PP phorbol-12-myristate NN B-NP acetate NN I-NP ( ( O PMA NN B-NP ) ) O and CC O calcium NN B-NP ionophore NN I-NP ( ( O A23187 NN B-NP ) ) O in IN B-PP human JJ B-NP T NN I-NP cell NN I-NP leukemia NN I-NP Jurkat NN I-NP cells NNS I-NP . . O The DT B-NP expression NN I-NP of IN B-PP GM-CSF NN B-NP and CC O IL-2 NN B-NP is VBZ B-VP inhibited VBN I-VP by IN B-PP immunosuppressive JJ B-NP drugs NNS I-NP such JJ B-PP as IN I-PP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O FK506 NN B-NP . . O Earlier JJR B-NP studies NNS I-NP on IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP expression NN I-NP showed VBD B-VP that IN B-SBAR overexpression NN B-NP of IN B-PP calcineurin NN B-NP ( ( O CN NN B-NP ) ) O COMMA COMMA O a DT B-NP Ca2+\/calmodulin-dependent JJ I-NP protein NN I-NP phosphatase NN I-NP COMMA COMMA O can MD B-VP stimulate VB I-VP transcription NN B-NP from IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP through IN B-PP the DT B-NP NF-AT-binding JJ I-NP site NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP obtained VBD B-VP evidence NN B-NP that IN B-SBAR transfection NN B-NP of IN B-PP the DT B-NP cDNAs NNS I-NP for IN B-PP CN NN B-NP A NN I-NP ( ( O catalytic JJ B-ADJP ) ) O and CC O CN NN B-NP B NN I-NP ( ( O regulatory JJ B-ADJP ) ) O subunits NNS B-NP also RB B-ADVP augments VBZ B-VP transcription NN B-NP from IN B-PP the DT B-NP GM-CSF NN I-NP promoter NN I-NP and CC O recovers VBZ B-VP the DT B-NP transcription NN I-NP inhibited VBN B-VP by IN B-PP CsA NN B-NP . . O The DT B-NP constitutively RB I-NP active JJ I-NP type NN I-NP of IN B-PP the DT B-NP CN NN I-NP A NN I-NP subunit NN I-NP COMMA COMMA O which WDT B-NP lacks VBZ B-VP the DT B-NP auto-inhibitory JJ I-NP and CC I-NP calmodulin-binding JJ I-NP domains NNS I-NP COMMA COMMA O acts VBZ B-VP in IN B-PP synergy NN B-NP with IN B-PP PMA NN B-NP to TO B-VP activate VB I-VP transcription NN B-NP from IN B-PP the DT B-NP GM-CSF NN I-NP promoter NN I-NP . . O We PRP B-NP also RB B-ADVP found VBD B-VP that IN B-SBAR the DT B-NP active JJ I-NP CN NN I-NP partially RB B-ADVP replaces VBZ B-VP calcium NN B-NP ionophore NN I-NP in IN B-PP synergy NN B-NP with IN B-PP PMA NN B-NP to TO B-VP induce VB I-VP expression NN B-NP of IN B-PP endogenous JJ B-NP GM-CSF NN B-NP and CC O IL-2 NN B-NP . . O By IN B-PP multimerizing VBG B-VP the DT B-NP regulatory JJ I-NP elements NNS I-NP of IN B-PP the DT B-NP GM-CSF NN I-NP promoter NN I-NP COMMA COMMA O we PRP B-NP found VBD B-VP that IN B-SBAR one CD B-NP of IN B-PP the DT B-NP target NN I-NP sites NNS I-NP for IN B-PP the DT B-NP CN NN I-NP action NN I-NP is VBZ B-VP the DT B-NP conserved VBN I-NP lymphokine NN I-NP element NN I-NP 0 CD I-NP ( ( O CLE0 NN B-NP ) ) O COMMA COMMA O located JJ B-ADJP at IN B-PP positions NNS B-NP between IN B-PP -54 CD B-NP and CC O -40 CD B-NP . . O Mobility NN B-NP shift NN I-NP assays NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP CLE0 NN I-NP sequence NN I-NP has VBZ B-VP an DT B-NP AP1-binding JJ I-NP site NN I-NP and CC O is VBZ B-VP associated VBN I-VP with IN B-PP an DT B-NP NF-AT-like JJ I-NP factor NN I-NP COMMA COMMA O termed VBN B-VP NF-CLE0 NN B-NP gamma NN I-NP . . O NF-CLE0 NN B-NP gamma NN I-NP binding NN I-NP is VBZ B-VP induced VBN I-VP by IN B-PP PMA\/A23187 NN B-NP and CC O is VBZ B-VP inhibited VBN I-VP by IN B-PP treatment NN B-NP with IN B-PP CsA NN B-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR CN NN B-NP is VBZ B-VP involved VBN I-VP in IN B-PP the DT B-NP coordinated VBN I-NP induction NN I-NP of IN B-PP the DT O GM-CSF NN B-NP and CC O IL-2 NN B-NP genes NNS B-NP and CC O that IN B-SBAR the DT B-NP CLE0 NN I-NP sequence NN I-NP of IN B-PP the DT B-NP GM-CSF NN I-NP gene NN I-NP is VBZ B-VP a DT B-NP functional JJ I-NP analogue NN I-NP of IN B-PP the DT B-NP NF-AT-binding JJ I-NP site NN I-NP in IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP COMMA COMMA O which WDT B-NP mediates VBZ B-VP signals NNS B-NP downstream RB B-ADJP of IN B-PP T NN B-NP cell NN I-NP activation NN I-NP . . O Novel JJ B-NP aldosterone NN I-NP receptors NNS I-NP : : O specificity-conferring JJ B-NP mechanism NN I-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP the DT B-NP cell NN I-NP membrane NN I-NP . . O Functional JJ B-NP studies NNS I-NP in IN B-PP extra-renal JJ B-NP COMMA COMMA I-NP nonepithelial JJ I-NP cells NNS I-NP such JJ B-PP as IN I-PP smooth JJ B-NP muscle NN I-NP cells NNS I-NP and CC O more RBR B-ADVP recently RB I-ADVP circulating VBG B-NP human JJ I-NP lymphocytes NNS I-NP have VBP B-VP provided VBN I-VP increasing VBG B-NP evidence NN I-NP that IN B-SBAR aldosterone NN B-NP produces VBZ B-VP not RB B-CONJP only RB I-CONJP classical JJ B-NP genomic JJ I-NP effects NNS I-NP COMMA COMMA O but CC B-CONJP also RB I-CONJP rapid JJ B-NP non-genomic JJ I-NP effects NNS I-NP on IN B-PP transmembrane NN B-NP electrolyte NN I-NP movements NNS I-NP . . O These DT B-NP involve VBP B-VP activation NN B-NP of IN B-PP the DT B-NP sodium\/proton-exchanger NN I-NP of IN B-PP the DT B-NP cell NN I-NP membrane NN I-NP at IN B-PP very RB B-NP low JJ I-NP COMMA COMMA I-NP physiological JJ I-NP concentrations NNS I-NP of IN B-PP aldosterone NN B-NP with IN B-PP an DT B-NP acute JJ I-NP onset NN I-NP within IN B-PP 1-2 CD B-NP minutes NNS I-NP . . O A DT B-NP second JJ I-NP messenger NN I-NP cascade NN I-NP involved VBN B-VP is VBZ B-VP the DT B-NP inositol-1COMMA4COMMA5-trisphosphate\/calcium NN I-NP pathway NN I-NP which WDT B-NP responds VBZ B-VP over IN B-PP the DT B-NP same JJ I-NP rapid JJ I-NP time NN I-NP course NN I-NP . . O Such JJ B-NP changes NNS I-NP clearly RB B-ADVP can MD B-VP not RB I-VP be VB I-VP explained VBN I-VP by IN B-PP genomic JJ B-NP mechanisms NNS I-NP COMMA COMMA O which WDT B-NP are VBP B-VP responsible JJ B-ADJP for IN B-PP later JJ B-NP effects NNS I-NP than IN B-PP the DT B-NP membrane-related JJ I-NP rapid JJ I-NP responses NNS I-NP . . O In IN B-PP addition NN I-PP to TO I-PP its PRP$ B-NP rapid JJ I-NP time NN I-NP course NN I-NP the DT B-NP unique JJ I-NP characteristics NNS I-NP of IN B-PP this DT B-NP new JJ I-NP pathway NN I-NP for IN B-PP steroid NN B-NP action NN I-NP include VBP B-VP a DT B-NP 10000-fold JJ I-NP selectivity NN I-NP for IN B-PP aldosterone NN B-NP over IN B-PP cortisol NN B-NP and CC O the DT B-NP ineffectiveness NN I-NP of IN B-PP spironolactones NNS B-NP COMMA COMMA O classical JJ B-NP mineralocorticoid NN I-NP antagonists NNS I-NP COMMA COMMA O as IN B-PP antagonists NNS B-NP of IN B-PP the DT B-NP response NN I-NP . . O Subsequently RB B-NP binding VBG I-NP sites NNS I-NP have VBP B-VP been VBN I-VP demonstrated VBN I-VP in IN B-PP the DT B-NP plasma NN I-NP membrane NN I-NP of IN B-PP human JJ B-NP lymphocytes NNS I-NP which WDT B-NP show VBP B-VP pharmacological JJ B-NP ( ( O aldosterone NN B-NP specificity NN I-NP ) ) O and CC O kinetic JJ B-NP ( ( O high JJ B-NP turnover NN I-NP ) ) O properties NNS B-NP identical JJ B-ADJP with IN B-PP those DT B-NP of IN B-PP the DT B-NP rapid JJ I-NP aldosterone NN I-NP effects NNS I-NP in IN B-PP the DT B-NP same JJ I-NP cells NNS I-NP . . O SDS-PAGE NN B-NP analysis NN I-NP of IN B-PP the DT B-NP receptor NN I-NP protein NN I-NP has VBZ B-VP shown VBN I-VP a DT B-NP molecular JJ I-NP weight NN I-NP of IN B-PP approximately RB B-NP 50 CD I-NP kD NN I-NP . . O The DT B-NP present JJ I-NP paper NN I-NP reviews VBZ B-VP the DT B-NP data NNS I-NP supporting VBG B-VP a DT B-NP new JJ I-NP COMMA COMMA I-NP two-step JJ I-NP model NN I-NP for IN B-PP non-genomic JJ B-NP and CC I-NP genomic JJ I-NP aldosterone NN I-NP effects NNS I-NP . . O It PRP B-NP also RB B-ADVP suggests VBZ B-VP a DT B-NP novel JJ I-NP specificity-conferring JJ I-NP mechanism NN I-NP for IN B-PP mineralocorticoid NN B-NP action NN I-NP at IN B-PP the DT B-NP membrane NN I-NP level NN I-NP . . O Glucocorticoid-mediated JJ B-NP inhibition NN I-NP of IN B-PP interleukin-2 NN O receptor NN O alpha NN B-NP and CC O -beta NN B-NP subunit NN B-NP expression NN I-NP by IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP . . O To TO B-VP determine VB I-VP the DT B-NP mechanism NN I-NP of IN B-PP glucocorticoid NN B-NP ( ( I-NP GC NN I-NP ) ) I-NP -mediated JJ I-NP inhibition NN I-NP of IN B-PP T NN B-NP cell NN I-NP functions NNS I-NP COMMA COMMA O the DT B-NP effect NN I-NP of IN B-PP dexamethasone NN B-NP ( ( O DM NN B-NP ) ) O on IN B-PP T NN B-NP cell NN I-NP proliferation NN I-NP and CC O interleukin-2 NN B-NP receptor NN I-NP ( ( O IL-2R NN B-NP ) ) O generation NN B-NP were VBD B-VP studied VBN I-VP . . O Dexamethasone NN B-NP inhibited VBD B-VP IL-2-induced JJ B-NP T NN I-NP cell NN I-NP proliferation NN I-NP by IN B-PP 30 CD B-NP % NN I-NP - TO I-NP 88 CD I-NP % NN I-NP COMMA COMMA O relative JJ B-PP to TO I-PP its PRP$ B-NP concentration NN I-NP within IN B-PP the DT B-NP cultures NNS I-NP . . O The DT B-NP effect NN I-NP of IN B-PP DM NN B-NP on IN B-PP expression NN B-NP of IN B-PP IL-2R NN B-NP alpha NN I-NP ( ( O Tac NN B-NP COMMA COMMA O p55 NN B-NP COMMA COMMA O CD25 NN B-NP ) ) O and CC O beta NN B-NP ( ( O p75 NN B-NP ) ) O genes NNS B-NP in IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP was VBD B-VP examined VBN I-VP next RB B-ADVP . . O In IN B-PP T NN B-NP cells NNS I-NP stimulated VBN B-VP with IN B-PP purified VBN B-NP phytohemagglutinin NN I-NP ( ( O PHA-p NN B-NP ) ) O and CC O 4 CD B-NP beta-phorbol NN I-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O addition NN B-NP of IN B-PP DM NN B-NP to TO B-PP the DT B-NP cultures NNS I-NP resulted VBD B-VP in IN B-PP a DT B-NP 60 CD I-NP % NN I-NP reduction NN I-NP in IN B-PP IL-2R NN B-NP alpha NN I-NP and CC O a DT B-NP 30 CD I-NP % NN I-NP reduction NN I-NP in IN B-PP IL-2R NN B-NP beta NN I-NP membrane NN I-NP expression NN I-NP compared VBN B-VP to TO B-PP T NN B-NP cells NNS I-NP cultured VBN B-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP DM NN B-NP ( ( O p NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O . . O Inhibition NN B-NP of IN B-PP membrane NN O IL-2R NN B-NP alpha NN I-NP and CC O IL-2R NN B-NP beta NN I-NP expression NN B-NP by IN B-PP 10(-6) CD B-NP M NN I-NP DM NN I-NP was VBD B-VP partially RB B-ADJP reversible JJ I-ADJP by IN B-PP recombinant JJ B-NP human JJ I-NP IL-2 NN I-NP ( ( O rhIL-2 NN B-NP ) ) O . . O By IN B-PP Northern JJ B-NP blot NN I-NP analysis NN I-NP COMMA COMMA O DM NN B-NP caused VBD B-VP a DT B-NP comparable JJ I-NP decrease NN I-NP in IN B-PP IL-2R NN B-NP alpha NN I-NP and CC B-PP in IN B-PP IL-2R NN B-NP beta NN I-NP mRNA NN B-NP levels NNS I-NP to TO B-PP membrane NN B-NP receptor NN I-NP expression NN I-NP in IN B-PP mitogen-stimulated JJ B-NP T NN I-NP cells NNS I-NP . . O By IN B-PP in FW B-NP vitro FW I-NP transcription NN I-NP assays NNS I-NP COMMA COMMA O DM NN B-NP regulated VBD B-VP IL-2R NN B-NP alpha NN I-NP gene NN I-NP expression NN I-NP at IN B-PP a DT B-NP transcriptional JJ I-NP level NN I-NP while IN B-SBAR transcription NN B-NP of IN B-PP IL-2R NN B-NP beta NN I-NP gene NN I-NP was VBD B-VP unaffected VBN I-VP by IN B-PP DM NN B-NP . . O The DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP of IN B-PP DM NN B-NP on IN B-PP IL-2R NN B-NP alpha NN I-NP transcription NN I-NP was VBD B-VP examined VBN I-VP by IN B-PP determining VBG B-VP the DT B-NP mRNA NN I-NP levels NNS I-NP of IN B-PP the DT B-NP p50 NN I-NP subunit NN I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O COMMA COMMA O a DT B-NP transcription NN I-NP factor NN I-NP that WDT B-NP stimulates VBZ B-VP IL-2R NN B-NP alpha NN I-NP gene NN I-NP expression NN I-NP . . O The DT B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR 10(-6) CD B-NP M NN I-NP DM NN I-NP increased VBD B-VP T NN B-NP cell NN I-NP p50 NN I-NP NF-kappa NN I-NP B NN I-NP mRNA NN I-NP levels NNS I-NP by IN B-PP four-fold JJ B-NP compared VBN B-VP to TO B-PP the DT B-NP levels NNS I-NP obtained VBN B-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP DM NN B-NP . . O Further RB B-ADVP COMMA COMMA O the DT B-NP level NN I-NP of IN B-PP nuclear JJ B-NP proteins NNS I-NP capable JJ B-ADJP of IN B-PP binding VBG B-VP to TO B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP sites NNS I-NP in IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP increased VBD B-VP in IN B-PP response NN I-PP to TO I-PP DM NN B-NP . . O In IN B-PP sum NN B-NP COMMA COMMA O DM NN B-NP regulates VBZ B-VP T NN B-NP cell NN I-NP membrane NN I-NP expression NN I-NP of IN B-PP IL-2R NN B-NP by IN B-PP more JJR B-NP than IN I-NP one CD I-NP molecular JJ I-NP mechanism NN I-NP . . O Function NN B-NP and CC O activation NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O NF-kappa NN B-NP B NN I-NP is VBZ B-VP a DT B-NP ubiquitous JJ I-NP transcription NN I-NP factor NN I-NP . . O Nevertheless RB B-ADVP COMMA COMMA O its PRP$ B-NP properties NNS I-NP seem VBP B-VP to TO I-VP be VB I-VP most RBS I-VP extensively RB I-VP exploited VBN I-VP in IN B-PP cells NNS B-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O Among IN B-PP these DT B-NP properties NNS I-NP are VBP B-VP NF-kappa NN B-NP B NN I-NP 's POS B-NP rapid JJ I-NP posttranslational JJ I-NP activation NN I-NP in IN B-PP response NN I-PP to TO I-PP many JJ B-NP pathogenic JJ I-NP signals NNS I-NP COMMA COMMA O its PRP$ B-NP direct JJ I-NP participation NN I-NP in IN B-PP cytoplasmic\/nuclear JJ B-NP signaling NN I-NP COMMA COMMA O and CC O its PRP$ B-NP potency NN I-NP to TO B-VP activate VB I-VP transcription NN B-NP of IN B-PP a DT B-NP great JJ I-NP variety NN I-NP of IN B-PP genes NNS B-NP encoding VBG B-VP immunologically RB B-NP relevant JJ I-NP proteins NNS I-NP . . O In IN B-PP vertebrates NNS B-NP COMMA COMMA O five CD B-NP distinct JJ I-NP DNA NN I-NP binding NN I-NP subunits NNS I-NP are VBP B-VP currently RB I-VP known VBN I-VP which WDT B-NP might MD B-VP extensively RB I-VP heterodimerize VB I-VP COMMA COMMA O thereby RB B-ADVP forming VBG B-VP complexes NNS B-NP with IN B-PP distinct JJ B-NP transcriptional JJ I-NP activity NN I-NP COMMA COMMA O DNA NN B-NP sequence NN I-NP specificity NN I-NP COMMA COMMA O and CC O cell NN B-NP type- NN I-NP and CC O cell NN B-NP stage- NN I-NP specific JJ B-NP distribution NN I-NP . . O The DT B-NP activity NN I-NP of IN B-PP DNA NN B-NP binding NN I-NP NF-kappa NN I-NP B NN I-NP dimers NNS I-NP is VBZ B-VP tightly RB I-VP controlled VBN I-VP by IN B-PP accessory NN B-NP proteins NNS I-NP called VBN B-VP I NN B-NP kappa NN I-NP B NN I-NP subunits NNS I-NP of IN B-PP which WDT B-NP there EX B-NP are VBP B-VP also RB B-ADVP five CD B-NP different JJ I-NP species NNS I-NP currently RB B-VP known VBN I-VP in IN B-PP vertebrates NNS B-NP . . O I NN B-NP kappa NN I-NP B NN I-NP proteins NNS I-NP inhibit VBP B-VP DNA NN B-NP binding NN I-NP and CC O prevent VBP B-VP nuclear JJ B-NP uptake NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP complexes NNS I-NP . . O An DT B-NP exception NN I-NP is VBZ B-VP the DT B-NP Bcl-3 NN I-NP protein NN I-NP which WDT B-NP in IN B-PP addition NN B-NP can MD B-VP function VB I-VP as IN B-PP a DT B-NP transcription NN I-NP activating NN I-NP subunit NN I-NP in IN B-PP th DT B-NP nucleus NN I-NP . . O Other JJ B-NP I NN I-NP kappa NN I-NP B NN I-NP proteins NNS I-NP are VBP B-VP rather RB I-VP involved VBN I-VP in IN B-PP terminating VBG B-VP NF-kappa NN B-NP B NN I-NP 's POS B-NP activity NN I-NP in IN B-PP the DT B-NP nucleus NN I-NP . . O The DT B-NP intracellular JJ I-NP events NNS I-NP that WDT B-NP lead VBP B-VP to TO B-PP the DT B-NP inactivation NN I-NP of IN B-PP I NN B-NP kappa NN I-NP B NN I-NP COMMA COMMA O i.e. FW B-ADVP the DT B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O are VBP B-VP complex JJ B-ADJP . . O They PRP B-NP involve VBP B-VP phosphorylation NN B-NP and CC O proteolytic JJ B-NP reactions NNS I-NP and CC O seem VBP B-VP to TO I-VP be VB I-VP controlled VBN I-VP by IN B-PP the DT B-NP cells NNS I-NP ' POS B-NP redox NN I-NP status NN I-NP . . O Interference NN B-NP with IN B-PP the DT B-NP activation NN B-NP or CC O activity NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP may MD B-VP be VB I-VP beneficial JJ B-ADJP in IN B-PP suppressing VBG B-VP toxic\/septic JJ B-NP shock NN I-NP COMMA COMMA O graft-vs-host JJ B-NP reactions NNS I-NP COMMA COMMA O acute JJ B-NP inflammatory JJ I-NP reactions NNS I-NP COMMA COMMA O acute JJ B-NP phase NN I-NP response NN I-NP COMMA COMMA O and CC O radiation NN B-NP damage NN I-NP . . O The DT B-NP inhibition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP by IN B-PP antioxidants NNS B-NP and CC O specific JJ B-NP protease NN I-NP inhibitors NNS I-NP may MD B-VP provide VB I-VP a DT B-NP pharmacological JJ I-NP basis NN I-NP for IN B-PP interfering VBG B-VP with IN B-PP these DT B-NP acute JJ I-NP processes NNS I-NP . . O Pentoxifylline NN B-NP for IN B-PP the DT B-NP treatment NN I-NP of IN B-PP infection NN B-NP with IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP . . O Cytokine NN B-NP dysregulation NN I-NP in IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O infection NN B-NP has VBZ B-VP been VBN I-VP documented VBN I-VP in IN B-PP numerous JJ B-NP studies NNS I-NP and CC O has VBZ B-VP been VBN I-VP cited VBN I-VP as IN B-PP an DT B-NP important JJ I-NP component NN I-NP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP this DT B-NP retroviral JJ I-NP infection NN I-NP . . O Pharmacological JJ B-NP modification NN I-NP of IN B-PP cytokine NN B-NP dysregulation NN I-NP COMMA COMMA O therefore RB B-ADVP COMMA COMMA O has VBZ B-VP been VBN I-VP suggested VBN I-VP as IN B-PP a DT B-NP therapeutic JJ I-NP modality NN I-NP for IN B-PP HIV-1 NN B-NP infection NN I-NP . . O Dr. NNP B-NP Dezube NNP I-NP of IN B-PP Beth NNP B-NP Israel NNP I-NP Hospital NNP I-NP ( ( O Boston NNP B-NP ) ) O concisely RB B-ADVP reviews VBZ B-VP the DT B-NP state NN I-NP of IN B-PP our PRP$ B-NP knowledge NN I-NP regarding VBG B-PP the DT B-NP effects NNS I-NP of IN B-PP pentoxifylline NN B-NP on IN B-PP expression NN B-NP of IN B-PP tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP COMMA COMMA O a DT B-NP cytokine NN I-NP known VBN B-VP to TO B-VP influence VB I-VP HIV-1 NN B-NP replication NN I-NP and CC O to TO B-VP play VB I-VP a DT B-NP possible JJ I-NP role NN I-NP in IN B-PP the DT B-NP clinical JJ I-NP manifestations NNS I-NP of IN B-PP advanced JJ B-NP infection NN I-NP with IN B-PP this DT B-NP virus NN I-NP . . O Pentoxifylline NN B-NP COMMA COMMA O a DT B-NP trisubstituted JJ I-NP xanthine NN I-NP derivative NN I-NP COMMA COMMA O has VBZ B-VP been VBN I-VP used VBN I-VP to TO B-VP decrease VB I-VP blood NN B-NP viscosity NN I-NP and CC O is VBZ B-VP reasonably RB I-VP well RB I-VP tolerated VBN I-VP by IN B-PP most JJS B-NP recipients NNS I-NP of IN B-PP the DT B-NP drug NN I-NP . . O Results NNS B-NP of IN B-PP preliminary JJ B-NP studies NNS I-NP COMMA COMMA O many JJ B-NP of IN B-PP which WDT B-NP were VBD B-VP conducted VBN I-VP by IN B-PP Dr. NNP B-NP Dezube NNP B-NP COMMA COMMA O suggest VBP O that IN B-NP use NN O of IN B-NP this DT I-NP agent NN O in IN B-NP combination NN O with IN B-NP antiretroviral JJ I-NP compounds NNS B-VP may MD I-VP prove VB B-ADJP useful JJ B-PP in IN B-NP the DT I-NP treatment NN O of IN B-NP patients NNS O with IN B-NP HIV-1 NN I-NP infection NN O Increased VBN B-NP interleukin NN I-NP 2 CD I-NP transcription NN I-NP in IN B-PP murine JJ B-NP lymphocytes NNS I-NP by IN B-PP ciprofloxacin NN B-NP . . O The DT B-NP fluoroquinolone JJ I-NP antibiotic JJ I-NP COMMA COMMA O ciprofloxacin NN B-NP ( ( O cipro NN B-NP ) ) O COMMA COMMA O induces VBZ B-VP hyperproduction NN B-NP of IN B-PP interleukin NN B-NP 2 CD I-NP ( ( O IL-2 NN B-NP ) ) O and CC O interferon-gamma NN B-NP ( ( O IFN-gamma NN B-NP ) ) O in IN B-PP stimulated VBN B-NP human JJ I-NP peripheral JJ I-NP blood NN I-NP lymphocytes NNS I-NP . . O In IN B-PP this DT B-NP investigation NN I-NP an DT O enhanced VBN O and CC O prolonged JJ O IL-2 NN B-NP and CC O IL-2 NN B-NP mRNA NN I-NP response NN B-NP was VBD B-VP also RB I-VP detected VBN I-VP in IN B-PP both CC I-PP stimulated VBN O ( ( O T NN B-NP cell NN I-NP mitogens NNS B-NP or CC O alloantigens NNS B-NP ) ) B-NP murine JJ I-NP splenocytes NNS I-NP and CC B-PP in IN B-PP the DT B-NP stimulated VBN I-NP murine JJ I-NP T NN I-NP cell NN I-NP line NN I-NP EL-4 NN I-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP ciprofloxacin NN B-NP ( ( O 5-80 CD B-NP micrograms\/ml NN I-NP ) ) O as IN B-SBAR compared VBN B-VP to TO B-PP control NN B-NP cells NNS I-NP without IN B-PP antibiotics NNS B-NP . . O However RB B-ADVP COMMA COMMA O in IN B-PP contrast NN I-PP to TO I-PP human JJ B-NP lymphocytes NNS I-NP COMMA COMMA O IFN-gamma NN B-NP production NN I-NP was VBD B-VP inhibited VBN I-VP and CC O IFN-gamma NN B-NP mRNA NN I-NP levels NNS I-NP were VBD B-VP unaffected JJ I-VP at IN B-PP 24 CD B-NP h NN I-NP and CC O only RB B-VP slightly RB I-VP upregulated VBN I-VP at IN B-PP 48 CD B-NP and CC I-NP 72 CD I-NP h NN I-NP of IN B-PP culture NN B-NP in IN B-PP murine JJ B-NP splenocytes NNS I-NP incubated VBN B-VP with IN B-PP cipro NN B-NP ( ( O 20 CD B-NP micrograms\/ml NNS I-NP ) ) O . . O EL-4 NN B-NP cells NNS I-NP were VBD B-VP transfected VBN I-VP with IN B-PP a DT B-NP plasmid NN I-NP containing VBG B-VP the DT O IL-2 NN O promoter NN B-NP and CC O enhancer NN B-NP region NN B-NP linked VBN B-VP to TO B-PP the DT O chloramphenicol NN B-NP acetyltransferase NN I-NP ( ( O CAT NN B-NP ) ) O reporter NN B-NP gene NN I-NP . . O Analysis NN B-NP of IN B-PP CAT NN B-NP activity NN I-NP revealed VBD B-VP that IN B-SBAR cipro NN B-NP enhanced VBD B-VP IL-2 NN B-NP gene NN I-NP induction NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O EL-4 NN B-NP cells NNS I-NP incubated VBN B-VP with IN B-PP ciprofloxacin NN B-NP showed VBD B-VP an DT B-NP early JJ I-NP peak NN I-NP and CC O more RBR B-NP activated VBN I-NP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NFAT-1 NN B-NP ) ) O as IN B-SBAR compared VBN B-VP to TO B-PP control NN B-NP cells NNS I-NP without IN B-PP antibiotics NNS B-NP . . O Cipro NN B-NP did VBD B-VP not RB I-VP affect VB I-VP the DT B-NP nuclear JJ I-NP transcription NN I-NP factors NNS I-NP AP-1 NN B-NP or CC O NFIL-2A NN B-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O cipro NN B-NP inhibited VBD B-VP IFN-gamma NN B-NP synthesis NN I-NP COMMA COMMA O but CC O enhanced VBD B-VP IL-2 NN B-NP production NN I-NP in IN B-PP murine JJ B-NP lymphocytes NNS I-NP by IN B-PP means NNS I-PP of IN I-PP influencing VBG B-VP NFAT-1 NN B-NP and CC O causing VBG B-VP an DT B-NP increased VBN I-NP IL-2 NN I-NP transcription NN I-NP . . O Multiple JJ B-NP prolactin-responsive JJ I-NP elements NNS I-NP mediate VBP B-VP G1 NN B-NP and CC O S NN B-NP phase NN B-NP expression NN I-NP of IN B-PP the DT B-NP interferon NN I-NP regulatory JJ I-NP factor-1 NN I-NP gene NN I-NP . . O The DT O interferon NN B-NP regulatory JJ I-NP factor-1 NN I-NP ( ( O IRF-1 NN B-NP ) ) O gene NN B-NP is VBZ B-VP both CC O an DT B-NP immediate-early JJ I-NP G1 NN I-NP phase NN I-NP gene NN I-NP and CC O an DT B-NP S NN I-NP phase NN I-NP gene NN I-NP inducible JJ B-ADJP by IN B-PP PRL NN B-NP in IN B-PP rat NN B-NP Nb2 NN I-NP T NN I-NP lymphocytes NNS I-NP . . O To TO B-VP understand VB I-VP the DT B-NP mechanism NN I-NP by IN B-PP which WDT B-NP PRL NN B-NP regulates VBZ B-VP the DT B-NP biphasic JJ I-NP expression NN I-NP of IN B-PP IRF-1 NN B-NP COMMA COMMA O we PRP B-NP cloned VBD B-VP the DT B-NP rat NN I-NP IRF-1 NN I-NP gene NN I-NP and CC O functionally RB B-VP characterized VBD I-VP the DT B-NP IRF-1 NN I-NP promoter NN I-NP . . O Upon IN B-PP transfection NN B-NP into IN B-PP Nb2 NN B-NP T NN I-NP cells NNS I-NP COMMA COMMA O 1.7 CD B-NP kilobases NNS B-NP ( ( O kb NN B-NP ) ) O of IN B-PP IRF-1 NN B-NP 5'-flanking JJ I-NP DNA NN I-NP linked VBN B-VP to TO B-PP a DT O chloramphenicol NN B-NP acetyl JJ I-NP transferase NN I-NP ( ( O CAT NN B-NP ) ) O reporter NN B-NP gene NN I-NP mediated VBD B-VP a DT B-NP 30-fold JJ I-NP induction NN I-NP of IN B-PP CAT NN B-NP enzyme NN I-NP activity NN I-NP in IN B-PP response NN I-PP to TO I-PP 24 CD B-NP h NN I-NP of IN B-PP PRL NN B-NP stimulation NN I-NP . . O Deletion NN B-NP mutants NNS I-NP containing VBG B-VP 1.3 CD B-NP COMMA COMMA I-NP 0.6 CD I-NP COMMA COMMA I-NP and CC I-NP 0.2 CD I-NP kb NN I-NP 5'-flanking JJ I-NP DNA NN I-NP were VBD B-VP incrementally RB B-ADJP less RBR I-ADJP transcriptionally RB I-ADJP active JJ I-ADJP COMMA COMMA O although IN B-SBAR 0.2 CD B-NP kb NN I-NP still RB B-ADVP mediated VBD B-VP a DT B-NP 12-fold JJ I-NP induction NN I-NP by IN B-PP PRL NN B-NP . . O The DT B-NP sequence NN I-NP between IN B-PP -1.7 CD B-NP and CC I-NP -0.2 CD I-NP kb NN I-NP linked VBN B-VP to TO B-PP a DT B-NP heterologous JJ I-NP thymidine NN I-NP kinase NN I-NP promoter NN I-NP failed VBD B-VP to TO I-VP respond VB I-VP to TO B-PP PRL NN B-NP stimulation NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR the DT B-NP activity NN I-NP of IN B-PP upstream JJ B-NP PRL NN I-NP response NN I-NP elements NNS I-NP may MD B-VP require VB I-VP an DT B-NP interaction NN I-NP with IN B-PP promoter-proximal JJ B-NP elements NNS I-NP . . O By IN B-PP assaying VBG B-VP CAT NN B-NP enzyme NN I-NP activity NN I-NP across IN B-PP a DT B-NP 24-h JJ I-NP PRL NN I-NP induction NN I-NP time NN I-NP course NN I-NP COMMA COMMA O we PRP B-NP were VBD B-VP able JJ B-ADJP to TO B-VP assign VB I-VP G1 NN B-NP vs. CC O S NN B-NP phase NN B-NP PRL NN I-NP responses NNS I-NP of IN B-PP the DT B-NP IRF-1 NN I-NP gene NN I-NP to TO B-PP different JJ B-NP regions NNS I-NP of IN B-PP the DT O IRF-1 NN O 5'-flanking JJ O and CC O promoter NN B-NP DNA NN B-NP . . O The DT B-NP 0.2-kb JJ I-NP IRF-CAT NN I-NP construct NN I-NP was VBD B-VP induced VBN I-VP by IN B-PP PRL NN B-NP stimulation NN I-NP during IN B-PP the DT B-NP G1 NN I-NP phase NN I-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP 1.7-kb JJ I-NP IRF-CAT NN I-NP construct NN I-NP was VBD B-VP inducible JJ B-ADJP by IN B-PP PRL NN B-NP during IN B-PP both CC O G1 NN B-NP and CC O S NN B-NP phase NN B-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP . . O Hence RB B-ADVP COMMA COMMA O the DT B-NP PRL-induced JJ I-NP biphasic JJ I-NP expression NN I-NP of IN B-PP the DT B-NP IRF-1 NN I-NP gene NN I-NP appears VBZ B-VP to TO I-VP be VB I-VP controlled VBN I-VP by IN B-PP separate JJ B-NP PRL-responsive JJ I-NP elements NNS I-NP : : O elements NNS B-NP in IN B-PP the DT B-NP first JJ I-NP 0.2 CD I-NP kb NN I-NP of IN B-PP the DT B-NP IRF-1 NN I-NP promoter NN I-NP region NN I-NP act VBP B-VP during IN B-PP early JJ B-NP activation NN I-NP COMMA COMMA O and CC O elements NNS B-NP between IN B-PP 0.2 CD B-NP and CC I-NP 1.7 CD I-NP kb NN I-NP act VBP B-VP in IN B-PP concert NN I-PP with IN I-PP the DT B-NP proximal JJ I-NP 0.2-kb JJ I-NP region NN I-NP during IN B-PP S NN B-NP phase NN I-NP progression NN I-NP . . O Description NN B-NP and CC O functional JJ B-NP implications NNS I-NP of IN B-PP a DT B-NP novel JJ I-NP mutation NN I-NP in IN B-PP the DT B-NP sex-determining JJ I-NP gene NN I-NP SRY NN I-NP . . O The DT B-NP sex-determining JJ I-NP gene NN I-NP SRY NN I-NP was VBD B-VP screened VBN I-VP for IN B-PP molecular JJ B-NP alteration NN I-NP in IN B-PP an DT B-NP XY NN I-NP sex-reversed JJ I-NP female NN I-NP by IN B-PP single-strand JJ B-NP conformation NN I-NP polymorphism NN I-NP ( ( O SSCP NN B-NP ) ) O technique NN B-NP . . O An DT B-NP A-to-G JJ I-NP transition NN I-NP was VBD B-VP detected VBN I-VP which WDT B-NP leads VBZ B-VP to TO B-PP an DT B-NP exchange NN I-NP of IN B-PP a DT B-NP tyrosine NN I-NP by IN B-PP a DT B-NP cysteine NN I-NP in IN B-PP the DT B-NP SRY NN I-NP protein NN I-NP . . O The DT B-NP affected VBN I-NP tyrosine NN I-NP residue NN I-NP located JJ B-ADJP at IN B-PP the DT B-NP C NN I-NP terminus NN I-NP of IN B-PP the DT B-NP DNA NN I-NP binding NN I-NP protein NN I-NP is VBZ B-VP evolutionarily RB I-VP strongly RB I-VP conserved VBN I-VP among IN B-PP the DT B-NP members NNS I-NP of IN B-PP the DT B-NP HMG NN I-NP box NN I-NP containing VBG I-NP proteins NNS I-NP . . O Using VBG B-VP gel NN B-NP shift NN I-NP assay NN I-NP and CC O peptide NN B-NP synthesis NN I-NP such PDT B-NP a DT I-NP mutation NN I-NP is VBZ B-VP shown VBN I-VP to TO I-VP abolish VB I-VP the DT B-NP SRY NN I-NP protein NN I-NP DNA NN I-NP binding NN I-NP ability NN I-NP . . O The DT B-NP involvement NN I-NP of IN B-PP this DT B-NP particular JJ I-NP amino NN I-NP acid NN I-NP in IN B-PP the DT B-NP binding NN I-NP specificity NN I-NP is VBZ B-VP also RB I-VP discussed VBN I-VP . . O Evidence NN B-NP for IN B-PP a DT B-NP trans-acting JJ I-NP activator NN I-NP function NN I-NP regulating VBG B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP human JJ I-NP CD5 NN I-NP antigen NN I-NP . . O Interspecies JJ B-NP somatic JJ I-NP cell NN I-NP hybrids NNS I-NP were VBD B-VP generated VBN I-VP by IN B-PP fusing VBG B-VP the DT B-NP mouse NN I-NP T-lymphoma NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O BW5147 NN B-NP COMMA COMMA O with IN B-PP normal JJ B-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP at IN B-PP different JJ B-NP stages NNS I-NP of IN B-PP differentiation NN B-NP . . O Thymocytes NNS B-NP COMMA COMMA O activated VBN B-NP peripheral JJ I-NP T NN I-NP lymphocytes NNS I-NP COMMA COMMA O or CC O an DT B-NP activated VBN I-NP T-cell NN I-NP clone NN I-NP were VBD B-VP used VBN I-VP as IN B-PP human JJ B-NP partners NNS I-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O in IN B-PP three CD B-NP independent JJ I-NP fusions NNS I-NP . . O Irrespective JJ B-PP of IN I-PP the DT B-NP human JJ I-NP cell NN I-NP partner NN I-NP used VBN B-VP for IN B-PP fusion NN B-NP COMMA COMMA O a DT B-NP certain JJ I-NP number NN I-NP of IN B-PP hybrids NNS B-NP lost VBD B-VP CD5 NN B-NP surface NN I-NP expression NN I-NP over IN B-PP a DT B-NP period NN I-NP of IN B-PP time NN B-NP in IN B-PP culture NN B-NP . . O Analysis NN B-NP at IN B-PP the DT O phenotype NN B-NP and CC O genetic JJ B-ADJP level NN B-NP showed VBD B-VP that IN B-SBAR lack NN B-NP of IN B-PP CD5 NN B-NP expression NN I-NP was VBD B-VP due JJ B-PP neither CC O to TO B-PP segregation NN B-NP of IN B-PP human JJ B-NP autosome NN I-NP 11 CD I-NP COMMA COMMA O on IN B-PP which WDT B-NP the DT B-NP CD5 NN I-NP gene NN I-NP has VBZ B-VP been VBN I-VP mapped VBN I-VP COMMA COMMA O nor CC B-PP to TO B-PP deletion NN B-NP of IN B-PP the DT B-NP CD5 NN I-NP structural JJ I-NP gene NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O loss NN B-NP of IN B-PP CD5 NN B-NP surface NN I-NP expression NN I-NP correlated VBD B-VP with IN B-PP the DT B-NP absence NN I-NP of IN B-PP specific JJ B-NP mRNA NN I-NP . . O Since IN B-SBAR these DT B-NP hybrids NNS I-NP preferentially RB B-ADVP segregate VBP B-VP human JJ B-NP chromosomes NNS I-NP COMMA COMMA O these DT B-NP results NNS I-NP indicate VBP B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP non-syntenic JJ I-NP trans-active JJ I-NP locus NN B-NP COMMA COMMA O or CC O loci NNS B-NP COMMA COMMA O positively RB B-VP controlling VBG I-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP human JJ I-NP CD5 NN I-NP gene NN I-NP . . O Prevalence NN B-NP of IN B-PP aneuploidy NN B-NP COMMA COMMA O overexpressed JJ B-NP ER NN I-NP COMMA COMMA O and CC O overexpressed JJ B-NP EGFR NN I-NP in IN B-PP random JJ B-NP breast NN I-NP aspirates NNS I-NP of IN B-PP women NNS B-NP at IN B-PP high JJ B-NP and CC I-NP low JJ I-NP risk NN I-NP for IN B-PP breast NN B-NP cancer NN I-NP . . O Breast NN B-NP tissue NN I-NP biomarkers NNS I-NP which WDT B-NP accurately RB B-ADVP predict VBP B-VP breast NN B-NP cancer NN I-NP development NN I-NP within IN B-PP a DT B-NP 10 CD I-NP year NN I-NP period NN I-NP in IN B-PP high JJ B-NP risk NN I-NP women NNS I-NP are VBP B-VP needed VBN B-VP but CC O currently RB B-ADJP not RB I-ADJP available JJ I-ADJP . . O We PRP B-NP initiated VBD B-VP this DT B-NP study NN I-NP to TO B-VP determine VB I-VP 1 LS B-LST ) ) O the DT B-NP prevalence NN I-NP of IN B-PP one CD B-NP or CC I-NP more JJR I-NP breast NN I-NP tissue NN I-NP abnormalities NNS I-NP in IN B-PP a DT B-NP group NN I-NP of IN B-PP women NNS B-NP at IN B-PP high JJ B-NP risk NN I-NP for IN B-PP breast NN B-NP cancer NN I-NP COMMA COMMA O and CC O 2 LS B-LST ) ) O if IN B-SBAR the DT B-NP prevalence NN I-NP of IN B-PP biomarker NN B-NP abnormalities NNS I-NP is VBZ B-VP greater JJR B-ADJP in IN B-PP high JJ B-NP risk NN I-NP than IN B-PP in IN B-PP low JJ B-NP risk NN I-NP women NNS I-NP . . O Eligible JJ B-NP high JJ I-NP risk NN I-NP women NNS I-NP were VBD B-VP those DT B-NP with IN B-PP a DT B-NP first JJ I-NP degree NN I-NP relative NN I-NP with IN B-PP breast NN B-NP cancer NN I-NP COMMA COMMA O prior JJ B-NP breast NN I-NP cancer NN I-NP COMMA COMMA O or CC O precancerous JJ B-NP mastopathy NN I-NP . . O Low JJ B-NP risk NN I-NP women NNS I-NP were VBD B-VP those DT B-NP without IN B-PP these DT B-NP or CC O other JJ B-NP major JJ I-NP identifiable JJ I-NP risk NN I-NP factors NNS I-NP . . O Ductal JJ B-NP cells NNS I-NP were VBD B-VP obtained VBN I-VP via IN B-PP random JJ B-NP fine JJ I-NP needle NN I-NP aspirations NNS I-NP and CC O cytologically RB B-VP classified VBN I-VP . . O Biomarkers NNS B-NP included VBD B-VP DNA NN B-NP ploidy NN I-NP COMMA COMMA O estrogen NN B-NP receptor NN I-NP ( ( O ER NN B-NP ) ) O COMMA COMMA O and CC O epidermal JJ B-NP growth NN I-NP factor NN I-NP receptor NN I-NP ( ( O EGFR NN B-NP ) ) O . . O The DT B-NP prevalence NN I-NP of IN B-PP DNA NN B-NP aneuploidy NN I-NP was VBD B-VP 30 CD B-NP % NN I-NP COMMA COMMA O overexpression NN B-NP of IN B-PP ER NN B-NP 10 CD B-NP % NN I-NP COMMA COMMA O and CC O overexpression NN B-NP of IN B-PP EGFR NN B-NP 35 CD B-NP % NN I-NP COMMA COMMA O in IN B-PP the DT B-NP 206 CD I-NP high JJ I-NP risk NN I-NP women NNS I-NP whose WP$ B-NP median JJ I-NP 10 CD I-NP year NN I-NP Gail NN I-NP risk NN B-NP ( ( O projected VBN B-NP probability NN I-NP ) ) O of IN B-PP developing VBG B-VP breast NN B-NP cancer NN I-NP was VBD B-VP 4.5 CD B-NP % NN I-NP . . O The DT B-NP prevalence NN I-NP of IN B-PP aneuploidy NN B-NP and CC O overexpressed JJ B-NP EGFR NN I-NP was VBD B-VP significantly RB B-ADJP higher JJR I-ADJP in IN B-PP the DT B-NP high JJ I-NP risk NN I-NP women NNS I-NP than IN B-PP in IN B-PP the DT B-NP 25 CD I-NP low JJ I-NP risk NN I-NP controls NNS I-NP ( ( O p NN B-NP < JJR B-NP 0.002 CD I-NP ) ) O COMMA COMMA O whose WP$ O median JJ O 10 CD B-ADJP year NN I-ADJP Gail NN B-NP risk NN I-NP was VBD B-VP 0.7 CD B-NP % NN I-NP . . O The DT B-NP difference NN I-NP in IN B-PP the DT B-NP prevalence NN I-NP of IN B-PP ER NN B-NP overexpression NN I-NP between IN B-PP high JJ B-NP and CC I-NP low JJ I-NP risk NN I-NP groups NNS I-NP was VBD B-VP not RB O statistically RB B-ADVP significant JJ B-ADJP ( ( O p NN B-NP = JJ B-VP 0.095 CD B-NP ) ) O . . O This DT B-NP may MD B-VP be VB I-VP due JJ B-PP to TO I-PP the DT B-NP low JJ I-NP prevalence NN I-NP of IN B-PP overexpressed JJ B-NP ER NN I-NP and CC O the DT B-NP small JJ I-NP number NN I-NP of IN B-PP controls NNS B-NP . . O A DT B-NP significant JJ I-NP difference NN I-NP was VBD B-VP noted VBN I-VP in IN B-PP the DT B-NP prevalence NN I-NP of IN B-PP one CD B-NP or CC I-NP more JJR I-NP abnormal JJ I-NP biomarkers NNS I-NP between IN B-PP the DT O high JJ B-NP risk NN I-NP and CC O low JJ B-NP risk NN I-NP women NNS B-NP ( ( O p NN B-NP < JJR B-NP 0.001 CD I-NP ) ) O . . O A DT B-NP large JJ I-NP prospective JJ I-NP trial NN I-NP is VBZ B-VP needed VBN I-VP to TO B-VP determine VB I-VP if IN B-SBAR one CD B-NP or CC I-NP more JJR I-NP of IN B-PP these DT B-NP biomarkers NNS I-NP COMMA COMMA O is VBZ B-VP predictive JJ B-ADJP of IN B-PP breast NN B-NP cancer NN I-NP development NN I-NP . . O { ( O The DT B-NP changes NNS I-NP in IN B-PP glucocorticoid NN B-NP receptors NNS I-NP in IN B-PP peripheral JJ B-NP leukocytes NNS I-NP in IN B-PP asthmatic JJ B-NP subjects NNS I-NP } ) O The DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP ( ( O GCR NN B-NP ) ) O in IN B-PP peripheral JJ B-NP leukocytes NNS I-NP was VBD B-VP determined VBN I-VP by IN B-PP radioligand-binding JJ B-NP assay NN I-NP in IN B-PP extrinsic JJ B-NP and CC I-NP intrinsic JJ I-NP asthmatics NNS I-NP . . O Their PRP$ B-NP corresponding JJ I-NP plasma NN I-NP cortisol NN I-NP levels NNS I-NP were VBD B-VP assessed VBN I-VP . . O The DT B-NP results NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP average JJ I-NP number NN I-NP of IN B-PP GCR NN B-NP in IN B-PP asthmatics NNS B-NP was VBD B-VP significantly RB B-ADJP lower JJR I-ADJP than IN B-PP that DT B-NP in IN B-PP healthy JJ B-NP subjects NNS I-NP ( ( O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O COMMA COMMA O and CC O there EX B-NP was VBD B-VP a DT B-NP linear JJ I-NP correlation NN I-NP between IN B-PP the DT B-NP number NN I-NP of IN B-PP GCR NN B-NP and CC O the DT B-NP course NN I-NP of IN B-PP asthma NN B-NP . . O Besides RB B-ADVP COMMA COMMA O there EX B-NP was VBD B-VP also RB B-ADVP a DT B-NP linear JJ I-NP correlation NN I-NP between IN B-PP the DT B-NP number NN I-NP of IN B-PP GCR NN B-NP and CC O the DT B-NP age NN I-NP of IN B-PP the DT B-NP initial JJ I-NP attack NN I-NP of IN B-PP asthma NN B-NP . . O No DT B-NP difference NN I-NP in IN B-PP plasma NN B-NP cortisol NN I-NP level NN I-NP was VBD B-VP found VBN I-VP between IN B-PP asthmatics NNS B-NP and CC O healthy JJ B-NP subjects NNS I-NP . . O These DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR there EX B-NP is VBZ B-VP no DT B-NP primary JJ I-NP and CC I-NP general JJ I-NP impairment NN I-NP of IN B-PP glucocorticoid NN B-NP metabolism NN I-NP in IN B-PP the DT B-NP asthmatics NNS I-NP COMMA COMMA O but CC O the DT B-NP number NN I-NP of IN B-PP GCR NN B-NP in IN B-PP the DT B-NP asthmatics NNS I-NP is VBZ B-VP lower JJR B-ADJP than IN B-PP that DT B-NP in IN B-PP healthy JJ B-NP controls NNS I-NP . . O The DT B-NP decrease NN I-NP of IN B-PP the DT B-NP number NN I-NP of IN B-PP GCR NN B-NP in IN B-PP asthmatics NNS B-NP COMMA COMMA O we PRP B-NP think VBP B-VP COMMA COMMA O is VBZ B-VP related JJ B-ADJP to TO B-PP heredity NN B-NP and CC O repeated VBN B-NP attacks NNS I-NP of IN B-PP asthma NN B-NP . . O Alternate JJ B-NP immune JJ I-NP system NN I-NP targets VBZ I-NP for IN B-PP TCDD NN B-NP : : O lymphocyte NN B-NP stem NN I-NP cells NNS I-NP and CC O extrathymic JJ B-NP T-cell NN I-NP development NN I-NP . . O We PRP B-NP here RB B-ADVP summarize VBP B-VP evidence NN B-NP that IN B-SBAR thymic JJ B-NP atrophy NN I-NP induced VBN B-VP by IN B-PP 2COMMA3COMMA7COMMA8-tetrachlorodibenzo-p-dioxin NN B-NP ( ( O TCDD NN B-NP ) ) O can MD B-VP be VB I-VP mediated VBN I-VP COMMA COMMA O at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP COMMA COMMA O by IN B-PP damage NN B-NP to TO B-PP extrathymic JJ B-NP T-cell NN I-NP precursors NNS I-NP in IN B-PP bone NN B-NP marrow NN I-NP and CC O fetal JJ B-NP liver NN I-NP . . O This DT B-NP atrophy NN I-NP induction NN I-NP does VBZ B-VP not RB I-VP involve VB I-VP apoptotic JJ B-NP mechanisms NNS I-NP in IN B-PP thymocytes NNS B-NP affected VBN B-VP by IN B-PP the DT B-NP bcl-2 NN I-NP proto-oncogene NN I-NP . . O TCDD NN B-NP mediates VBZ B-VP atrophy NN B-NP induction NN I-NP through IN B-PP its PRP$ B-NP specific JJ I-NP receptor NN I-NP ( ( O the DT B-NP AhR NN I-NP ) ) O and CC B-PP not RB B-PP through IN I-PP effects NNS B-NP on IN B-PP the DT B-NP estrogen NN I-NP receptor NN I-NP . . O Both CC O TCDD NN B-NP and CC O estradiol NN B-NP induce VBP B-VP extrathymic JJ B-NP T-cell NN I-NP differentiation NN I-NP in IN B-PP the DT B-NP liver NN I-NP . . O These DT B-NP extrathymic JJ I-NP T-cell NN I-NP populations NNS I-NP include VBP B-VP cells NNS B-NP expressing VBG B-VP elevated JJ B-NP levels NNS I-NP of IN B-PP V NN B-NP beta NN I-NP T-cell NN I-NP receptors NNS I-NP that WDT B-NP are VBP B-VP normally RB I-VP deleted VBN I-VP in IN B-PP thymic JJ B-NP development NN I-NP . . O Alteration NN B-NP of IN B-PP structural JJ B-NP order NN I-NP of IN B-PP human JJ B-NP erythrocyte NN I-NP ghost NN I-NP membrane NN I-NP by IN B-PP glucocorticoids NNS B-NP and CC O the DT B-NP influence NN I-NP of IN B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP antagonist NN I-NP RU NN I-NP 486 CD I-NP . . O High-dose JJ B-NP pulse NN I-NP glucocorticoid NN I-NP therapy NN I-NP has VBZ B-VP been VBN I-VP used VBN I-VP successfully RB B-ADVP in IN B-PP the DT B-NP clinic NN I-NP in IN B-PP severe JJ B-NP pathological JJ I-NP conditions NNS I-NP for IN B-PP about RB B-NP 20 CD I-NP years NNS I-NP . . O The DT B-NP mode NN I-NP of IN B-PP glucocorticoid NN B-NP action NN I-NP after IN B-PP administration NN B-NP of IN B-PP such JJ B-NP megadoses NNS I-NP is VBZ B-VP inexplicable JJ B-ADJP up RP B-PP to TO I-PP now RB B-NP . . O It PRP B-NP is VBZ B-VP supposed VBN I-VP that IN B-SBAR some DT B-NP effects NNS I-NP may MD B-VP be VB I-VP due JJ B-PP to TO I-PP membrane NN B-NP alterations NNS I-NP . . O In IN B-PP the DT B-NP present JJ I-NP in-vitro FW I-NP experiments NNS I-NP the DT B-NP effect NN I-NP of IN B-PP dexamethasone NN B-NP COMMA COMMA O of IN B-PP further JJ B-NP glucocorticoids NNS I-NP COMMA COMMA B-PP and CC I-PP of IN B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP antagonist NN I-NP RU NN I-NP 486 CD I-NP COMMA COMMA O on IN B-PP structural JJ B-NP order NN I-NP of IN B-PP human JJ B-NP erythrocyte NN I-NP ghost NN I-NP membranes NNS I-NP was VBD B-VP investigated VBN I-VP by IN B-PP determining VBG B-VP the DT B-NP steady-state JJ I-NP fluorescence NN I-NP anisotropy NN I-NP of IN B-PP diphenylhexatriene NN B-NP ( ( O DPH NN B-NP ) ) O . . O Dexamethasone NN B-NP was VBD B-VP found VBN I-VP to TO I-VP induce VB I-VP a DT B-NP significant JJ I-NP decrease NN I-NP in IN B-PP membrane NN B-NP structural JJ I-NP order NN I-NP at IN B-PP concentrations NNS B-NP of IN B-PP about RB B-NP 10(-6) CD I-NP M NN I-NP in IN B-PP a DT B-NP concentration-dependent JJ I-NP manner NN I-NP . . O We PRP B-NP found VBD B-VP a DT B-NP correlation NN I-NP between IN B-PP the DT B-NP uptake NN I-NP of IN B-PP dexamethasone NN B-NP by IN B-PP the DT B-NP ghost NN I-NP membranes NNS I-NP and CC O the DT B-NP decrease NN I-NP in IN B-PP the DT B-NP structural JJ I-NP order NN I-NP . . O The DT B-NP other JJ I-NP glucocorticoids NNS I-NP tested VBN B-VP COMMA COMMA O methylprednisolone NN B-NP and CC O corticosterone NN B-NP COMMA COMMA O were VBD B-VP also RB B-ADVP effective JJ B-ADJP at IN B-PP concentrations NNS B-NP of IN B-PP 10(-5) CD B-NP M NN I-NP or CC I-NP greater JJR I-NP . . O We PRP B-NP observed VBD B-VP no DT B-NP change NN I-NP in IN B-PP membrane NN B-NP structural JJ I-NP order NN I-NP with IN B-PP RU NN B-NP 486 CD I-NP up IN B-PP to TO I-PP a DT B-NP concentration NN I-NP of IN B-PP 10(-4) CD B-NP M NN I-NP . . O However RB B-ADVP COMMA COMMA O simultaneous JJ B-NP incubation NN I-NP of IN B-PP RU NN B-NP 486 CD I-NP with IN B-PP dexamethasone NN B-NP caused VBD B-VP a DT B-NP distinct JJ I-NP interference NN I-NP of IN B-PP RU NN B-NP 486 CD I-NP with IN B-PP dexamethasone NN B-NP . . O Thus RB B-ADVP COMMA COMMA O the DT B-NP glucocorticoid-induced JJ I-NP membrane NN I-NP perturbation NN I-NP COMMA COMMA O the DT B-NP possibility NN I-NP to TO B-VP inhibit VB I-VP it PRP B-NP by IN B-PP RU NN B-NP 486 CD I-NP COMMA COMMA O and CC O the DT B-NP inactivity NN I-NP of IN B-PP the DT B-NP structurally RB I-NP related JJ I-NP progesterone NN I-NP COMMA COMMA O refer VBP B-VP to TO B-PP relatively RB B-NP specific JJ I-NP binding VBG I-NP sites NNS I-NP for IN B-PP the DT B-NP glucocorticoids NNS I-NP in IN B-PP the DT B-NP membrane NN I-NP of IN B-PP erythrocyte NN B-NP ghosts NNS I-NP . . O Cloning NN B-NP and CC O characterization NN B-NP of IN B-PP NF-ATc NN B-NP and CC O NF-ATp NN B-NP : : O the DT B-NP cytoplasmic JJ I-NP components NNS I-NP of IN B-PP NF-AT NN B-NP . . O Present JJ B-NP evidence NN I-NP indicates VBZ B-VP a DT B-NP pathway NN I-NP of IN B-PP signal NN B-NP transmission NN I-NP in IN B-PP T NN B-NP cells NNS I-NP that WDT B-NP is VBZ B-VP outlined VBN I-VP in IN B-PP figure NN B-NP 1 CD I-NP . . O The DT B-NP elevation NN I-NP in IN B-PP intracellular JJ B-NP calcium NN I-NP that WDT B-NP is VBZ B-VP induced VBN I-VP by IN B-PP interactions NNS B-NP at IN B-PP the DT B-NP antigen NN I-NP receptor NN I-NP leads VBZ B-VP to TO B-PP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP calcium-dependent JJ I-NP phosphatase NN I-NP calcineurin NN I-NP . . O This DT B-NP in IN B-PP turn NN B-NP leads VBZ B-VP to TO B-PP the DT B-NP nuclear JJ I-NP association NN I-NP of IN B-PP the DT B-NP cytosolic JJ I-NP component NN I-NP of IN B-PP NF-ATc NN B-NP . . O The DT B-NP activation NN I-NP of IN B-PP calcineurin NN B-NP and CC O the DT B-NP nuclear JJ I-NP import NN I-NP of IN B-PP NF-ATc NN B-NP can MD B-VP both DT I-VP be VB I-VP blocked VBN I-VP by IN B-PP cyclosporin NN B-NP A NN I-NP or CC O FK506 NN B-NP in IN B-PP complex NN B-NP with IN B-PP their PRP$ B-NP respective JJ I-NP immunophilins NNS I-NP . . O Once RB O in IN B-PP the DT B-NP nucleus NN I-NP COMMA COMMA O NF-ATc NN B-NP interacts VBZ B-VP with IN B-PP NF-ATn NN B-NP to TO B-VP form VB I-VP an DT B-NP active JJ I-NP transcriptional JJ I-NP complex NN I-NP . . O NF-ATn NN B-NP is VBZ B-VP a DT B-NP ubiquitous JJ I-NP protein NN I-NP COMMA COMMA O can MD B-VP be VB I-VP synthesized VBN I-VP in IN B-PP response NN I-PP to TO I-PP PMA NN B-NP COMMA COMMA O and CC O has VBZ B-VP many JJ B-NP similarities NNS I-NP to TO B-PP AP-1 NN B-NP . . O The DT B-NP mechanism NN I-NP by IN B-PP which WDT B-NP NF-ATc NN B-NP enters VBZ B-VP the DT B-NP nucleus NN I-NP is VBZ B-VP unknown JJ B-ADJP COMMA COMMA O and CC O although IN B-SBAR it PRP B-NP appears VBZ B-VP to TO I-VP require VB I-VP calcineurin NN B-NP COMMA COMMA O NF-ATc NN B-NP has VBZ B-VP not RB I-VP yet RB I-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP an DT B-NP in FW I-NP vivo FW I-NP substrate NN I-NP of IN B-PP calcineurin NN B-NP . . O Alternative JJ B-NP mechanisms NNS I-NP include VBP B-VP the DT B-NP possibility NN I-NP that IN B-SBAR NF-ATc NN B-NP operates VBZ B-VP on IN B-PP some DT B-NP cytoplasmic JJ I-NP anchor NN I-NP or CC O that IN B-SBAR other JJ B-NP proteins NNS I-NP that WDT B-NP are VBP B-VP controlled VBN I-VP by IN B-PP calcineurin NN B-NP carry VBP B-VP out RP B-PRT the DT B-NP nuclear JJ I-NP import NN I-NP of IN B-PP NF-ATc NN B-NP . . O Although IN B-SBAR NF-ATp NN B-NP copurifies VBZ B-VP with IN B-PP NF-ATc NN B-NP COMMA COMMA O there EX B-NP is VBZ B-VP as RB B-ADVP yet RB I-ADVP no DT B-NP understanding NN I-NP of IN B-PP how WRB B-ADVP NF-ATp NN B-NP is VBZ B-VP functioning VBG I-VP in FW B-ADVP vivo FW I-ADVP . . O Now RB B-ADVP that IN B-SBAR these DT B-NP proteins NNS I-NP are VBP B-VP purified VBN I-VP and CC O cloned VBN B-VP COMMA COMMA O the DT B-NP major JJ I-NP goals NNS I-NP will MD B-VP be VB I-VP to TO B-VP understand VB I-VP their PRP$ B-NP role NN I-NP and CC O the DT B-NP roles NNS I-NP of IN B-PP other JJ B-NP family NN I-NP members NNS I-NP in IN B-PP thymic JJ B-NP development NN I-NP . . O Changes NNS B-NP in IN B-PP triiodothyronine NN B-NP ( ( O T3 NN B-NP ) ) O mononuclear JJ B-NP leukocyte NN I-NP receptor NN I-NP kinetics NNS I-NP after IN B-PP T3 NN B-NP administration NN I-NP and CC O multiple JJ B-NP cold-air JJ I-NP exposures NNS I-NP . . O Repeated VBN B-NP cold-air JJ I-NP exposures NNS I-NP increase VBP B-VP human JJ O triiodothyronine NN B-NP ( ( O T3 CD B-NP ) ) O plasma NN B-NP clearance NN I-NP rates NNS I-NP . . O To TO B-VP study VB I-VP the DT B-NP response NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP T3 NN I-NP receptor NN I-NP ( ( O NT3R NN B-NP ) ) O in IN B-PP this DT B-NP condition NN I-NP COMMA COMMA O binding VBG B-NP characteristics NNS I-NP were VBD B-VP analyzed VBN I-VP in IN B-PP human JJ B-NP mononuclear JJ B-NP leukocytes NNS I-NP ( ( O MNL NN B-NP ) ) O . . O In IN B-PP addition NN B-NP COMMA COMMA O we PRP B-NP supplemented VBD B-VP one CD B-NP group NN I-NP of IN B-PP individuals NNS B-NP with IN B-PP a DT B-NP daily RB I-NP oral JJ I-NP replacement NN I-NP dose NN I-NP of IN B-PP T3 NN B-NP to TO B-VP isolate VB I-VP the DT B-NP influence NN I-NP of IN B-PP serum NN B-NP thyroxine NN I-NP ( ( O T4 NN B-NP ) ) O and CC O thyrotropin NN B-NP ( ( O TSH NN B-NP ) ) O levels NNS B-NP on IN B-PP receptor NN B-NP kinetics NNS I-NP . . O The DT B-NP subjects NNS I-NP were VBD B-VP exposed VBN I-VP to TO B-PP cold JJ B-NP air NN I-NP ( ( O 4 CD B-NP degrees NNS I-NP C NN I-NP ) ) O twice\/d RB B-ADVP COMMA COMMA O 30 CD B-NP min\/exposure NN I-NP COMMA COMMA O for IN B-PP a DT B-NP total NN I-NP of IN B-PP 80 CD B-NP exposures NNS I-NP . . O The DT B-NP T3- JJ I-NP subjects NNS I-NP received VBD B-VP placebo NN B-NP { ( O n NN B-NP = JJ B-VP 8 CD B-NP } ) O and CC O the DT B-NP T3+ JJ I-NP subjects NNS I-NP received VBD B-VP T3 CD B-NP ( ( O 30 CD B-NP micrograms\/d NN I-NP ) ) O { ( O n NN B-NP = JJ B-VP 8 CD B-NP } ) O in IN B-PP a DT B-NP double-blind JJ I-NP fashion NN I-NP . . O Mononuclear JJ B-NP leukocytes NNS I-NP were VBD B-VP isolated VBN I-VP from IN B-PP peripheral JJ B-NP blood NN I-NP before IN B-SBAR the DT B-NP cold JJ I-NP exposure NN I-NP and CC O drug NN B-NP regimen NNS I-NP began VBD B-VP COMMA COMMA O and CC O then RB O after IN B-PP every DT B-NP 20 CD I-NP exposures NNS I-NP . . O The DT B-NP dissociation NN B-NP constant NN I-NP ( ( O Kd NN B-NP ) ) O and CC O maximum NN B-NP binding NN I-NP capacity NN I-NP ( ( O MBC NN B-NP ) ) O of IN B-PP the DT B-NP NT3R NN I-NP values NNS I-NP were VBD B-VP log NN I-VP transformed VBN I-VP to TO B-VP minimize VB I-VP between-subject JJ B-NP variability NN I-NP . . O In IN B-PP the DT B-NP T3+ JJ I-NP group NN I-NP COMMA COMMA O serum NN B-NP total VBP I-NP thyroxine NN I-NP ( ( O TT4 NN B-NP ) ) O COMMA COMMA O free JJ B-NP T4 NN I-NP ( ( O FT4 NN B-NP ) ) O COMMA COMMA O and CC O TSH NN B-NP were VBD B-VP approx RB B-NP 50 CD I-NP % NN I-NP lower JJR B-ADJP than IN B-PP both CC O basal JJ B-NP and CC O T3-values NNS B-NP . . O The DT B-NP log10Kd NN I-NP increased VBD B-VP 0.304 CD B-NP +\/- CC I-NP 0.139 CD I-NP ( ( O p NN B-NP < JJR B-NP 0.04 CD I-NP ) ) O and CC O the DT B-NP log10MBC NN I-NP increased VBD B-VP 0.49 CD B-NP +\/- CC I-NP 0.10 CD I-NP ( ( O p NN B-NP < JJR B-NP 0.001 CD I-NP ) ) O in IN B-PP the DT B-NP T3+ JJ I-NP subjects NNS I-NP compared VBN B-PP to TO B-PP baseline NN B-NP . . O This DT B-NP change NN I-NP in IN B-PP MBC NN B-NP represents VBZ B-VP a DT B-NP 311 CD I-NP % NN I-NP increase NN I-NP in IN B-PP the DT B-NP MBC NN I-NP over IN B-PP baseline NN B-NP and CC O a DT B-NP fivefold JJ I-NP increase NN I-NP over IN B-PP placebo-treated JJ B-NP subjects NNS I-NP . . O The DT B-NP T3- JJ I-NP group NN I-NP showed VBD B-VP no DT B-NP change NN I-NP in IN B-PP MBC NN B-NP over IN B-PP the DT B-NP study NN I-NP . . O These DT B-NP results NNS I-NP describe VBP B-VP for IN B-PP the DT B-NP first JJ I-NP time NN I-NP the DT B-NP rapid JJ I-NP modulation NN I-NP of IN B-PP the DT B-NP NT3R NN I-NP in IN B-PP response NN I-PP to TO I-PP the DT B-NP combined JJ I-NP influence NN I-NP of IN B-PP cold JJ B-NP exposure NN I-NP and CC O reduced VBN B-NP circulating VBG I-NP T4 NN B-NP and CC O TSH NN B-NP . . O BCL-6 NN B-NP and CC O the DT B-NP molecular JJ I-NP pathogenesis NN I-NP of IN B-PP B-cell NN B-NP lymphoma NN I-NP . . O The DT B-NP results NNS I-NP presented VBN B-VP identify VBP B-VP the DT B-NP first JJ I-NP genetic JJ I-NP lesion NN I-NP associated VBN B-VP with IN B-PP DLCL NN B-NP COMMA COMMA O the DT B-NP most RBS I-NP clinically RB I-NP relevant JJ I-NP form NN I-NP of IN B-PP NHL NN B-NP . . O Although IN B-SBAR no DT B-NP proof NN I-NP yet RB B-ADVP exists VBZ B-VP of IN B-PP a DT B-NP role NN I-NP for IN B-PP these DT B-NP lesions NNS I-NP in IN B-PP DLCL NN B-NP pathogenesis NN I-NP COMMA COMMA O the DT B-NP feature NN I-NP of IN B-PP the DT B-NP BCL-6 NN I-NP gene NN I-NP product NN I-NP COMMA COMMA O its PRP$ B-NP specific JJ I-NP pattern NN I-NP of IN B-PP expression NN B-NP in IN B-PP B NN B-NP cells NNS I-NP COMMA COMMA O and CC O the DT B-NP clustering NN I-NP of IN B-PP lesions NNS B-NP disrupting VBG B-VP its PRP$ B-NP regulatory JJ I-NP domain NN I-NP strongly RB B-ADVP suggest VBP B-VP that IN B-SBAR deregulation NN B-NP of IN B-PP BCL-6 NN B-NP expression NN I-NP may MD B-VP contribute VB I-VP to TO B-PP DLCL NN B-NP development NN I-NP . . O A DT B-NP more RBR I-NP precise JJ I-NP definition NN I-NP of IN B-PP the DT B-NP role NN I-NP of IN B-PP BCL-6 NN B-NP in IN B-PP normal JJ B-NP and CC I-NP neoplastic JJ I-NP B-cell NN I-NP development NN I-NP is VBZ B-VP the DT B-NP goal NN I-NP of IN B-PP ongoing JJ B-NP study NN I-NP of IN B-PP transgenic JJ B-NP mice NNS I-NP engineered VBN B-VP either CC O to TO B-VP express VB I-VP BCL-6 NN B-NP under IN B-PP heterologous JJ B-NP promoters NNS I-NP or CC O lacking VBG B-VP BCL-6 NN B-NP function NN I-NP due JJ B-PP to TO I-PP targeted VBN B-NP deletions NNS I-NP . . O In IN B-PP addition NN I-PP to TO I-PP contributing VBG B-VP to TO B-PP the DT B-NP understanding NN I-NP of IN B-PP DLCL NN B-NP pathogenesis NN I-NP COMMA COMMA O the DT B-NP identification NN I-NP of IN B-PP BCL-6 NN B-NP lesions NNS I-NP may MD B-VP have VB I-VP relevant JJ B-NP clinical JJ I-NP implications NNS I-NP . . O DLCL NN B-NP represent VBP B-VP a DT B-NP heterogeneous JJ I-NP group NN I-NP of IN B-PP neoplasms NNS B-NP which WDT B-NP are VBP B-VP treated VBN I-VP homogeneously RB B-ADVP despite IN B-PP the DT B-NP fact NN I-NP that IN B-SBAR only RB B-NP 50 CD I-NP % NN I-NP of IN B-PP patients NNS B-NP experience VBP B-VP long-term JJ B-NP disease-free JJ I-NP survival NN I-NP ( ( O Schneider NNP B-NP et FW B-ADVP al. FW I-ADVP 1990 CD B-NP ) ) O . . O The DT B-NP fact NN I-NP that IN B-SBAR BCL-6 NN B-NP rearrangements NNS I-NP identify VBP B-VP biologically RB B-ADVP and CC B-ADVP clinically RB B-ADVP distinct JJ B-NP subsets NNS I-NP of IN B-PP DLCL NN B-NP suggests VBZ B-VP that IN B-SBAR these DT B-NP lesions NNS I-NP may MD B-VP be VB I-VP useful JJ B-ADJP as IN B-PP markers NNS B-NP in IN B-PP selection NN B-NP of IN B-PP differential JJ B-NP therapeutic JJ I-NP strategies NNS I-NP based VBN B-PP on IN B-PP different JJ B-NP risk NN I-NP groups NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP BCL-6 NN I-NP rearrangements NNS I-NP can MD B-VP be VB I-VP used VBN I-VP to TO B-VP identify VB I-VP and CC O monitor VB B-VP the DT B-NP malignant JJ I-NP clone NN I-NP with IN B-PP sensitive JJ B-NP PCR-based JJ I-NP techniques NNS I-NP . . O Since IN B-SBAR clinical JJ B-NP remission NN I-NP has VBZ B-VP been VBN I-VP observed VBN I-VP in IN B-PP a DT B-NP significant JJ I-NP fraction NN I-NP of IN B-PP DLCL NN B-NP cases NNS I-NP COMMA COMMA O these DT B-NP markers NNS I-NP may MD B-VP serve VB I-VP as IN B-PP critical JJ B-NP tools NNS I-NP for IN B-PP sensitive JJ B-NP monitoring NN I-NP of IN B-PP minimal JJ B-NP residual JJ I-NP disease NN I-NP and CC O early JJ B-NP diagnosis NN I-NP of IN B-PP relapse NN B-NP ( ( O Gribben NNP B-NP et FW B-ADVP al. FW I-ADVP 1993 CD B-NP ) ) O . . O Selective JJ B-NP effects NNS I-NP of IN B-PP DNA NN B-NP damaging NN I-NP agents NNS I-NP on IN B-PP HIV NN B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP activation NN I-NP and CC O virus NN B-NP replication NN I-NP in FW B-ADVP vitro FW I-ADVP . . O Much JJ B-NP attention NN I-NP has VBZ B-VP recently RB I-VP focused VBN I-VP on IN B-PP the DT B-NP observation NN I-NP that IN B-SBAR UV NN B-NP light NN I-NP can MD B-VP activate VB I-VP the DT B-NP long JJ I-NP terminal JJ I-NP repeat NN I-NP ( ( O LTR NN B-NP ) ) O of IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP ( ( O HIV NN B-NP ) ) O . . O Although IN B-SBAR the DT B-NP mechanism NN I-NP of IN B-PP LTR NN B-NP activation NN I-NP remains VBZ B-VP obscure JJ B-ADJP COMMA COMMA O several JJ B-NP lines NNS I-NP of IN B-PP investigation NN B-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR it PRP B-NP is VBZ B-VP a DT B-NP result NN I-NP of IN B-PP activation NN B-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP ( ( I-NP s NNS I-NP ) ) O following VBG B-PP signaling NN B-NP events NNS I-NP related JJ B-ADJP to TO B-PP generalized VBN B-NP DNA NN I-NP damage NN I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP present VBP B-VP data NNS B-NP demonstrating NN B-VP that IN B-SBAR HIV NN B-NP LTR NN I-NP activation NN I-NP is VBZ B-VP not RB B-NP a DT B-NP general JJ I-NP consequence NN I-NP of IN B-PP cellular JJ B-NP DNA NN I-NP damage NN I-NP COMMA COMMA O but CC B-CONJP rather RB I-CONJP a DT B-NP process NN I-NP unique JJ B-ADJP to TO B-PP specific JJ B-NP genotoxic JJ I-NP stimuli NNS I-NP COMMA COMMA O and CC O that IN B-SBAR it PRP B-NP does VBZ B-VP not RB I-VP necessarily RB I-VP depend VB I-VP on IN B-PP activation NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR several JJ B-NP of IN B-PP these DT B-NP agents NNS I-NP can MD B-VP significantly RB I-VP increase VB I-VP HIV NN B-NP replication NN I-NP and CC O accelerate VB B-VP CD4-positive JJ B-NP lymphocyte NN I-NP cytotoxicity NN I-NP in FW B-ADVP vitro FW I-ADVP . . O These DT B-NP findings NNS I-NP COMMA COMMA O therefore RB B-ADVP COMMA COMMA O could MD B-VP have VB I-VP clinical JJ B-NP significance NN I-NP to TO B-PP AIDS NN B-NP patients NNS I-NP with IN B-PP malignancies NNS B-NP who WP B-NP are VBP B-VP undergoing VBG I-VP radiotherapy NN B-NP and CC O chemotherapy NN B-NP . . O Characterization NN B-NP and CC O purification NN B-NP of IN B-PP a DT B-NP protein NN I-NP kinase NN I-NP C NN I-NP substrate NN I-NP in IN B-PP human JJ B-NP B NN I-NP cells NNS I-NP . . O Identification NN B-NP as IN B-PP lymphocyte-specific JJ B-NP protein NN I-NP 1 CD I-NP ( ( O LSP1 NN B-NP ) ) O . . O Incubation NN B-NP of IN B-PP B-chronic JJ B-NP lymphocytic JJ I-NP leukemia NN I-NP ( ( O B-CLL NN B-NP ) ) O cells NNS B-NP with IN B-PP phorbol NN B-NP esters NNS I-NP resulted VBD B-VP in IN B-PP the DT B-NP phosphorylation NN I-NP of IN B-PP two CD B-NP major JJ I-NP PKC NN I-NP substrates NNS I-NP COMMA COMMA O MARCKS NN B-NP ( ( O myristoylated VBN B-NP COMMA COMMA I-NP alanine-rich JJ I-NP C NN I-NP kinase NN I-NP substrate NN I-NP ) ) O and CC O MRP NN B-NP ( ( O MARCKS-related JJ B-NP protein NN I-NP ) ) O COMMA COMMA O and CC B-PP of IN B-PP a DT B-NP third JJ I-NP protein NN I-NP COMMA COMMA O with IN B-PP an DT B-NP apparent JJ I-NP m.w. NN I-NP of IN B-PP 60COMMA000 CD B-NP that WDT B-NP was VBD B-VP the DT B-NP most RBS I-NP prominent JJ I-NP protein NN I-NP kinase NN I-NP C NN I-NP substrate NN I-NP in IN B-PP these DT B-NP cells NNS I-NP . . O p60 NN B-NP phosphorylation NN I-NP was VBD B-VP time NN B-NP and CC O PMA NN B-NP dose NN I-NP dependent JJ B-ADJP COMMA COMMA O and CC O was VBD B-VP induced VBN I-VP by IN B-PP cell-permeable JJ B-NP diacylglycerol NN I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP by IN I-PP inactive JJ B-NP phorbol NN I-NP esters NNS I-NP . . O Two-dimensional JJ B-NP electrophoretic JJ I-NP analysis NN I-NP of IN B-PP the DT B-NP protein NN I-NP phosphorylation NN I-NP pattern NN I-NP from IN B-PP the DT B-NP B NN I-NP cell NN I-NP line NN I-NP CESS NN I-NP demonstrated VBD B-VP the DT B-NP identity NN I-NP between IN B-PP the DT B-NP p60 NN I-NP protein NN I-NP expressed VBN B-VP in IN B-PP this DT B-NP cell NN I-NP line NN I-NP and CC O that DT B-NP expressed VBN B-VP in IN B-PP B-CLL NN B-NP cells NNS I-NP . . O p60 NN B-NP was VBD B-VP purified VBN I-VP from IN B-PP CESS NN B-NP cells NNS I-NP and CC O peptide NN B-NP microsequencing NN I-NP of IN B-PP this DT B-NP protein NN I-NP revealed VBD B-VP that IN B-SBAR it PRP B-NP was VBD B-VP lymphocyte-specific JJ B-NP protein NN I-NP 1 CD I-NP ( ( O LSP1 NN B-NP ) ) O COMMA COMMA O that WDT B-NP is VBZ B-VP here RB I-VP characterized VBN I-VP as IN B-PP the DT B-NP most RBS I-NP prominent JJ I-NP protein NN I-NP kinase NN I-NP C NN I-NP substrate JJ I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Differential JJ B-NP regulation NN I-NP of IN B-PP IL-6 NN B-NP gene NN I-NP transcription NN B-NP and CC O expression NN B-NP by IN B-PP IL-4 NN B-NP and CC O IL-10 NN B-NP in IN B-PP human JJ B-NP monocytic JJ I-NP cell NN I-NP lines NNS I-NP . . O IL-4 NN B-NP and CC O IL-10 NN B-NP inhibit VBP B-VP the DT B-NP cytokine NN B-NP production NN I-NP and CC O mRNA NN B-NP expression NN I-NP by IN B-PP monocytes\/macrophages NNS B-NP . . O To TO B-VP investigate VB I-VP the DT B-NP molecular JJ I-NP mechanism NN I-NP of IN B-PP the DT B-NP inhibitory JJ I-NP effect NN I-NP on IN B-PP transcriptional JJ B-NP or CC I-NP post-transcriptional JJ I-NP regulation NN I-NP of IN B-PP IL-6 NN B-NP gene NN I-NP expression NN I-NP by IN B-PP IL-4 NN B-NP and CC O IL-10 NN B-NP COMMA COMMA O we PRP B-NP studied VBD B-VP IL-6 NN B-NP production NN I-NP COMMA COMMA O expression NN B-NP level NN I-NP of IN B-PP IL-6 NN B-NP mRNA NN I-NP COMMA COMMA O IL-6 NN B-NP promoter NN I-NP activity NN I-NP COMMA COMMA O transcriptional JJ B-NP activity NN I-NP of IN B-PP NF-kappaB NN B-NP and CC O NF-IL-6 NN B-NP COMMA COMMA O and CC O IL-6 NN B-NP mRNA NN I-NP stability NN I-NP in IN B-PP human JJ B-NP monocytic JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O THP-1 NN B-NP and CC O U937 NN B-NP COMMA COMMA O stimulated VBN B-VP by IN B-PP PMA NN B-NP and CC O LPS NN B-NP in IN B-PP the DT B-NP absence NN I-NP or CC O the DT B-NP presence NN I-NP of IN B-PP IL-4 NN B-NP or CC O IL-10 NN B-NP . . O Both CC O IL-4 NN B-NP and CC O IL-10 NN B-NP were VBD B-VP seen VBN I-VP to TO I-VP inhibit VB I-VP IL-6 NN B-NP production NN I-NP and CC O the DT B-NP expression NN I-NP of IN B-PP IL-6 NN B-NP mRNA NN I-NP in IN B-PP both DT B-NP monocytic JJ I-NP cell NN I-NP lines NNS I-NP studied VBN B-VP . . O In IN B-PP chloramphenicol NN B-NP acetyltransferase NN I-NP assays NNS I-NP COMMA COMMA O utilizing VBG B-VP the DT B-NP transient JJ I-NP transfection NN I-NP of IN B-PP a DT B-NP chloramphenicol NN I-NP acetyltransferase NN I-NP reporter NN I-NP plasmid NN I-NP containing VBG B-VP the DT B-NP IL-6 NN I-NP gene NN I-NP promoter NN I-NP COMMA COMMA O IL-4 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP IL-10 NN B-NP COMMA COMMA O suppressed VBD B-VP the DT B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP the DT B-NP IL-6 NN I-NP gene NN I-NP promoter NN I-NP stimulated VBN B-VP by IN B-PP PMA NN B-NP and CC O LPS NN B-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP showed VBD B-VP that IN B-SBAR IL-4 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP IL-10 NN B-NP COMMA COMMA O inhibited VBD B-VP nuclear JJ B-NP NF-kappaB NN I-NP activity NN I-NP COMMA COMMA O and CC O that IN B-SBAR IL-4 NN B-NP and CC O IL-10 NN B-NP did VBD B-VP not RB I-VP affect VB I-VP NF-IL-6 NN B-NP activity NN I-NP . . O On IN B-PP the DT B-NP other JJ I-NP hand NN I-NP COMMA COMMA O IL-10 NN B-NP enhanced VBD B-VP the DT B-NP degradation NN I-NP of IN B-PP IL-6 NN B-NP mRNA NN I-NP in IN B-PP a DT B-NP mRNA NN I-NP stability NN I-NP assay NN I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR IL-4 NN B-NP may MD B-VP inhibit VB I-VP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP IL-6 NN I-NP gene NN I-NP by IN B-PP affecting VBG B-VP NF-kappaB NN B-NP binding NN I-NP activity NN I-NP COMMA COMMA O while IN B-SBAR IL-10 NN B-NP may MD B-VP inhibit VB I-VP the DT B-NP IL-6 NN I-NP mRNA NN I-NP levels NNS I-NP post-transcriptionally RB B-ADVP COMMA COMMA O without IN B-PP suppressing VBG B-VP promoter NN B-NP activity NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP conclude VBP B-VP that IN B-SBAR IL-4 NN B-NP and CC O IL-10 NN B-NP inhibit VBP B-VP IL-6 NN B-NP production NN I-NP by IN B-PP different JJ B-NP mechanisms NNS I-NP in IN B-PP human JJ B-NP monocytic JJ I-NP cell NN I-NP lines NNS I-NP . . O IL-13 NN B-NP induces VBZ B-VP phosphorylation NN B-NP and CC O activation NN B-NP of IN B-PP JAK2 NN B-NP Janus NN I-NP kinase NN I-NP in IN B-PP human JJ B-NP colon NN I-NP carcinoma NN I-NP cell NN I-NP lines NNS I-NP : : O similarities NNS B-NP between IN B-PP IL-4 NN B-NP and CC O IL-13 NN B-NP signaling NN B-NP . . O We PRP B-NP have VBP B-VP recently RB I-VP reported VBN I-VP that IN B-SBAR IL-13R NN B-NP may MD B-VP share VB I-VP a DT B-NP component NN I-NP with IN B-PP IL-4R NN B-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR both CC O IL-4 NN B-NP and CC O IL-13 NN B-NP share VBP B-VP signaling NN B-NP events NNS I-NP in IN B-PP human JJ B-NP colon NN I-NP carcinoma NN I-NP cell NN I-NP lines NNS I-NP ( ( O HT-29 NN B-NP and CC O WiDr NN B-NP ) ) O . . O IL-13 NN B-NP caused VBD B-VP rapid JJ B-NP phosphorylation NN I-NP of IN B-PP the DT B-NP three CD I-NP out IN I-NP of IN I-NP four CD I-NP members NNS I-NP of IN B-PP the DT B-NP known JJ I-NP Janus NN B-NP family NN I-NP of IN B-PP kinases NNS B-NP ( ( O JAKs NNS B-NP ) ) O . . O We PRP B-NP show VBP B-VP that IN B-SBAR JAK2 NN B-NP kinase NN I-NP is VBZ B-VP rapidly RB I-VP phosphorylated VBN I-VP and CC O activated VBN B-VP in IN B-PP response NN I-PP to TO I-PP IL-13 NN B-NP . . O Within IN B-PP 1 CD B-NP min NN I-NP of IN B-PP activation NN B-NP COMMA COMMA O JAK2 NN B-NP was VBD B-VP phosphorylated VBN I-VP COMMA COMMA O and CC O peaked VBD B-VP in IN B-PP 10 CD B-NP min NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O IL-13 NN B-NP phosphorylated VBD B-VP insulin NN B-NP response NN I-NP substrate-1 NN I-NP COMMA COMMA O IL-4R NN B-NP p140 NN I-NP COMMA COMMA O JAK1 NN B-NP COMMA COMMA O and CC O Tyk2 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP JAK3 NN B-NP kinase NN I-NP . . O IL-4 NN B-NP also RB B-ADVP stimulated VBD B-VP all DT B-NP three CD I-NP kinases NNS B-NP and CC O substrates NNS B-NP COMMA COMMA O but CC O unlike IN B-PP in IN B-PP immune JJ B-NP cells NNS I-NP COMMA COMMA O IL-4 NN B-NP did VBD B-VP not RB I-VP involve VB I-VP JAK3 NN B-NP activation NN I-NP for IN B-PP its PRP$ B-NP signaling NN I-NP in IN B-PP colon NN B-NP cancer NN I-NP cell NN I-NP lines NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O JAK2 NN B-NP associated VBN B-VP with IN B-PP the DT B-NP IL-4R NN I-NP p140 NN I-NP before IN B-PP and CC B-PP after IN B-PP stimulation NN B-NP with IN B-PP IL-13 NN B-NP . . O Both CC O IL-13 NN B-NP and CC O IL-4 NN B-NP induced VBD B-VP phosphorylation NN B-NP of IN B-PP IL-4 NN B-NP STAT NN I-NP ( ( O STAT6 NN B-NP ) ) O but CC B-CONJP not RB I-CONJP STAT1 NN B-NP COMMA COMMA O STAT3 NN B-NP COMMA COMMA O or CC O STAT5 NN B-NP . . O 125I-IL-13 NN B-NP did VBD B-VP not RB I-VP bind VB I-VP to TO B-PP colon NN B-NP cancer NN I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O but CC O unlabeled JJ B-NP IL-13 NN I-NP competed VBD B-VP for IN B-PP the DT B-NP binding NN I-NP of IN B-PP 125I-IL-4 NN B-NP . . O Our PRP$ B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR IL-13 NN B-NP utilizes VBZ B-VP IL-4R NN B-NP and CC O its PRP$ B-NP signaling NN I-NP pathway NN I-NP COMMA COMMA O and CC O JAK2 NN B-NP may MD B-VP play VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP function NN I-NP of IN B-PP IL-4R NN B-NP and CC O IL-13R NN B-NP in IN B-PP colon NN B-NP cancer NN I-NP cells NNS I-NP . . O Effects NNS B-NP of IN B-PP interleukin-10 NN B-NP on IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP mononuclear JJ I-NP cell NN I-NP responses NNS I-NP to TO B-PP Cryptococcus NN B-NP neoformans NNS I-NP COMMA COMMA O Candida NN B-NP albicans NNS I-NP COMMA COMMA O and CC O lipopolysaccharide NN B-NP . . O Deactivation NN B-NP of IN B-PP mononuclear JJ B-NP phagocytes NNS I-NP is VBZ B-VP critical JJ B-ADJP to TO B-VP limit VB I-VP the DT B-NP inflammatory JJ I-NP response NN I-NP but CC O can MD B-VP be VB I-VP detrimental JJ B-ADJP in IN B-PP the DT B-NP face NN I-NP of IN B-PP progressive JJ B-NP infection NN I-NP . . O We PRP B-NP compared VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP the DT B-NP deactivating VBG I-NP cytokine NN I-NP interleukin NN B-NP 10 CD I-NP ( ( O IL-10 NN B-NP ) ) O on IN B-PP human JJ O peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cell NN I-NP ( ( O PBMC NN B-NP ) ) O responses NNS B-NP to TO B-PP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O COMMA COMMA O Cryptococcus NN B-NP neoformans NNS I-NP COMMA COMMA O and CC O Candida NN B-NP albicans NNS I-NP . . O IL-10 NN B-NP effected VBD B-VP dose-dependent JJ B-NP inhibition NN I-NP of IN B-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O release NN B-NP in IN B-PP PBMC NN B-NP stimulated VBN B-VP by IN B-PP LPS NN B-NP and CC O C. FW B-NP neoformans FW I-NP COMMA COMMA O with IN B-SBAR significant JJ B-NP inhibition NN I-NP seen VBN B-VP with IN B-PP 0.1 CD B-NP U\/ml NN I-NP and CC O greater JJR B-NP than IN I-NP 90 CD I-NP % NN I-NP inhibition NN B-NP noted VBN B-VP with IN B-PP 10 CD B-NP U\/ml NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O even RB B-PP at IN I-PP doses NNS B-NP as RB B-NP high JJ I-NP as IN I-NP 100 CD I-NP U\/ml NN I-NP COMMA COMMA O IL-10 NN B-NP inhibited VBD B-VP TNF-alpha NN B-NP release NN I-NP in IN B-PP response NN I-PP to TO I-PP C. FW B-NP albicans FW I-NP by IN B-NP only RB B-NP 50 CD I-NP % NN I-NP . . O IL-10 NN B-NP profoundly RB B-ADVP inhibited VBD B-VP release NN B-NP of IN B-PP IL-1beta NN B-NP from IN B-PP PBMC NN B-NP stimulated VBN B-VP by IN B-PP all DT B-NP three CD I-NP stimuli NNS I-NP . . O TNF-alpha NN B-NP mRNA NN I-NP and CC I-NP release NN I-NP was VBD B-VP inhibited VBN I-VP even RB B-SBAR if IN I-SBAR IL-10 NN B-NP was VBD B-VP added VBN I-VP up RP B-NP to TO I-NP 8 CD I-NP h NN I-NP after IN B-PP cryptococcal JJ B-NP stimulation NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O inhibition NN B-NP of IN B-PP IL-1 NN B-NP beta NN I-NP mRNA NN I-NP was VBD B-VP of IN B-PP lesser JJR B-NP magnitude NN I-NP and CC O occurred VBD B-VP only RB B-ADVP when WRB I-ADVP IL-10 NN B-NP was VBD B-VP added VBN I-VP within IN B-PP 2 CD B-NP h NN I-NP of IN B-PP cryptococcal JJ B-NP stimulation NN I-NP . . O IL-10 NN B-NP inhibited VBD B-VP translocation NN B-NP of IN B-PP NF-kappaB NN B-NP in IN B-PP response NN I-PP to TO I-PP LPS NN B-NP but CC B-CONJP not RB I-CONJP the DT B-NP fungal JJ I-NP stimuli NNS I-NP . . O All DT B-NP three CD I-NP stimuli NNS I-NP induced VBD B-VP IL-10 NN B-NP production NN I-NP in IN B-PP PBMC NN B-NP COMMA COMMA O although IN B-SBAR over IN B-NP 10-fold RB I-NP less JJR I-NP IL-10 NN I-NP was VBD B-VP released VBN I-VP in IN B-PP response NN I-PP to TO I-PP C. FW B-NP neoformans FW I-NP compared VBN B-PP with IN B-PP LPS NN B-NP and CC O C. NN B-NP albicans NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O while IN B-SBAR IL-10 NN B-NP has VBZ B-VP deactivating VBG B-NP effects NNS I-NP on IN B-PP PBMC NN B-NP responses NNS I-NP to TO B-PP all DT B-NP three CD I-NP stimuli NNS I-NP COMMA COMMA O disparate JJ O stimulus- NN B-NP and CC O response-specific JJ B-ADJP patterns NNS B-NP of IN B-PP deactivation NN B-NP are VBP B-VP seen VBN I-VP . . O Inhibition NN B-NP by IN B-PP IL-10 NN B-NP of IN B-PP proinflammatory JJ B-NP cytokine NN I-NP release NN I-NP appears VBZ B-VP to TO I-VP occur VB I-VP at IN B-PP the DT B-NP level NN I-NP of IN B-PP gene NN B-NP transcription NN I-NP for IN B-PP TNF-alpha NN B-NP and CC O both CC O transcriptionally RB B-ADVP and CC B-ADVP posttranscriptionally RB B-ADVP for IN B-PP IL-1beta NN B-NP . . O Activation NN B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP in IN B-PP a DT B-NP cyclosporin NN I-NP A-resistant JJ I-NP pathway NN I-NP . . O The DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP of IN B-PP the DT B-NP immunosuppressive JJ I-NP drug NN I-NP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O is VBZ B-VP the DT B-NP inactivation NN I-NP of IN B-PP the DT B-NP Ca2+\/calmodulin-dependent JJ I-NP serine-threonine NN I-NP phosphatase NN I-NP calcineurin NN I-NP by IN B-PP the DT B-NP drug-immunophilin JJ I-NP complex NN I-NP . . O Inactive JJ B-NP calcineurin NN I-NP is VBZ B-VP unable JJ B-ADJP to TO B-VP activate VB I-VP the DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NFAT NN B-NP ) ) O COMMA COMMA O a DT B-NP transcription NN I-NP factor NN I-NP required VBN B-VP for IN B-PP expression NN B-NP of IN B-PP the DT O interleukin NN B-NP 2 CD I-NP ( ( O IL-2 NN B-NP ) ) O gene NN B-NP . . O IL-2 NN B-NP production NN I-NP by IN B-PP CsA-treated JJ B-NP cells NNS I-NP is VBZ B-VP therefore RB I-VP dramatically RB I-VP reduced VBN I-VP . . O We PRP B-NP demonstrate VBP B-VP here RB B-ADVP COMMA COMMA O however RB B-ADVP COMMA COMMA O that IN B-SBAR NFAT NN B-NP can MD B-VP be VB I-VP activated VBN I-VP COMMA COMMA O and CC O significant JJ B-NP levels NNS I-NP of IN B-PP IL-2 NN B-NP can MD B-VP be VB I-VP produced VBN I-VP by IN B-PP the DT B-NP CsA-resistant JJ I-NP CD28-signaling JJ I-NP pathway NN I-NP . . O In IN B-PP transient JJ B-NP transfection NN I-NP assays NNS I-NP COMMA COMMA O both CC O multicopy JJ B-NP NFAT- NN I-NP and CC O IL-2 NN B-NP promoter-beta-galactosidase NN I-NP reporter NN I-NP gene NN I-NP constructs NNS B-NP could MD B-VP be VB I-VP activated VBN I-VP by IN B-PP phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( I-NP PMA NN I-NP ) ) I-NP \/alpha-CD28 NN I-NP stimulation NN I-NP COMMA COMMA O and CC O this DT B-NP activation NN I-NP was VBD B-VP resistant JJ B-ADJP to TO B-PP CsA NN B-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assay NN I-NP showed VBD B-VP the DT B-NP induction NN I-NP of IN B-PP a DT B-NP CsA-resistant JJ I-NP NFAT NN I-NP complex NN I-NP in IN B-PP the DT B-NP nuclear JJ I-NP extracts NNS I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP T NN I-NP cells NNS I-NP stimulated VBN B-VP with IN B-PP PMA NN B-NP plus CC O alphaCD28 NN B-NP . . O Peripheral JJ B-NP blood NN I-NP T NN I-NP cells NNS I-NP stimulated VBN B-VP with IN B-PP PMA\/alphaCD28 NN B-NP produced VBD B-VP IL-2 NN B-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP CsA NN B-NP . . O Collectively RB B-ADVP COMMA COMMA O these DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR NFAT NN B-NP can MD B-VP be VB I-VP activated VBN I-VP and CC O IL-2 NN B-NP can MD B-VP be VB I-VP produced VBN I-VP in IN B-PP a DT B-NP calcineurin NN I-NP independent JJ I-NP manner NN I-NP . . O Age-related JJ B-NP decreases NNS I-NP in IN B-PP IL-2 NN B-NP production NN I-NP by IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP are VBP B-VP associated VBN I-VP with IN B-PP impaired JJ B-NP activation NN I-NP of IN B-PP nuclear JJ B-NP transcriptional JJ I-NP factors NNS I-NP AP-1 NN B-NP and CC O NF-AT NN B-NP . . O Although IN B-SBAR transcriptional JJ B-NP factors NNS I-NP AP-1 NN I-NP and CC O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O are VBP B-VP important JJ B-ADJP for IN B-PP the DT B-NP normal JJ I-NP induction NN I-NP of IN B-PP IL-2 NN B-NP COMMA COMMA O it PRP B-NP is VBZ B-VP unknown JJ B-ADJP if IN B-SBAR the DT B-NP age-related JJ I-NP decline NN I-NP in IN B-PP IL-2 NN B-NP production NN I-NP by IN B-PP activated VBN B-NP human JJ I-NP T NN I-NP cells NNS I-NP may MD B-VP be VB I-VP associated VBN I-VP with IN B-PP aberrancies NNS B-NP in IN B-PP transcriptional JJ B-NP regulatory JJ I-NP proteins NNS I-NP . . O In IN B-PP the DT B-NP current JJ I-NP studies NNS I-NP COMMA COMMA O IL-2 NN B-NP production NN I-NP by IN B-PP T NN B-NP cells NNS I-NP from IN B-PP elderly JJ O ( ( O mean NN B-NP 78 CD B-NP years NNS I-NP ) ) O and CC O young JJ O ( ( O mean NN B-NP 37 CD B-NP years NNS I-NP ) ) O humans NNS B-NP was VBD B-VP measured VBN I-VP in IN B-PP cultures NNS B-NP stimulated VBN B-VP with IN B-PP PHA NN B-NP COMMA COMMA O PHA NN B-NP plus CC O PMA NN B-NP COMMA COMMA O crosslinked VBN B-NP anti-CD3 JJ I-NP mAB NN I-NP OKT3 NN I-NP plus CC O PMA NN B-NP COMMA COMMA O or CC O PMA NN B-NP plus CC O ionomycin NN B-NP . . O Substantial JJ B-NP decreases NNS I-NP of IN B-PP IL-2 NN B-NP production NN I-NP were VBD B-VP observed VBN I-VP for IN B-PP cell NN B-NP cultures NNS I-NP from IN B-PP 7 CD B-NP of IN I-NP 12 CD I-NP elderly JJ I-NP individuals NNS I-NP in IN B-PP response NN I-PP to TO I-PP the DT B-NP different JJ I-NP stimuli NNS I-NP COMMA COMMA O whereas IN O the DT B-NP levels NNS I-NP of IN B-PP IL-2 NN B-NP produced VBN B-VP by IN B-PP stimulated VBN B-NP T NN I-NP cells NNS I-NP from IN B-PP other JJ B-NP elderly JJ I-NP individuals NNS I-NP were VBD B-VP equivalent JJ B-ADJP to TO B-PP those DT B-NP observed VBN B-VP for IN B-PP stimulated VBN B-NP T NN I-NP cells NNS I-NP of IN B-PP young JJ B-NP subjects NNS I-NP . . O Analyses NNS B-NP of IN B-PP nuclear JJ B-NP extracts NNS I-NP by IN B-PP electrophoretic JJ B-NP DNA NN I-NP mobility NN I-NP shift NN I-NP assays NNS I-NP showed VBD B-VP that IN B-SBAR decreased VBN B-NP IL-2 NN I-NP production NN I-NP by IN B-PP stimulated VBN B-NP T NN I-NP cells NNS I-NP of IN B-PP elderly JJ B-NP individuals NNS I-NP was VBD B-VP closely RB I-VP associated VBN I-VP with IN B-PP impairments NNS B-NP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP both CC O AP-1 NN B-NP and CC O NF-AT NN B-NP . . O By IN B-PP contrast NN B-NP COMMA COMMA O T NN B-NP cells NNS I-NP from IN B-PP elderly JJ B-NP subjects NNS I-NP with IN B-PP normal JJ B-NP levels NNS I-NP of IN B-PP IL-2 NN B-NP production NN I-NP exhibited VBD B-VP normal JJ B-NP activation NN I-NP of IN B-PP AP-1 NN B-NP and CC O NF-AT NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O the DT B-NP results NNS I-NP of IN B-PP competition NN B-NP experiments NNS I-NP analyzing VBG B-VP the DT B-NP normal JJ I-NP components NNS I-NP of IN B-PP NF-AT NN B-NP showed VBD B-VP that IN B-SBAR the DT B-NP age-related JJ I-NP reductions NNS I-NP in IN B-PP stimulus-dependent JJ B-NP NF-AT NN I-NP complexes NNS I-NP corresponded VBD B-VP to TO B-PP the DT B-NP slow JJ I-NP migrating VBG I-NP complexes NNS I-NP that WDT B-NP were VBD B-VP composed VBN I-VP of IN B-PP c-Fos\/c-Jun NN B-NP AP-1 NN I-NP . . O The DT B-NP resting JJ I-NP and CC I-NP stimulated JJ I-NP levels NNS I-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP were VBD B-VP reduced VBN I-VP in IN B-PP T NN B-NP cells NNS I-NP from IN B-PP certain JJ B-NP elderly JJ I-NP individuals NNS I-NP ; : O however RB B-ADVP COMMA COMMA O alterations NNS B-NP of IN B-PP NF NN B-NP kappa NN I-NP B NN I-NP did VBD B-VP not RB I-VP correlate VB I-VP with IN B-PP changes NNS B-NP in IN B-PP IL-2 NN B-NP expression NN I-NP . . O Thus RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR age-related JJ B-NP impairments NNS I-NP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP AP-1 NN B-NP and CC O NF-AT NN B-NP are VBP B-VP closely RB I-VP associated VBN I-VP with IN B-PP decreased VBN B-NP expression NN I-NP of IN B-PP IL-2 NN B-NP and CC O further RB B-VP suggest VBP I-VP that IN B-SBAR aberrancies NNS B-NP in IN B-PP the DT B-NP signaling NN I-NP pathways NNS I-NP important JJ B-ADJP for IN B-PP the DT B-NP induction NN I-NP of IN B-PP transcriptionally RB B-NP active JJ I-NP c-Fos\/c-Jun NN I-NP AP-1 NN I-NP may MD B-VP contribute VB I-VP to TO B-PP the DT B-NP impaired JJ I-NP activation NN I-NP of IN B-PP NF-AT NN B-NP . . O Transcription NN B-NP factors NNS I-NP of IN B-PP T NN B-NP and CC O B NN B-NP lymphocytes NNS B-NP -- : O basic JJ B-NP research NN I-NP and CC O clinical JJ B-NP perspectives NNS I-NP for IN B-PP gastroenterology NN B-NP . . O Tissue NN B-NP specific JJ I-NP regulation NN I-NP of IN B-PP gene NN B-NP expression NN I-NP by IN B-PP transcription NN B-NP factors NNS I-NP is VBZ B-VP a DT B-NP fascinating JJ I-NP new JJ I-NP field NN I-NP in IN B-PP molecular JJ B-NP immunology NN I-NP . . O This DT B-NP review NN I-NP summarizes VBZ B-VP data NNS B-NP on IN B-PP specific JJ B-NP regulation NN I-NP of IN B-PP promoters NNS B-NP and CC O enhancers NNS B-NP by IN B-PP nuclear JJ B-NP trans-acting JJ I-NP factors NNS I-NP in IN B-PP lymphocytes NNS B-NP . . O The DT B-NP structural JJ I-NP classes NNS I-NP of IN B-PP transcription NN B-NP factors NNS I-NP are VBP B-VP described VBN I-VP and CC O basic JJ B-NP methods NNS I-NP for IN B-PP detection NN B-NP and CC O analysis NN B-NP of IN B-PP transcription NN B-NP factors NNS I-NP are VBP B-VP detailed VBN I-VP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP most RBS I-NP important JJ I-NP trans-acting JJ I-NP factors NNS I-NP of IN B-PP T NN B-NP and CC O B NN B-NP lymphocytes NNS B-NP ( ( O e.g. FW B-ADVP NF-kB NN B-NP COMMA COMMA O NF-AT NN B-NP and CC O STAT NN B-NP families NNS B-NP ) ) O and CC O their PRP$ B-NP functional JJ I-NP importance NN I-NP are VBP B-VP described VBN I-VP . . O Several JJ B-NP methods NNS I-NP for IN B-PP specific JJ B-NP down-regulation NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP are VBP B-VP shown VBN I-VP that IN B-NP may MD B-VP be VB I-VP relevant JJ B-ADJP to TO B-PP treatment NN B-NP of IN B-PP human JJ B-NP disease NN I-NP . . O The DT B-NP data NNS I-NP are VBP B-VP discussed VBN I-VP with IN B-PP regard NN I-PP to TO I-PP their PRP$ B-NP potential JJ I-NP clinical JJ I-NP relevance NN I-NP for IN B-PP gastroenterology NN B-NP . . O Modulation NN B-NP of IN B-PP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP IFN-gamma NN I-NP receptor NN I-NP beta-chain NN I-NP controls VBZ B-VP responsiveness NN B-NP to TO B-PP IFN-gamma NN B-NP in IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP . . O IFN-gamma NN B-NP has VBZ B-VP potent JJ B-NP antiproliferative JJ I-NP and CC I-NP apoptotic JJ I-NP effects NNS I-NP in IN B-PP T NN B-NP cells NNS I-NP that WDT B-NP are VBP B-VP important JJ B-ADJP in IN B-PP determining VBG B-VP T NN B-NP cell NN I-NP development NN B-NP and CC O polarized VBN B-NP differentiation NN I-NP . . O In IN B-PP this DT B-NP work NN I-NP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR human JJ B-NP peripheral JJ I-NP blood NN I-NP T NN I-NP cells NNS I-NP that WDT B-NP are VBP B-VP stimulated VBN I-VP through IN B-PP the DT B-NP TCR NN I-NP and CC O expanded VBN B-VP with IN B-PP IL-2 NN B-NP are VBP B-VP unresponsive JJ B-ADJP to TO B-PP IFN-gamma NN B-NP COMMA COMMA O as IN B-SBAR determined VBN B-VP by IN B-PP a DT B-NP lack NN I-NP of IN B-PP activation NN B-NP of IN B-PP jak NN B-NP kinases NNS I-NP and CC O the DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O STAT1(alpha) NN B-NP COMMA COMMA O a DT B-NP signal NN I-NP transducer NN I-NP and CC O activator NN B-NP of IN B-PP transcription NN B-NP . . O Expression NN B-NP of IN B-PP the DT B-NP beta-chain NN I-NP can MD B-VP be VB I-VP restored VBN I-VP by IN B-PP secondary JJ B-NP TCR NN I-NP ligation NN I-NP or CC O PMA NN B-NP treatment NN I-NP . . O T NN B-NP cell NN I-NP blasts NNS I-NP treated VBN B-VP with IN B-PP PMA NNS B-NP are VBP B-VP now RB B-ADVP responsive JJ B-ADJP to TO B-PP IFN-gamma NN B-NP . . O When WRB B-ADVP freshly RB B-ADVP isolated VBN B-VP COMMA COMMA O highly RB O enriched VBN O ( ( O > JJR B-NP 98 CD I-NP % NN I-NP ) ) O T NN B-NP cells NNS I-NP are VBP B-VP examined VBN I-VP for IN B-PP IFN-gamma NN B-NP responsiveness NN I-NP ; : O these DT B-NP cells NNS I-NP can MD B-VP respond VB I-VP to TO B-PP IFN-gamma NN B-NP and CC O express VB B-VP beta-chain NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O as IN B-SBAR T NN B-NP cells NNS I-NP progress VBP B-VP from IN B-PP primary JJ B-NP TCR NN I-NP activation NN I-NP through IN B-PP IL-2-dependent JJ B-NP proliferation NN I-NP COMMA COMMA O followed VBN B-VP by IN B-PP secondary JJ B-NP TCR NN I-NP stimulation NN I-NP COMMA COMMA O their PRP$ B-NP responsiveness NN I-NP to TO B-PP IFN-gamma NN B-NP varies VBZ B-VP COMMA COMMA O and CC O this DT B-NP may MD B-VP affect VB I-VP their PRP$ B-NP ability NN I-NP to TO B-VP participate VB I-VP in IN B-PP an DT B-NP ongoing JJ I-NP immune JJ I-NP response NN I-NP . . O Recombinant JJ B-NP NFAT1 NN I-NP ( ( O NFATp NN B-NP ) ) O is VBZ B-VP regulated VBN I-VP by IN B-PP calcineurin NN B-NP in IN B-PP T NN B-NP cells NNS I-NP and CC O mediates VBZ B-VP transcription NN B-NP of IN B-PP several JJ B-NP cytokine NN I-NP genes NNS I-NP . . O Transcription NN B-NP factors NNS I-NP of IN B-PP the DT B-NP NFAT NN I-NP family NN I-NP play VBP B-VP a DT B-NP key JJ I-NP role NN I-NP in IN B-PP the DT B-NP transcription NN I-NP of IN B-PP cytokine NN B-NP genes NNS I-NP and CC O other JJ B-NP genes NNS I-NP during IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O We PRP B-NP have VBP B-VP identified VBN I-VP two CD B-NP new JJ I-NP isoforms NNS I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NFAT1 NN I-NP ( ( O previously RB B-VP termed VBN I-VP NFATp NN B-NP ) ) O that WDT B-NP are VBP B-VP the DT B-NP predominant JJ I-NP isoforms NNS I-NP expressed VBN B-VP in IN B-PP murine JJ B-NP and CC I-NP human JJ I-NP T NN I-NP cells NNS I-NP . . O When WRB B-ADVP expressed VBN B-VP in IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP COMMA COMMA O recombinant JJ B-NP NFAT1 NN I-NP is VBZ B-VP regulated VBN I-VP COMMA COMMA O as IN B-SBAR expected VBN B-VP COMMA COMMA O by IN B-PP the DT B-NP calmodulin-dependent JJ I-NP phosphatase NN I-NP calcineurin NN I-NP COMMA COMMA O and CC O its PRP$ B-NP function NN I-NP is VBZ B-VP inhibited VBN I-VP by IN B-PP the DT B-NP immunosuppressive JJ I-NP agent NN I-NP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O . . O Transactivation NN B-NP by IN B-PP recombinant JJ B-NP NFAT1 NN I-NP in IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP requires VBZ B-VP dual JJ B-NP stimulation NN I-NP with IN B-PP ionomycin NN B-NP and CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ; : O this DT B-NP activity NN I-NP is VBZ B-VP potentiated VBN I-VP by IN B-PP coexpression NN B-NP of IN B-PP constitutively RB B-NP active JJ I-NP calcineurin NN I-NP and CC O is VBZ B-VP inhibited VBN I-VP by IN B-PP CsA NN B-NP . . O Immunocytochemical JJ B-NP analysis NN I-NP indicates VBZ B-VP that IN B-SBAR recombinant JJ B-NP NFAT1 NN I-NP localizes VBZ B-VP in IN B-PP the DT B-NP cytoplasm NN I-NP of IN B-PP transiently RB B-NP transfected VBN I-NP T NN I-NP cells NNS I-NP and CC O translocates VBZ B-VP into IN B-PP the DT B-NP nucleus NN I-NP in IN B-PP a DT B-NP CsA-sensitive JJ I-NP manner NN I-NP following VBG B-PP ionomycin NN B-NP stimulation NN I-NP . . O When WRB B-ADVP expressed VBN B-VP in IN B-PP COS NN B-NP cells NNS I-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O NFAT1 NN B-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP transactivation NN B-NP COMMA COMMA O but CC O it PRP B-NP is VBZ B-VP not RB I-VP regulated VBN I-VP correctly RB B-ADVP : : O its PRP$ B-NP subcellular JJ B-NP localization NN I-NP and CC O transcriptional JJ B-NP function NN I-NP are VBP B-VP not RB I-VP affected VBN I-VP by IN B-PP stimulation NN B-NP of IN B-PP the DT B-NP COS NN I-NP cells NNS I-NP with IN B-PP ionomycin NN B-NP and CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP . . O Recombinant JJ B-NP NFAT1 NN I-NP can MD B-VP mediate VB I-VP transcription NN B-NP of IN B-PP the DT O interleukin-2 NN B-NP COMMA COMMA O interleukin-4 NN B-NP COMMA COMMA O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP COMMA COMMA O and CC O granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP promoters NNS B-NP in IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR NFAT1 NN B-NP contributes VBZ B-VP to TO B-PP the DT B-NP CsA-sensitive JJ I-NP transcription NN I-NP of IN B-PP these DT B-NP genes NNS I-NP during IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O Epstein-Barr JJ B-NP virus NN I-NP nuclear JJ I-NP antigen NN I-NP 2 CD I-NP and CC O latent JJ B-NP membrane NN I-NP protein NN I-NP independently RB B-ADVP transactivate VBP B-VP p53 NN B-NP through IN B-PP induction NN B-NP of IN B-PP NF-kappaB NN B-NP activity NN I-NP . . O B-cell NN B-NP immortalization NN I-NP by IN B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O is VBZ B-VP dependent JJ B-ADJP on IN B-PP permanent JJ B-NP control NN I-NP of IN B-PP the DT B-NP cellular JJ I-NP processes NNS I-NP which WDT B-NP normally RB B-VP regulate VB I-VP cell NN B-NP division NN B-NP and CC O apoptosis NN B-NP COMMA COMMA O functions NNS B-NP possessed VBN B-VP by IN B-PP p53 NN B-NP in IN B-PP a DT B-NP number NN I-NP of IN B-PP normal JJ B-NP cell NN I-NP types NNS I-NP . . O In IN B-PP studies NNS B-NP initiated VBN B-VP to TO I-VP evaluate VB I-VP relationships NNS B-NP between IN B-PP EBV NN B-NP latent JJ I-NP genes NNS I-NP and CC O p53 NN B-NP COMMA COMMA O p53 NN B-NP levels NNS I-NP were VBD B-VP found VBN I-VP to TO I-VP increase VB I-VP approximately RB B-ADVP 10-fold RB I-ADVP 4 CD B-NP to TO I-NP 5 CD I-NP days NNS I-NP after IN B-PP EBV NN B-NP infection NN I-NP of IN B-PP purified VBN B-NP resting VBG I-NP human JJ I-NP B NN I-NP cells NNS I-NP ; : O the DT B-NP induced VBN I-NP p53 NN I-NP was VBD B-VP transcriptionally RB B-ADVP active JJ B-ADJP . . O Latent JJ B-NP membrane NN I-NP protein NN I-NP 1 CD I-NP and CC O COMMA COMMA O to TO B-PP a DT B-NP lesser JJR I-NP extent NN I-NP COMMA COMMA O EBV NN B-NP nuclear JJ I-NP antigen NN I-NP 2 CD I-NP mediated VBD B-VP the DT B-NP increase NN I-NP in IN B-PP p53 NN B-NP levels NNS I-NP via IN B-PP activation NN B-NP of IN B-PP the DT B-NP NF-kappaB NN I-NP transcription NN I-NP factor NN I-NP . . O Differential JJ B-NP utilization NN I-NP of IN B-PP Janus NN B-NP kinase-signal JJ I-NP transducer NN I-NP activator NN I-NP of IN B-PP transcription NN B-NP signaling NN I-NP pathways NNS I-NP in IN B-PP the DT B-NP stimulation NN I-NP of IN B-PP human JJ B-NP natural JJ I-NP killer NN I-NP cells NNS I-NP by IN B-PP IL-2 NN B-NP COMMA COMMA O IL-12 NN B-NP COMMA COMMA O and CC O IFN-alpha NN B-NP . . O IL-2- NN B-NP COMMA COMMA O IL-12- NN B-NP COMMA COMMA O and CC O IFN-alpha-mediated JJ B-ADJP signaling NN B-NP pathways NNS I-NP were VBD B-VP analyzed VBN I-VP in IN B-PP primary JJ B-NP NK NN I-NP cells NNS I-NP and CC B-PP in IN B-PP the DT B-NP NK3.3 NN I-NP cell NN I-NP line NN I-NP . . O Gel NN B-NP mobility NN I-NP shift NN I-NP and CC O immunoprecipitation NN B-NP analyses NNS B-NP revealed VBD B-VP that IN B-SBAR in IN B-PP addition NN I-PP to TO I-PP activating VBG B-VP STAT3 NN B-NP ( ( O signal NN B-NP transducer NN I-NP and CC O activator NN B-NP of IN B-PP transcription-3 NN B-NP ) ) O and CC O STAT5 NN B-NP COMMA COMMA O IL-2 NN B-NP induced VBD B-VP tyrosine NN B-NP and CC O serine NN B-NP phosphorylation NN B-NP of IN B-PP STAT1 NN B-NP alpha NN I-NP COMMA COMMA O which WDT B-NP formed VBD B-VP IFN-gamma-activated JJ B-NP sequence-binding NN I-NP complexes NNS I-NP by IN B-PP itself PRP B-NP and CC B-PP with IN B-PP STAT3 NN B-NP . . O Although IN B-SBAR IL-2 NN B-NP and CC O IFN-alpha NN B-NP activated VBD B-VP STAT1 NN B-NP alpha NN I-NP and CC O STAT5 NN B-NP COMMA COMMA O IL-2 NN B-NP predominantly RB B-ADVP activated VBN B-VP STAT5 NN B-NP COMMA COMMA O while IN B-SBAR IFN-alpha NN B-NP predominantly RB B-ADVP activated VBD B-VP STAT1 NN B-NP alpha NN I-NP . . O IL-2 NN B-NP induced VBD B-VP less RBR B-NP STAT1 NN I-NP alpha NN I-NP activation NN I-NP and CC O IFN-alpha NN B-NP induced VBD B-VP greater JJR B-NP STAT5 NN I-NP activation NN I-NP in IN B-PP NK3.3 NN B-NP cells NNS I-NP compared VBN B-PP with IN B-PP preactivated JJ B-NP primary JJ I-NP NK NN I-NP cells NNS I-NP . . O In IN B-PP NK3.3 NN B-NP cells NNS I-NP COMMA COMMA O IL-2 NN B-NP induced VBD B-VP comparable JJ B-NP formation NN I-NP of IN B-PP c-fos NN B-NP promoter NN I-NP sis-inducible JJ I-NP element NN I-NP IFN-gamma-activated JJ I-NP sequence-binding NN I-NP complexes NNS I-NP containing VBG B-VP STAT3 NN B-NP alone RB B-ADVP with IN B-PP complexes NNS B-NP containing VBG B-VP STAT3 NN B-NP and CC O STAT1 NN B-NP alpha NN I-NP COMMA COMMA O while IN B-SBAR in IN B-PP preactivated JJ B-NP primary JJ I-NP NK NN I-NP cells NNS I-NP COMMA COMMA O it PRP B-NP preferentially RB B-ADVP induced VBD B-VP complexes NNS B-NP containing VBG B-VP STAT3 NN B-NP and CC O STAT1 NN B-NP alpha NN I-NP . . O Thus RB B-ADVP COMMA COMMA O signaling NN B-NP in IN B-PP NK3.3 NN B-NP cells NNS I-NP is VBZ B-VP not RB O always RB B-ADVP identical JJ B-ADJP with IN B-PP that DT B-NP in IN B-PP primary JJ B-NP NK NN I-NP cells NNS I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP IL-2 NN B-NP and CC O IFN-alpha NN B-NP COMMA COMMA O IL-12 NN B-NP induced VBD B-VP strong JJ B-NP tyrosine NN I-NP phosphorylation NN I-NP of IN B-PP STAT4 NN B-NP and CC O variable JJ B-NP weak JJ I-NP phosphorylation NN I-NP of IN B-PP STAT3 NN B-NP . . O However RB B-ADVP COMMA COMMA O supershift NN B-NP analyses NNS I-NP using VBG B-VP the DT B-NP c-fos NN I-NP promoter NN I-NP sis-inducible JJ I-NP element NN I-NP probe NN I-NP showed VBD B-VP that IN B-SBAR IL-12 NN B-NP activated VBD B-VP STAT4 NN B-NP COMMA COMMA O STAT1 NN B-NP alpha NN I-NP COMMA COMMA O and CC O STAT3 NN B-NP COMMA COMMA O and CC O induced VBD B-VP complexes NNS B-NP containing VBG B-VP STAT4 NN B-NP only RB B-ADVP COMMA COMMA O STAT4 NN B-NP with IN B-PP STAT1 NN B-NP alpha NN I-NP COMMA COMMA O STAT3 NN B-NP with IN B-PP STAT1 NN B-NP alpha NN I-NP COMMA COMMA O or CC O STAT1 NN B-NP alpha NN I-NP only RB B-ADVP in IN B-PP preactivated JJ B-NP primary JJ I-NP NK NN I-NP cells NNS I-NP . . O STAT1 NN B-NP alpha NN I-NP activation NN I-NP by IN B-PP IL-12 NN B-NP correlated VBD B-VP with IN B-PP increased VBN B-NP phosphorylation NN I-NP of IN B-PP serine NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP tyrosine NN B-NP . . O Finally RB B-ADVP COMMA COMMA O IL-2 NN B-NP induced VBD B-VP tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP JAK1 NN B-NP and CC O JAK3 NN B-NP COMMA COMMA O while IN B-SBAR IL-12 NN B-NP induced VBD B-VP phosphorylation NN B-NP of IN B-PP JAK2 NN B-NP and CC O TYK2 NN B-NP in IN B-PP both CC O preactivated JJ B-NP primary JJ I-NP NK NN I-NP and CC O NK3.3 NN B-NP cells NNS B-NP . . O Differential JJ B-NP phosphorylation NN I-NP and CC O consequent JJ B-NP differential JJ I-NP activation NN I-NP of IN B-PP both CC B-NP separate JJ I-NP and CC I-NP overlapping JJ I-NP STAT NN I-NP proteins NNS I-NP by IN B-PP IL-2 NN B-NP COMMA COMMA O IL-12 NN B-NP COMMA COMMA O and CC O IFN-alpha NN B-NP may MD B-VP provide VB I-VP a DT B-NP molecular JJ I-NP basis NN I-NP for IN B-PP the DT B-NP similarities NNS B-NP and CC O differences NNS B-NP in IN B-PP the DT B-NP actions NNS I-NP of IN B-PP these DT B-NP cytokines NNS I-NP on IN B-PP NK NN B-NP cells NNS I-NP . . O Sublethal JJ B-NP levels NNS I-NP of IN B-PP oxidative JJ B-NP stress NN I-NP stimulate VBP B-VP transcriptional JJ B-NP activation NN I-NP of IN B-PP c-jun NN B-NP and CC O suppress VBP B-VP IL-2 NN B-NP promoter NN I-NP activation NN I-NP in IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP . . O Sublethal JJ B-NP levels NNS I-NP of IN B-PP oxidative JJ B-NP stress NN I-NP are VBP B-VP well RB I-VP known VBN I-VP to TO I-VP alter VB I-VP T NN B-NP cell NN I-NP functional JJ I-NP responses NNS I-NP COMMA COMMA O but CC O the DT B-NP underlying JJ I-NP mechanisms NNS I-NP are VBP B-VP unknown JJ B-ADJP . . O The DT B-NP current JJ I-NP study NN I-NP examined VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP oxidative JJ B-NP stress NN I-NP on IN B-PP transcriptional JJ B-NP activities NNS I-NP mediated VBN B-VP by IN B-PP c-Fos\/c-Jun NN B-NP AP-1 NN I-NP and CC O the DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O . . O The DT B-NP present JJ I-NP results NNS I-NP show VBP B-VP that IN B-SBAR Jurkat NN B-NP T NN I-NP cells NNS I-NP acutely RB B-VP exposed VBN I-VP to TO B-PP micromolar JJ B-NP concentrations NNS I-NP of IN B-PP H2O2 NN B-NP exhibit VBP B-VP substantial JJ B-NP increases NNS I-NP in IN B-PP AP-1 NN B-NP binding NN I-NP activity NN I-NP and CC O the DT B-NP expression NN I-NP of IN B-PP c-jun NN B-NP but CC B-CONJP not RB I-CONJP c-fos NN B-NP mRNA NN B-NP . . O The DT B-NP preferential JJ I-NP induction NN I-NP of IN B-PP c-jun NN B-NP by IN B-PP H2O2 NN B-NP did VBD B-VP not RB I-VP represent VB I-VP redox NN B-NP stabilization NN I-NP of IN B-PP mRNA NN B-NP transcripts NNS I-NP COMMA COMMA O and CC O oxidative JJ B-NP signals NNS I-NP closely RB B-ADVP resembled VBD B-VP PHA\/PMA NN B-NP stimulation NN I-NP by IN B-PP effectively RB B-VP transactivating VBG I-VP the DT B-NP full JJ I-NP length NN I-NP c-jun NN I-NP promoter NN I-NP via IN B-PP the DT O proximal JJ O jun1 NN O tumor NN B-NP promoter-responsive JJ I-NP element NN I-NP ( ( B-NP TRE NN I-NP ) ) I-NP -like JJ I-NP promoter NN I-NP element NN I-NP . . O Similarly RB B-ADVP COMMA COMMA O the DT B-NP complexes NNS I-NP binding VBG B-VP the DT B-NP consensus NN I-NP AP-1 NN I-NP TRE NN I-NP and CC O jun NN B-NP TRE-like JJ I-NP motifs NNS I-NP in IN B-PP cells NNS B-NP exposed VBN B-VP to TO B-PP oxidative JJ B-NP signals NNS I-NP or CC O PHA\/PMA NN B-NP were VBD B-VP indistinguishable JJ B-ADJP COMMA COMMA O being VBG B-VP composed VBN I-VP of IN B-PP c-Fos NN B-NP COMMA COMMA O c-Jun NN B-NP COMMA COMMA O and CC O JunD NN B-NP . . O However RB B-ADVP COMMA COMMA O PHA\/PMA NN B-NP but CC O not RB B-ADJP oxidative JJ I-ADJP signals NNS B-NP induced VBD B-VP the DT B-NP coordinate JJ B-NP activation NN I-NP of IN B-PP reporter NN B-NP constructs NNS I-NP containing VBG B-VP the DT O AP-1-TRE NN B-NP COMMA COMMA O NF-AT NN B-NP COMMA COMMA O and CC O IL-2 NN B-NP promoter NN B-NP regions NNS I-NP along IN B-CONJP with IN I-CONJP IL-2 NN B-NP mRNA NN I-NP expression NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O sublethal JJ B-NP levels NNS I-NP of IN B-PP H2O2 NN B-NP actively RB B-ADVP suppressed VBD B-VP the DT B-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP NF-AT NN B-NP and CC O IL-2 NN B-NP reporters NNS B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP the DT B-NP expression NN I-NP of IN B-PP IL-2 NN B-NP mRNA NN I-NP in IN B-PP cells NNS B-NP stimulated VBN B-VP with IN B-PP PHA\/PMA NN B-NP . . O Gel NN B-NP shift NN I-NP analysis NN I-NP revealed VBD B-VP that IN B-SBAR oxidative JJ B-NP suppression NN I-NP of IN B-PP NF-AT NN B-NP represented VBD B-VP inhibition NN B-NP in IN B-PP the DT B-NP early JJ I-NP generation NN I-NP of IN B-PP NFAT NN B-NP complexes NNS I-NP rather RB B-CONJP than IN I-CONJP the DT B-NP binding NN I-NP of IN B-PP preformed JJ B-NP NF-AT NN I-NP complexes NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR oxidative JJ B-NP signals NNS I-NP can MD O positively RB B-ADVP and CC O negatively RB B-ADVP regulate VB B-VP T NN B-NP cell NN I-NP transcriptional JJ I-NP events NNS I-NP and CC O that IN B-SBAR changes NNS B-NP in IN B-PP cellular JJ B-NP redox NN I-NP can MD B-VP uncouple VB I-VP AP-1 NN B-NP regulation NN I-NP of IN B-PP c-jun NN B-NP from IN B-PP transcriptional JJ B-NP up-regulation NN I-NP of IN B-PP IL-2 NN B-NP via IN B-PP NF-AT NN B-NP . . O Glucocorticoids NNS B-NP and CC O interferon-alpha NN B-NP in IN B-PP the DT B-NP acquired VBN I-NP immunodeficiency NN I-NP syndrome NN I-NP . . O Some DT B-NP patients NNS I-NP with IN B-PP acquired VBN B-NP immunodeficiency NN I-NP syndrome NN I-NP ( ( O AIDS NN B-NP ) ) O develop VBP B-VP glucocorticoid NN B-NP resistance NN I-NP characterized VBN B-VP by IN B-PP low JJ B-NP receptor NN B-NP affinity NN I-NP ( ( O Kd NN B-NP ) ) O for IN B-PP glucocorticoids NNS B-NP in IN B-PP mononuclear JJ B-NP COMMA COMMA I-NP cells NNS I-NP and CC O high JJ B-NP values NNS I-NP of IN B-PP ACTH NN B-NP and CC O cortisol NN B-NP . . O As IN B-SBAR glucocorticoids NNS B-NP regulate VBP B-VP interferon-alpha NN B-NP ( ( O IFN NN B-NP alpha NN I-NP ) ) O production NN B-NP COMMA COMMA O we PRP B-NP hypothesized VBD B-VP that IN B-SBAR IFN NN B-NP alpha NN I-NP COMMA COMMA O a DT B-NP cytokine NN I-NP produced VBN B-VP predominantly RB B-PP by IN I-PP monocytes NNS B-NP in IN B-PP AIDS NN B-NP COMMA COMMA O should MD B-VP be VB I-VP increased VBN I-VP in IN B-PP cortisol-resistant JJ B-NP AIDS NN I-NP COMMA COMMA O attributing VBG B-VP the DT B-NP lack NN I-NP of IN B-PP cortisol NN B-NP inhibition NN I-NP to TO B-PP IFN NN B-NP alpha NN I-NP production NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP examined VBD B-VP glucocorticoid NN B-NP receptor NN I-NP characteristics NNS I-NP on IN B-PP monocytes NNS B-NP by IN B-PP {3H}dexamethasone NN B-NP binding NN I-NP and CC O measured VBD B-VP IFN NN B-NP alpha NN I-NP COMMA COMMA O cortisol NN B-NP COMMA COMMA O and CC O ACTH NN B-NP in IN B-PP AIDS NN B-NP patients NNS I-NP with IN B-PP ( ( O AIDS-GR NN B-NP ) ) O or CC O without IN B-PP glucocorticoid NN B-NP resistance NN I-NP ( ( O AIDS-C NN B-NP ) ) O and CC O controls NNS B-NP ( ( O C NN B-NP ) ) O . . O Monocytes NNS B-NP of IN B-PP AIDS-GR NN B-NP patients NNS I-NP had VBD B-VP a DT B-NP receptor NN I-NP Kd NN I-NP of IN B-PP 10.5 CD B-NP +\/- CC I-NP 4.2 CD I-NP nmol\/L NN I-NP that WDT B-NP was VBD B-VP higher JJR B-ADJP than IN B-PP that DT B-NP in IN B-PP the DT B-NP AIDS-C NN I-NP group NN I-NP ( ( O 2.9 CD B-NP +\/- CC I-NP 0.8 CD I-NP nmol\/L NN I-NP ) ) O and CC O normal JJ B-NP subjects NNS I-NP ( ( O 2.0 CD B-NP +\/- CC I-NP 0.8 CD I-NP nmol\/L NN I-NP ; : O P NN B-NP < JJR B-ADJP 0.01 CD O ) ) O . . O IFN NN B-NP alpha NN I-NP levels NNS I-NP were VBD B-VP increased VBN I-VP in IN B-PP the DT B-NP AIDS-GR NN I-NP group NN I-NP ( ( O 17 CD B-NP +\/- CC I-NP 6 CD I-NP vs. CC O 4 CD B-NP +\/- CC I-NP 1 CD I-NP U\/mL NN I-NP in IN B-PP the DT B-NP AIDS-C NN I-NP group NN I-NP and CC O 2 CD B-NP +\/- CC I-NP 0.5 CD I-NP U\/mL NN I-NP in IN B-PP the DT B-NP C NN I-NP group NN I-NP ; : O P NN B-NP < JJR B-ADJP 0.01 CD O ) ) O . . O Correlations NNS B-NP were VBD B-VP found VBN I-VP between IN B-PP plasma NN B-NP IFN NN I-NP alpha NN I-NP and CC O receptor NN B-NP Kd NN I-NP on IN B-PP monocytes NNS B-NP of IN B-PP AIDS-GR NN B-NP ( ( O r NN B-NP = JJ B-VP 0.77 CD B-NP ) ) O and CC B-PP between IN B-PP IFN NN B-NP alpha NN I-NP and CC O plasma NN B-NP cortisol NN I-NP in IN B-PP the DT B-NP same JJ I-NP group NN I-NP ( ( O r NN B-NP = JJ B-VP 0.74 CD B-NP ) ) O . . O The DT B-NP poly(I)-poly(C)-induced JJ I-NP IFN NN I-NP alpha NN I-NP production NN I-NP by IN B-PP monocytes NNS B-NP was VBD B-VP inhibited VBN I-VP by IN B-PP glucocorticoids NNS B-NP in IN B-PP the DT O C NN B-NP and CC O AIDS-C NN B-NP groups NNS B-NP ( ( O approximately RB B-NP 80 CD I-NP % NN I-NP inhibition NN B-NP in IN B-PP both DT B-NP groups NNS I-NP ) ) O ; : O the DT B-NP effect NN I-NP was VBD B-VP reversed VBN I-VP by IN B-PP the DT B-NP receptor NN I-NP antagonist NN I-NP RU-38486 NN I-NP . . O By IN B-PP contrast NN B-NP COMMA COMMA O glucocorticoids NNS B-NP failed VBD B-VP to TO I-VP inhibit VB I-VP IFNalpha NN B-NP production NN I-NP from IN B-PP AIDS-GR NN B-NP monocytes NNS I-NP ( ( O approximately RB B-NP 20 CD I-NP % NN I-NP inhibition NN B-NP ) ) O . . O In IN B-PP conclusion NN B-NP COMMA COMMA O elevated JJ B-NP IFN NN I-NP alpha NN I-NP levels NNS I-NP in IN B-PP AIDS-GR NN B-NP may MD B-VP be VB I-VP due JJ B-PP to TO I-PP the DT B-NP lack NN I-NP of IN B-PP inhibitory JJ B-NP effect NN I-NP of IN B-PP cortisol NN B-NP on IN B-PP IFN NN B-NP alpha NN I-NP production NN I-NP due IN B-PP to TO I-PP cortisol JJ B-NP resistance NN I-NP in IN B-PP monocytes NNS B-NP . . O Cooperation NN B-NP between IN B-PP core NN B-NP binding NN I-NP factor NN I-NP and CC O adjacent JJ B-NP promoter NN I-NP elements NNS I-NP contributes VBZ B-VP to TO B-PP the DT B-NP tissue-specific JJ I-NP expression NN I-NP of IN B-PP interleukin-3 NN B-NP . . O Tissue-specific JJ B-NP expression NN I-NP of IN B-PP interleukin-3 NN B-NP ( ( O IL-3 NN B-NP ) ) O is VBZ B-VP mediated VBN I-VP via IN B-PP cis-acting JJ B-NP elements NNS I-NP located JJ B-ADJP within IN B-PP 315 CD B-NP base NN I-NP pairs NNS I-NP of IN B-PP the DT B-NP transcription NN I-NP start NN I-NP . . O This DT B-NP is VBZ B-VP achieved VBN I-VP in IN B-PP part NN B-NP through IN B-PP the DT B-NP positive JJ I-NP activities NNS I-NP of IN B-PP the DT O AP-1 NN B-NP and CC O Elf-1 NN B-NP sites NNS B-NP in IN B-PP the DT B-NP IL-3 NN I-NP promoter NN I-NP . . O The DT B-NP contribution NN I-NP to TO B-PP T NN B-NP cell-specific JJ I-NP expression NN I-NP by IN B-PP other JJ B-NP promoter NN I-NP sites NNS I-NP was VBD B-VP assessed VBN I-VP in IN B-PP a DT B-NP transient JJ I-NP expression NN I-NP assay NN I-NP with IN B-PP IL-3 NN B-NP promoter NN I-NP constructs NNS I-NP linked VBN B-VP to TO B-PP a DT B-NP luciferase NN I-NP gene NN I-NP COMMA COMMA O focusing VBG B-VP initially RB B-ADVP on IN B-PP the DT O core NN B-NP binding NN I-NP factor NN I-NP ( ( O CBF NN B-NP ) ) O site NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP footprinted JJ I-VP in FW B-ADVP vivo FW I-ADVP upon IN B-PP T NN B-NP cell NN I-NP activation NN I-NP . . O Activity NN B-NP of IN B-PP the DT B-NP CBF NN I-NP site NN I-NP is VBZ B-VP shown VBN I-VP to TO I-VP be VB I-VP critically RB B-ADJP dependent JJ I-ADJP on IN B-PP the DT B-NP adjacent JJ I-NP activator NN I-NP site NN I-NP Act-1 CD I-NP . . O Together RB B-ADVP the DT O Act-1 NN B-NP and CC O CBF NN B-NP sites NNS B-NP form VBP B-VP a DT B-NP functional JJ I-NP unit NN I-NP ( ( O AC NN B-NP unit NN I-NP ) ) O with IN B-PP dual JJ B-NP activity NN I-NP . . O The DT B-NP AC NN I-NP unit NN I-NP is VBZ B-VP demonstrated VBN I-VP to TO I-VP enhance VB B-NP basal JJ B-NP activity NN I-NP of IN B-PP promoters NNS B-NP both CC B-ADVP in IN B-PP fibroblasts NNS B-NP and CC O T NN B-NP cells NNS I-NP . . O This DT B-NP activity NN I-NP is VBZ B-VP further RB B-ADJP inducible JJ I-ADJP in IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP COMMA COMMA B-PP but CC I-PP not RB B-PP in IN I-PP fibroblasts NNS B-NP . . O In IN B-PP addition NN I-PP to TO I-PP the DT B-NP already RB I-NP identified VBN I-NP NIP NN I-NP repressor NN I-NP site NN I-NP COMMA COMMA O evidence NN B-NP is VBZ B-VP presented VBN I-VP for IN B-PP a DT B-NP second JJ I-NP repressor NN I-NP region NN I-NP that WDT B-NP restricts VBZ B-VP promoter NN B-NP activity NN I-NP in IN B-PP fibroblasts NNS B-NP . . O Finally RB B-ADVP COMMA COMMA O a DT B-NP novel JJ I-NP positive JJ I-NP regulatory JJ I-NP element NN I-NP has VBZ B-VP been VBN I-VP mapped VBN I-VP in IN B-PP the DT B-NP IL-3 NN I-NP promoter NN I-NP between IN B-PP nucleotide NN B-NP -180 CD B-NP and CC O -210 CD B-NP that WDT B-NP leads VBZ B-VP to TO B-PP increased VBN B-NP expression NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O Together RB B-ADVP these DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR T NN B-NP cell NN I-NP expression NN I-NP of IN B-PP IL-3 NN B-NP is VBZ B-VP not RB I-VP specified VBN I-VP by IN B-PP the DT B-NP activity NN I-NP of IN B-PP a DT B-NP single JJ I-NP tissue-specific JJ I-NP element NN I-NP COMMA COMMA O but CC O instead RB O involves VBZ B-VP multiple JJ B-NP interacting VBG I-NP elements NNS I-NP that WDT B-NP provide VBP B-VP both CC O specific JJ B-NP positive JJ I-NP regulation NN I-NP in IN B-PP T NN B-NP cells NNS I-NP and CC O specific JJ B-NP negative JJ I-NP regulation NN I-NP in IN B-PP fibroblasts NNS B-NP . . O A DT O 3' JJ B-NP --> TO O 5' JJ B-NP XPB NN B-NP helicase NN I-NP defect NN I-NP in IN B-PP repair\/transcription NN B-NP factor NN I-NP TFIIH NN I-NP of IN B-PP xeroderma NN B-NP pigmentosum NN I-NP group NN I-NP B NN I-NP affects VBZ B-VP both CC B-NP DNA NN I-NP repair NN B-NP and CC O transcription NN B-NP . . O XPB NN B-NP is VBZ B-VP a DT B-NP subunit NN I-NP of IN B-PP the DT B-NP basal JJ I-NP transcription NN I-NP factor NN I-NP TFIIH NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP also RB I-VP involved VBN I-VP in IN B-PP nucleotide NN B-NP excision NN I-NP repair NN I-NP ( ( O NER NN B-NP ) ) O and CC O potentially RB B-ADVP in IN B-PP cell NN B-NP cycle NN I-NP regulation NN I-NP . . O A DT B-NP frameshift NN I-NP mutation NN I-NP in IN B-PP the DT B-NP 3'-end NN I-NP of IN B-PP the DT B-NP XPB NN I-NP gene NN I-NP is VBZ B-VP responsible JJ B-ADJP for IN B-PP a DT B-NP concurrence NN I-NP of IN B-PP two CD B-NP disorders NNS I-NP : : O xeroderma NN B-NP pigmentosum NN I-NP ( ( O XP NN B-NP ) ) O and CC O Cockayne NN B-NP 's POS B-NP syndrome NN I-NP ( ( O CS NN B-NP ) ) O . . O We PRP B-NP have VBP B-VP isolated VBN I-VP TFIIH NN B-NP from IN B-PP cells NNS B-NP derived VBN B-VP from IN B-PP a DT B-NP patient NN I-NP ( ( O XP11BE NN B-NP ) ) O who WP B-NP carries VBZ B-VP this DT B-NP frameshift NN I-NP mutation NN I-NP ( ( O TFIIHmut NN B-NP ) ) O and CC O from IN B-PP the DT B-NP mother NN I-NP of IN B-PP this DT B-NP patient NN I-NP ( ( O TFIIHwt NN B-NP ) ) O to TO B-VP determine VB I-VP the DT B-NP biochemical JJ I-NP consequences NNS I-NP of IN B-PP the DT B-NP mutation NN I-NP . . O Although IN B-SBAR identical JJ B-ADJP in IN B-PP composition NN B-NP and CC O stoichiometry NN B-NP to TO B-PP TFIIHwt NN B-NP COMMA COMMA O TFIIHmut NN B-NP shows VBZ B-VP a DT O reduced VBN O 3' JJ B-NP --> TO O 5' JJ B-NP XPB NN B-NP helicase NN I-NP activity NN I-NP . . O A DT B-NP decrease NN I-NP in IN B-PP helicase NN B-NP and CC O DNA-dependent JJ B-NP ATPase NN I-NP activities NNS B-NP was VBD B-VP also RB I-VP observed VBN I-VP with IN B-PP the DT B-NP mutated VBN I-NP recombinant JJ I-NP XPB NN I-NP protein NN I-NP . . O The DT B-NP XPB NN I-NP mutation NN I-NP causes VBZ B-VP a DT I-VP severe JJ I-VP NER NN I-VP defect NN I-VP . . O In IN B-PP addition NN B-NP COMMA COMMA O we PRP B-NP provide VBP B-VP evidence NN B-NP for IN B-PP a DT B-NP decrease NN I-NP in IN B-PP basal JJ B-NP transcription NN I-NP activity NN I-NP in FW B-ADVP vitro FW I-ADVP . . O The DT B-NP latter JJ I-NP defect NN I-NP may MD B-VP provide VB I-VP an DT B-NP explanation NN I-NP for IN B-PP many JJ B-NP of IN B-PP the DT O XP NN B-NP and CC O CS NN B-NP symptoms NNS B-NP that WDT B-NP are VBP B-VP difficult JJ B-ADJP to TO B-VP rationalize VB I-VP based VBN B-PP solely RB B-PP on IN I-PP an DT B-NP NER NN I-NP defect NN I-NP . . O Thus RB B-ADVP COMMA COMMA O this DT B-NP work NN I-NP presents VBZ B-VP the DT B-NP first JJ I-NP detailed JJ I-NP analysis NN I-NP of IN B-PP a DT B-NP naturally RB I-NP occurring VBG I-NP mutation NN I-NP in IN B-PP a DT B-NP basal JJ I-NP transcription NN I-NP factor NN I-NP and CC O supports VBZ B-VP the DT B-NP concept NN I-NP that IN B-SBAR the DT B-NP combined JJ I-NP XP\/CS NN I-NP clinical JJ I-NP entity NN I-NP is VBZ B-VP actually RB B-ADVP the DT B-NP result NN I-NP of IN B-PP a DT B-NP combined JJ I-NP transcription\/repair NN I-NP deficiency NN I-NP . . O Signals NNS B-NP leading VBG B-VP to TO B-PP the DT B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP transcription NN I-NP factor NN I-NP are VBP B-VP stronger JJR B-ADJP in IN B-PP neonatal JJ B-NP than IN B-PP adult JJ B-NP T NN I-NP lymphocytes NNS I-NP . . O The DT B-NP molecular JJ I-NP background NN I-NP of IN B-PP the DT B-NP defects NNS I-NP in IN B-PP the DT B-NP immune JJ I-NP reactivity NN I-NP of IN B-PP human JJ B-NP neonates NNS I-NP has VBZ B-VP not RB I-VP been VBN I-VP fully RB I-VP elucidated VBN I-VP . . O As IN B-SBAR the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP has VBZ B-VP a DT B-NP central JJ I-NP role NN I-NP in IN B-PP the DT B-NP control NN I-NP of IN B-PP transcription NN B-NP of IN B-PP several JJ B-NP genes NNS I-NP involved VBN B-VP in IN B-PP immune JJ B-NP and CC I-NP inflammatory JJ I-NP responses NNS I-NP COMMA COMMA O the DT B-NP authors NNS I-NP have VBP B-VP analysed VBN I-VP the DT B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP human JJ B-NP umbilical JJ I-NP cord NN I-NP T NN I-NP lymphocytes NNS I-NP . . O The DT B-NP activity NN I-NP was VBD B-VP tested VBN I-VP by IN B-PP quantitating VBG B-VP the DT B-NP nuclear JJ I-NP proteins NNS I-NP binding VBG B-VP to TO B-PP an DT B-NP oligonucleotide NN I-NP containing VBG B-VP the DT B-NP consensus NN I-NP kappa NN I-NP B NN I-NP binding NN I-NP sequence NN I-NP ( ( O electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assay NN I-NP ) ) O . . O The DT B-NP data NNS I-NP obtained VBN B-VP demonstrate VBP B-VP that IN B-SBAR phorbol NN B-NP dibutyrate\/calcium NN I-NP ionophore NN I-NP A23187 NN I-NP ( ( O PDBu\/iono NN B-NP ) ) O combination NN B-NP induced VBD B-VP a DT B-NP clearly RB I-NP higher JJR I-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP neonatal JJ B-NP than IN B-PP adult JJ B-NP T NN I-NP cells NNS I-NP . . O This DT B-NP higher JJR I-NP NF-kappa NN I-NP B NN I-NP activity NN I-NP was VBD B-VP restricted JJ I-VP to TO B-PP the DT B-NP CD4+ JJ I-NP T-cell NN I-NP subset NN I-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP nuclear JJ I-NP extracts NNS I-NP with IN B-PP antibodies NNS B-NP directed VBN B-VP against IN B-PP the DT B-NP major JJ I-NP components NNS I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP the DT O p50 NN B-NP and CC O RelA NN B-NP ( ( O p65 NN B-NP ) ) O proteins NNS B-NP COMMA COMMA O indicated VBD B-VP that IN B-SBAR the DT B-NP composition NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP was VBD B-VP similar JJ B-ADJP in IN B-PP neonatal JJ B-NP and CC I-NP adult JJ I-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR neonatal JJ B-NP T NN I-NP cells NNS I-NP are VBP B-VP exposed VBN I-VP to TO B-PP oxidative JJ B-NP stress-inducing JJ I-NP signals NNS I-NP during IN B-PP delivery NN B-NP and\/or CC O are VBP B-VP inherently RB B-ADVP more RBR B-ADJP sensitive JJ I-ADJP to TO B-PP NF-kappa NN B-NP B NN I-NP activating NN I-NP signals NNS I-NP than IN B-PP adult JJ B-NP T NN I-NP cells NNS I-NP . . O Characterization NN B-NP of IN B-PP Grb2-binding JJ B-NP proteins NNS I-NP in IN B-PP human JJ B-NP platelets NNS I-NP activated VBN B-VP by IN B-PP Fc NN B-NP gamma NN I-NP RIIA NN I-NP cross-linking NN I-NP . . O Glutathione-S-transferase NN B-NP ( ( I-NP GST NN I-NP ) ) I-NP -Grb2 NN I-NP fusion NN I-NP proteins NNS I-NP have VBP B-VP been VBN I-VP used VBN I-VP to TO B-VP identify VB I-VP the DT B-NP potential JJ I-NP role NN I-NP of IN B-PP Grb2-binding JJ B-NP proteins NNS I-NP in IN B-PP platelet NN B-NP activation NN I-NP by IN B-PP the DT B-NP platelet NN I-NP low-affinity NN I-NP IgG NN I-NP receptor NN I-NP COMMA COMMA O Fc NN B-NP gamma NN I-NP RIIA NN I-NP . . O Two CD B-NP tyrosine NN I-NP phosphoproteins NNS I-NP of IN B-PP 38 CD B-NP and CC I-NP 63 CD I-NP kD NN I-NP bind VBP B-VP to TO B-PP the DT B-NP SH2 NN I-NP domain NN I-NP of IN B-PP Grb2 NN B-NP following VBG B-PP Fc NN B-NP gamma NN I-NP RIIA NN I-NP stimulation NN I-NP of IN B-PP platelets NNS B-NP . . O Both DT B-NP are VBP B-VP located JJ B-ADJP in IN B-PP the DT B-NP particulate JJ I-NP fraction NN I-NP following VBG B-PP platelet NN B-NP activation NN I-NP and CC O are VBP B-VP also RB B-ADVP able JJ B-ADJP to TO B-VP bind VB I-VP to TO B-PP a DT B-NP GST-construct NN I-NP containing VBG B-VP the DT O SH2 NN B-NP and CC O SH3 NN B-NP domains NNS B-NP of IN B-PP phospholipase NN B-NP C NN I-NP gamma NN I-NP 1 CD I-NP . . O p38 NN B-NP also RB B-VP forms VBZ I-VP a DT B-NP complex NN I-NP with IN B-PP the DT B-NP tyrosine NN I-NP kinase NN I-NP csk NN I-NP in IN B-PP stimulated VBN B-NP cells NNS I-NP and CC O is VBZ B-VP a DT B-NP substrate NN I-NP for IN B-PP the DT B-NP kinase NN I-NP . . O The DT B-NP SH3 NN I-NP domains NNS I-NP of IN B-PP Grb2 NN B-NP form VBP B-VP a DT B-NP stable JJ I-NP complex NN I-NP with IN B-PP SOS1 NN B-NP and CC O two CD B-NP proteins NNS I-NP of IN B-PP 75 CD B-NP kD NN I-NP and CC O 120 CD B-NP kD NN I-NP COMMA COMMA O which WDT B-NP undergo VBP B-VP tyrosine NN B-NP phosphorylation NN I-NP in IN B-PP Fc NN B-NP gamma NN I-NP RIIA NN I-NP stimulated JJ B-NP cells NNS I-NP . . O The DT B-NP 75-kD JJ I-NP protein NN I-NP is VBZ B-VP recognized VBN I-VP by IN B-PP antibodies NNS B-NP to TO B-PP SLP-76 NN B-NP COMMA COMMA O which WDT B-NP has VBZ B-VP recently RB I-VP been VBN I-VP isolated VBN I-VP from IN B-PP T NN B-NP cells NNS I-NP and CC O sequenced VBN B-VP . . O Tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP p38 NN B-NP and CC O p63 NN B-NP is VBZ B-VP also RB I-VP observed VBN I-VP in IN B-PP platelets NNS B-NP stimulated VBN B-VP by IN B-PP the DT B-NP tyrosine NN I-NP kinase-linked JJ I-NP receptor NN I-NP agonist NN I-NP collagen NN I-NP and CC B-PP by IN B-PP the DT B-NP G NN I-NP protein-coupled JJ I-NP receptor NN I-NP agonist NN I-NP thrombin NN I-NP COMMA COMMA O although IN B-SBAR phosphorylation NN B-NP of IN B-PP SLP-76 NN B-NP is VBZ B-VP only RB I-VP observed VBN I-VP in IN B-PP collagen-stimulated JJ B-NP platelets NNS I-NP . . O p38 NN B-NP and CC O p63 NN B-NP may MD B-VP provide VB I-VP a DT B-NP docking NN I-NP site NN I-NP for IN B-PP Grb2 NN B-NP COMMA COMMA O thereby RB B-ADVP linking VBG B-VP Grb2 NN B-NP SH3-binding JJ I-NP proteins NNS I-NP SOS1 NN B-NP COMMA COMMA O SLP-76 NN B-NP COMMA COMMA O and CC O p120 NN B-NP to TO B-PP downstream JJ B-NP signalling NN I-NP events NNS I-NP . . O Retinoic JJ B-NP acid NN I-NP activates VBZ B-VP interferon NN B-NP regulatory JJ I-NP factor-1 JJ I-NP gene NN I-NP expression NN I-NP in IN B-PP myeloid JJ B-NP cells NNS I-NP . . O All-trans-retinoic JJ B-NP acid NN I-NP ( ( O ATRA NN B-NP ) ) O is VBZ B-VP the DT B-NP drug NN I-NP of IN B-PP choice NN B-NP in IN B-PP the DT B-NP treatment NN I-NP of IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP ( ( O APL NN B-NP ) ) O . . O ATRA NN B-NP induces VBZ B-VP both CC B-NP in FW I-NP vitro FW I-NP and CC I-NP in FW I-NP vivo FW I-NP differentiation NN I-NP of IN B-PP APL NN B-NP cells NNS I-NP into IN B-PP mature JJ B-NP granulocytes NNS I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP molecular JJ I-NP mechanisms NNS I-NP involved VBN B-VP in IN B-PP ATRA-dependent JJ B-NP growth NN B-NP inhibition NN I-NP and CC O cellular JJ B-NP differentiation NN I-NP are VBP B-VP not RB I-VP presently RB I-VP understood VBN I-VP . . O The DT B-NP NB4 NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP derived VBN I-VP from IN B-PP the DT B-NP bone NN I-NP marrow NN I-NP of IN B-PP a DT B-NP patient NN I-NP with IN B-PP APL NN B-NP during IN B-PP relapse NN B-NP COMMA COMMA O can MD B-VP be VB I-VP used VBN I-VP as IN B-PP a DT B-NP model JJ I-NP system NN I-NP to TO B-VP study VB I-VP the DT B-NP growth NN B-NP and CC O differentiation NN B-NP of IN B-PP APL NN B-NP cells NNS I-NP . . O Because IN B-SBAR interferon NN B-NP ( ( O IFN NN B-NP ) ) O regulatory JJ B-NP factors NNS I-NP ( ( O IRF-1 NN B-NP and CC O IRF-2 NN B-NP ) ) O and CC O other JJ B-NP IFN-inducible JJ I-NP gene NN I-NP products NNS I-NP regulate VBP B-VP cell NN B-NP growth NN I-NP COMMA COMMA O we PRP B-NP analyzed VBD B-VP the DT B-NP effects NNS I-NP of IN B-PP ATRA NN B-NP on IN B-PP the DT B-NP expression NN I-NP of IN B-PP these DT B-NP genes NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR ATRA NN B-NP directly RB B-ADVP activates VBZ B-VP IRF-1 NN B-NP gene NN I-NP expression NN I-NP COMMA COMMA O followed VBN B-VP by IN B-PP activation NN B-NP of IN B-PP IRF-2 NN B-NP and CC O 2'-5' JJ B-NP oligoadenylate NN B-NP synthetase NN I-NP ( ( O OAS NN B-NP ) ) O gene NN B-NP expression NN I-NP with IN B-PP slower JJR B-NP kinetics NNS I-NP . . O In IN B-PP addition NN I-PP to TO I-PP NB4 NN B-NP cells NNS I-NP COMMA COMMA O ATRA NN B-NP also RB B-ADVP activated VBD B-VP IRF-1 NN B-NP gene NN I-NP expression NN I-NP in IN B-PP HL-60 NN B-NP COMMA COMMA O U937 NN B-NP COMMA COMMA O and CC O THP-1 NN B-NP cells NNS B-NP COMMA COMMA O which WDT B-NP all DT B-NP respond VBP B-VP to TO B-PP ATRA NN B-NP by IN B-PP growth NN B-NP inhibition NN I-NP . . O A DT O more JJR O than IN B-PP additive JJ B-ADJP increase NN B-NP in IN B-PP IRF-1 NN B-NP gene NN I-NP expression NN I-NP was VBD B-VP seen VBN I-VP with IN B-PP ATRA NN B-NP and CC O IFN-gamma NN B-NP in IN B-PP NB4 NN B-NP cells NNS I-NP . . O ATRA NN B-NP did VBD B-VP not RB I-VP activate VB I-VP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP or CC O signal NN B-NP transducer NN I-NP and CC O activator NN B-NP of IN B-PP transcription NN B-NP ( ( O STAT NN B-NP ) ) O activation NN B-NP pathways NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR an DT B-NP alternate JJ I-NP mechanism NN I-NP is VBZ B-VP involved VBN I-VP in IN B-PP IRF-1 NN B-NP gene NN I-NP activation NN I-NP . . O The DT B-NP ATRA-induced JJ I-NP expression NN I-NP of IN B-PP IRF-1 NN B-NP COMMA COMMA O an DT B-NP activator NN B-NP of IN B-PP transcription NN B-NP and CC O repressor NN B-NP of IN B-PP transformation NN B-NP COMMA COMMA O may MD B-VP be VB I-VP one CD B-NP of IN B-PP the DT B-NP molecular JJ I-NP mechanisms NNS I-NP of IN B-PP ATRA-induced JJ B-NP growth NN I-NP inhibition NN I-NP COMMA COMMA O and CC O the DT B-NP basis NN I-NP for IN B-PP the DT B-NP synergistic JJ I-NP actions NNS I-NP of IN B-PP ATRA NN B-NP and CC O IFNs NN B-NP in IN B-PP myeloid JJ B-NP leukemia NN I-NP cells NNS I-NP . . O The DT B-NP c-Jun NN I-NP delta-domain NN I-NP inhibits VBZ B-VP neuroendocrine NN B-NP promoter NN I-NP activity NN I-NP in IN B-PP a DT O DNA NN B-NP sequence- NN I-NP and CC O pituitary-specific JJ B-ADJP manner NN B-NP . . O The DT O transcription NN B-NP and CC O transformation NN B-NP activity NN B-NP of IN B-PP c-Jun NN B-NP is VBZ B-VP governed VBN I-VP by IN B-PP a DT B-NP 27-amino JJ I-NP acid NN I-NP regulatory JJ I-NP motif NN I-NP COMMA COMMA O labeled VBN B-VP the DT B-NP delta-domain NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP deleted VBN I-VP in IN B-PP v-Jun NN B-NP . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR c-Jun NN B-NP is VBZ B-VP a DT B-NP potent JJ I-NP inhibitor NN I-NP of IN B-PP the DT O rat NN B-NP prolactin NN I-NP ( ( O rPRL NN B-NP ) ) O promoter NN B-NP activity NN I-NP induced VBN B-VP by IN B-PP either DT B-NP oncogenic JJ B-NP Ras NN I-NP or CC O phorbol NN B-NP esters NNS I-NP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP have VBP B-VP characterized VBN I-VP the DT B-NP structural JJ I-NP and CC I-NP cell-specific JJ I-NP requirements NNS I-NP for IN B-PP this DT B-NP c-Jun NN I-NP inhibitory JJ I-NP response NN I-NP COMMA COMMA O and CC O we PRP B-NP show VBP B-VP that IN B-SBAR this DT B-NP c-Jun NN I-NP inhibitory JJ I-NP response NN I-NP mapped VBD B-VP to TO B-PP the DT B-NP rPRL NN I-NP footprint NN I-NP II CD I-NP repressor NN I-NP site NN I-NP COMMA COMMA O was VBD B-VP pituitary-specific JJ B-ADJP and CC O required VBD B-VP the DT B-NP c-Jun NN I-NP delta-domain NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O alteration NN B-NP of IN B-PP any DT B-NP one CD I-NP of IN B-PP these DT B-NP features NNS I-NP ( ( O e.g. FW B-ADVP COMMA COMMA O cis-element NN B-NP COMMA COMMA O trans-factor NN B-NP COMMA COMMA O or CC O cell-specific JJ B-NP background NN I-NP ) ) O switched VBD B-VP c-Jun NN B-NP to TO B-PP a DT B-NP transcriptional JJ I-NP activator NN I-NP of IN B-PP the DT B-NP rPRL NN I-NP promoter NN I-NP . . O In IN B-PP HeLa NN B-NP nonpituitary JJ I-NP cells NNS I-NP COMMA COMMA O c-Jun NN B-NP alone RB B-ADVP activated VBD B-VP the DT B-NP rPRL NN I-NP promoter NN I-NP via IN B-PP the DT B-NP most RBS I-NP proximal JJ I-NP GHF-1\/Pit-1 NN I-NP binding NN I-NP site NN I-NP COMMA COMMA O footprint NN B-NP I NN I-NP COMMA COMMA O and CC O synergized VBD B-VP with IN B-PP GHF-1 NN B-NP . . O Finally RB B-ADVP COMMA COMMA O recombinant JJ B-NP GHF-1 NN I-NP interacted VBD B-VP directly RB B-ADVP with IN B-PP c-Jun NN B-NP but CC B-CONJP not RB I-CONJP c-Fos NN B-NP proteins NNS B-NP . . O These DT B-NP data NNS I-NP provide VBP B-VP important JJ B-NP fundamental JJ I-NP insights NNS I-NP into IN B-PP the DT B-NP molecular NN I-NP mechanisms NNS I-NP by IN B-PP which WDT B-NP the DT B-NP c-Jun NN I-NP delta-domain NN I-NP functions VBZ B-VP as IN B-PP a DT B-NP modulatory JJ I-NP switch NN I-NP and CC O further RB B-VP imply VBP I-VP that IN B-SBAR the DT B-NP functional JJ I-NP role NN I-NP of IN B-PP c-Jun NN B-NP is VBZ B-VP dictated VBN I-VP by IN B-PP cell-specific JJ B-NP influences NNS I-NP and CC O the DT B-NP delta-domain JJ I-NP motif NN I-NP . . O BCL-6 NN B-NP COMMA COMMA O a DT B-NP POZ\/zinc-finger NN I-NP protein NN I-NP COMMA COMMA O is VBZ B-VP a DT B-NP sequence-specific JJ I-NP transcriptional JJ I-NP repressor NN I-NP . . O Approximately RB B-NP 40 CD I-NP % NN I-NP of IN B-PP diffuse JJ B-NP large JJ I-NP cell NN I-NP lymphoma NN I-NP are VBP B-VP associated VBN I-VP with IN B-PP chromosomal JJ B-NP translocations NNS I-NP that WDT B-NP deregulate VBP B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP BCL6 NN I-NP gene NN I-NP by IN B-PP juxtaposing VBG B-VP heterologous JJ B-NP promoters NNS I-NP to TO B-PP the DT B-NP BCL-6 NN I-NP coding NN I-NP domain NN I-NP . . O The DT B-NP BCL6 NN I-NP gene NN I-NP encodes VBZ B-VP a DT B-NP 95-kDa JJ I-NP protein NN I-NP containing VBG B-VP six CD B-NP C-terminal JJ I-NP zinc-finger NN I-NP motifs NNS I-NP and CC O an DT B-NP N-terminal JJ I-NP POZ NN I-NP domain NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR it PRP B-NP may MD B-VP function VB I-VP as IN B-PP a DT B-NP transcription NN I-NP factor NN I-NP . . O By IN B-PP using VBG B-VP a DT B-NP DNA NN I-NP sequence NN I-NP selected VBN B-VP for IN B-PP its PRP$ B-NP ability NN I-NP to TO B-VP bind VB I-VP recombinant JJ B-NP BCL-6 NN I-NP in FW B-ADVP vitro FW I-ADVP COMMA COMMA O we PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR BCL-6 NN B-NP is VBZ B-VP present JJ B-ADJP in IN B-PP DNA-binding JJ B-NP complexes NNS I-NP in IN B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP various JJ B-NP B-cell NN I-NP lines NNS I-NP . . O In IN B-PP transient JJ B-NP transfectin NN I-NP experiments NNS I-NP COMMA COMMA O BCL6 NN B-NP can MD B-VP repress VB I-VP transcription NN B-NP from IN B-PP promoters NNS B-NP linked VBN B-VP to TO B-PP its PRP$ B-NP DNA NN I-NP target NN I-NP sequence NN I-NP and CC O this DT B-NP activity NN I-NP is VBZ B-VP dependent JJ B-ADJP upon IN B-PP specific JJ B-NP DNA-binding NN I-NP and CC O the DT B-NP presence NN I-NP of IN B-PP an DT B-NP intact JJ I-NP N-terminal JJ I-NP half NN I-NP of IN B-PP the DT B-NP protein NN I-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR this DT B-NP part NN I-NP of IN B-PP the DT B-NP BCL6 NN I-NP molecule NN I-NP contains VBZ B-VP an DT B-NP autonomous JJ I-NP transrepressor NN I-NP domain NN I-NP and CC O that IN B-SBAR two CD B-NP noncontiguous JJ I-NP regions NNS I-NP COMMA COMMA O including VBG B-PP the DT B-NP POZ NN I-NP motif NN I-NP COMMA COMMA O mediate VBP B-VP maximum JJ B-NP transrepressive JJ I-NP activity NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP BCL-6 NN I-NP protein NN I-NP can MD B-VP function VB I-VP as IN B-PP a DT B-NP sequence-specific JJ I-NP transcriptional JJ I-NP repressor NN I-NP and CC O have VBP B-VP implications NNS B-NP for IN B-PP the DT B-NP role NN I-NP of IN B-PP BCL6 NN B-NP in IN B-PP normal JJ B-NP lymphoid JJ I-NP development NN I-NP and CC O lymphomagenesis NN B-NP . . O Constitutive JJ B-NP expression NN I-NP of IN B-PP specific JJ B-NP interferon NN I-NP isotypes NNS I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP from IN B-PP normal JJ B-NP individuals NNS I-NP and CC B-PP in IN B-PP promonocytic JJ B-NP U937 NN I-NP cells NNS I-NP . . O Constitutive JJ B-NP expression NN I-NP of IN B-PP IFN-alpha5 NN B-NP and CC O IFN-beta NN B-NP was VBD B-VP detected VBN I-VP in IN B-PP different JJ B-NP lymphoid JJ I-NP cells NNS I-NP including VBG B-PP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP from IN B-PP normal JJ B-NP individuals NNS I-NP following VBG B-PP amplification NN B-NP of IN B-PP IFN NN B-NP mRNA NN I-NP by IN B-PP reverse JJ B-NP transcriptase-polymerase NN I-NP chain NN I-NP reaction NN I-NP and CC O direct JJ B-NP sequencing NN I-NP of IN B-PP the DT B-NP amplified VBN I-NP product NN I-NP . . O The DT B-NP activated JJ I-NP form NN I-NP of IN B-PP the DT B-NP interferon-induced JJ I-NP transcription NN I-NP factor NN I-NP complex NN I-NP ISGF3 NN I-NP was VBD B-VP also RB I-VP detected VBN I-VP in IN B-PP nuclear JJ B-NP extracts NNS I-NP from IN B-PP uninduced JJ B-NP cells NNS I-NP . . O Culture NN B-NP supernatants NNS I-NP from IN B-PP uninduced JJ B-NP U937 NN I-NP cells NNS I-NP were VBD B-VP also RB I-VP found VBN I-VP to TO I-VP activate VB I-VP an DT B-NP ISRE NN I-NP cloned VBN B-VP upstream RB B-ADVP of IN B-PP the DT B-NP luciferase NN I-NP reporter NN I-NP gene NN I-NP COMMA COMMA O indicating VBG B-VP the DT B-NP presence NN I-NP of IN B-PP endogenous JJ B-NP IFN NN I-NP activity NN I-NP equivalent JJ B-ADJP to TO B-PP approximately RB B-NP 0.3 CD I-NP to TO I-NP 0.5 CD I-NP IU\/mL NN I-NP . . O This DT B-NP endogenous JJ I-NP IFN NN I-NP was VBD B-VP also RB I-VP shown VBN I-VP to TO I-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP maintaining VBG B-VP the DT B-NP basal JJ I-NP level NN I-NP of IN B-PP expression NN B-NP of IN B-PP the DT B-NP major JJ I-NP histocompatibility NN I-NP class NN I-NP I CD I-NP genes NNS I-NP in IN B-PP lymphoid JJ B-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR IFN-alpha5 NN B-NP and CC O IFN-beta NN B-NP are VBP B-VP produced VBN I-VP at IN B-PP low JJ B-NP levels NNS I-NP in IN B-PP normal JJ B-NP tissues NNS I-NP and CC O play VBP B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP cell NN B-NP function NN I-NP and CC B-PP in IN B-PP the DT B-NP maintenance NN I-NP of IN B-PP homeostasis NN B-NP . . O Mechanisms NNS B-NP of IN B-PP transactivation NN B-NP by IN B-PP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells-1 NNS I-NP . . O Nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells-family NN I-NP proteins NNS B-NP ( ( O NFAT1\/NFATp NN B-NP COMMA COMMA O NFATc NN B-NP COMMA COMMA O NFAT3 NN B-NP COMMA COMMA O and CC O NFAT4\/NFATx/NFATc3 NN B-NP ) ) O play VBP B-VP a DT B-NP key JJ I-NP role NN I-NP in IN B-PP the DT B-NP transcription NN I-NP of IN B-PP cytokine NN B-NP genes NNS I-NP and CC O other JJ B-NP genes NNS I-NP during IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O We PRP B-NP have VBP B-VP defined VBN I-VP the DT B-NP mechanisms NNS I-NP of IN B-PP transactivation NN B-NP by IN B-PP NFAT1 NN B-NP . . O NFAT1 NNP B-NP possesses VBZ B-VP two CD B-NP transactivation NN I-NP domains NNS I-NP whose WP$ B-NP sequences NNS I-NP are VBP B-VP not RB I-VP conserved VBN I-VP in IN B-PP the DT B-NP other JJ I-NP NFAT-family NN I-NP proteins NNS I-NP COMMA COMMA O and CC O a DT B-NP conserved VBN I-NP DNA-binding JJ I-NP domain NN I-NP that WDT B-NP mediates VBZ B-VP the DT B-NP recruitment NN I-NP of IN B-PP cooperating VBG B-NP nuclear JJ I-NP transcription NN I-NP factors NNS I-NP even RB B-ADVP when WRB I-ADVP it PRP B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP other JJ B-NP regions NNS I-NP of IN B-PP the DT B-NP protein NN I-NP . . O The DT B-NP activity NN I-NP of IN B-PP the DT B-NP NH2-terminal JJ I-NP transactivation NN I-NP domain NN I-NP is VBZ B-VP modulated VBN I-VP by IN B-PP an DT B-NP adjacent JJ I-NP regulatory JJ I-NP region NN I-NP that WDT B-NP contains VBZ B-VP several JJ B-NP conserved VBN I-NP sequence NN I-NP motifs NNS I-NP represented VBN B-VP only RB B-PP in IN I-PP the DT B-NP NFAT NN I-NP family NN I-NP . . O Our PRP$ B-NP results NNS I-NP emphasize VBP B-VP the DT B-NP multiple JJ I-NP levels NNS I-NP at IN B-PP which WDT B-NP NFAT-dependent JJ B-NP transactivation NN I-NP is VBZ B-VP regulated VBN I-VP COMMA COMMA O and CC O predict VBP B-VP significant JJ B-NP differences NNS I-NP in IN B-PP the DT B-NP architecture NN I-NP of IN B-PP cooperative JJ B-NP transcription NN I-NP complexes NNS I-NP containing VBG B-VP different JJ B-NP NFAT-family NN I-NP proteins NNS I-NP . . O The DT B-NP Ets NN I-NP protein NN I-NP Spi-B NN I-NP is VBZ B-VP expressed VBN I-VP exclusively RB B-PP in IN I-PP B NN B-NP cells NNS I-NP and CC O T NN B-NP cells NNS I-NP during IN B-PP development NN B-NP . . O Spi-B NN B-NP and CC O PU.1 NN B-NP are VBP B-VP hematopoietic-specific JJ B-NP transcription NN I-NP factors NNS I-NP that WDT B-NP constitute VBP B-VP a DT B-NP subfamily NN I-NP of IN B-PP the DT B-NP Ets NN I-NP family NN I-NP of IN B-PP DNA-binding JJ B-NP proteins NNS I-NP . . O Here RB B-ADVP we PRP B-NP show VBP B-VP that IN B-SBAR contrary JJ B-PP to TO I-PP previous JJ B-NP reports NNS I-NP COMMA COMMA O PU.1 NN B-NP and CC O Spi-B NN B-NP have VBP B-VP very RB B-NP different JJ I-NP expression NN I-NP patterns NNS I-NP . . O PU.1 NN B-NP is VBZ B-VP expressed VBN I-VP at IN B-PP high JJ B-NP levels NNS I-NP in IN B-PP B NN B-NP cells NNS I-NP COMMA COMMA O mast NN B-NP cells NNS I-NP COMMA COMMA O megakaryocytes NNS B-NP COMMA COMMA O macrophages NNS B-NP COMMA COMMA O neutrophils NNS B-NP COMMA COMMA O and CC O immature JJ B-NP erythroid JJ I-NP cells NNS I-NP and CC O at IN B-PP lower JJR B-NP levels NNS I-NP in IN B-PP mature JJ B-NP erythrocytes NNS I-NP . . O PU.1 NN B-NP is VBZ B-VP completely RB B-ADJP absent JJ I-ADJP from IN B-PP peripheral JJ B-NP T NN I-NP cells NNS I-NP and CC O most JJS B-NP T JJ I-NP cell NN I-NP lines NNS I-NP based VBN B-PP on IN B-PP sensitive JJ B-NP RT-PCR NN I-NP assays NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O Spi-B NN B-NP is VBZ B-VP expressed VBN I-VP exclusively RB B-ADVP in IN B-PP lymphoid JJ B-NP cells NNS I-NP and CC O can MD B-VP be VB I-VP detected VBN I-VP in IN B-PP early JJ B-NP fetal JJ I-NP thymus NN B-NP and CC O spleen NN B-NP . . O In FW B-NP situ FW I-NP hybridizations NNS I-NP of IN B-PP adult JJ B-NP murine JJ I-NP tissues NNS I-NP demonstrate VBP B-VP Spi-B NN B-NP mRNA NN I-NP in IN B-PP the DT B-NP medulla NN I-NP of IN B-PP the DT B-NP thymus NN I-NP COMMA COMMA O the DT B-NP white JJ I-NP pulp NN I-NP of IN B-PP the DT B-NP spleen NN I-NP COMMA COMMA O and CC O the DT B-NP germinal JJ I-NP centers NNS I-NP of IN B-PP lymph NN B-NP nodes NNS I-NP . . O Spi-B JJ B-NP expression NN I-NP is VBZ B-VP very RB B-ADJP abundant JJ I-ADJP in IN B-PP B NN B-NP cells NNS I-NP and CC O both CC B-NP Spi-B NN I-NP mRNA NN B-NP and CC O protein NN B-NP are VBP B-VP detected VBN I-VP in IN B-PP some DT B-NP T NN I-NP cells NNS I-NP . . O In FW B-NP situ FW I-NP hybridization NN I-NP and CC O Northern NN B-NP blot NN I-NP analysis NN I-NP suggest VBP B-VP that IN B-SBAR Spi-B NN B-NP gene NN I-NP expression NN I-NP increases VBZ B-VP during IN B-PP B NN B-NP cell NN I-NP maturation NN I-NP and CC O decreases VBZ B-VP during IN B-PP T NN B-NP cell NN I-NP maturation NN I-NP . . O Gel-retardation JJ B-NP experiments NNS I-NP show VBP B-VP that IN B-SBAR Spi-B NN B-NP can MD B-VP bind VB I-VP to TO B-PP all DT B-NP putative JJ I-NP PU.1 NN I-NP binding NN I-NP sites NNS I-NP COMMA COMMA O but CC O do VBP B-VP not RB I-VP reveal VB I-VP any DT B-NP preferred JJ I-NP Spi-B NN I-NP binding NN I-NP site NN I-NP . . O Finally RB B-ADVP COMMA COMMA O both CC O PU.1 NN B-NP and CC O Spi-B NN B-NP function VBP B-VP as IN B-PP transcriptional JJ B-NP activators NNS I-NP of IN B-PP the DT B-NP immunoglobulin JJ I-NP light-chain NN I-NP enhancer NN I-NP E NN I-NP lambda NN I-NP 2.4 CD I-NP when WRB B-ADVP coexpressed VBN B-VP with IN B-PP Pip NN B-NP ( ( O PU.1-interaction JJ B-NP partner NN I-NP ) ) O in IN B-PP NIH-3T3 NN B-NP cells NNS I-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O these DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR differences NNS B-NP in IN B-PP patterns NNS B-NP of IN B-PP expression NN B-NP between IN B-PP Spi-B NN B-NP and CC O PU.1 NN B-NP distinguish VBP B-VP the DT B-NP function NN I-NP of IN B-PP each DT B-NP protein NN I-NP during IN B-PP development NN B-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O Precise JJ B-NP alignment NN I-NP of IN B-PP sites NNS B-NP required VBN B-VP for IN B-PP mu NN B-NP enhancer NN I-NP activation NN I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O The DT B-NP lymphocyte-specific JJ I-NP immunoglobulin NN I-NP mu NN I-NP heavy-chain JJ I-NP gene NN I-NP intronic JJ I-NP enhancer NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP multiple JJ B-NP nuclear JJ I-NP factors NNS I-NP . . O The DT B-NP previously RB I-NP defined VBN I-NP minimal JJ I-NP enhancer NN I-NP containing VBG B-VP the DT O muA NN B-NP COMMA COMMA O muE3 NN B-NP COMMA COMMA O and CC O muB NN B-NP sites NNS B-NP is VBZ B-VP transactivated VBN I-VP by IN B-PP a DT B-NP combination NN I-NP of IN B-PP the DT B-NP ETS-domain NN I-NP proteins NNS I-NP PU.1 NN B-NP and CC O Ets-1 NN B-NP in IN B-PP nonlymphoid JJ B-NP cells NNS I-NP . . O The DT B-NP core NN I-NP GGAAs NNS I-NP of IN B-PP the DT O muA NN B-NP and CC O muB NN B-NP sites NNS B-NP are VBP B-VP separated VBN I-VP by IN B-PP 30 CD B-NP nucleotides NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR ETS NNS B-NP proteins NNS I-NP bind VBP B-VP to TO B-PP these DT B-NP sites NNS I-NP from IN B-PP these DT B-NP same JJ I-NP side NN I-NP of IN B-PP the DT B-NP DNA NN I-NP helix NN I-NP . . O We PRP B-NP tested VBD B-VP the DT B-NP necessity NN I-NP for IN B-PP appropriate JJ B-NP spatial JJ I-NP alignment NN I-NP of IN B-PP these DT B-NP elements NNS I-NP by IN B-PP using VBG B-VP mutated VBN B-NP enhancers NNS I-NP with IN B-PP altered JJ B-NP spacings NNS I-NP . . O A DT O 4- CD B-NP or CC O 10-bp JJ B-ADJP insertion NN B-NP between IN B-PP muE3 NN B-NP and CC O muB NN B-NP inactivated VBD B-VP the DT B-NP mu NN I-NP enhancer NN I-NP in IN B-PP S194 NN B-NP plasma NN I-NP cells NNS I-NP but CC O did VBD B-VP not RB I-VP affect VB I-VP in FW B-NP vitro FW I-NP binding NN I-NP of IN B-PP Ets-1 NN B-NP COMMA COMMA O PU.1 NN B-NP COMMA COMMA O or CC O the DT B-NP muE3-binding JJ I-NP protein NN I-NP TFE3 NN I-NP COMMA COMMA O alone RB B-ADVP or CC O in IN B-PP pairwise JJ B-NP combinations NNS I-NP . . O Circular JJ B-NP permutation NN I-NP and CC O phasing NN B-NP analyses NNS B-NP demonstrated VBD B-VP that IN B-SBAR PU.1 NN B-NP binding NN I-NP but CC B-CONJP not RB I-CONJP TFE3 NN B-NP or CC O Ets-1 NN B-NP bends VBZ B-VP mu NN B-NP enhancer NN I-NP DNA NN I-NP toward IN B-PP the DT B-NP major JJ I-NP groove NN I-NP . . O We PRP B-NP propose VBP B-VP that IN B-SBAR the DT B-NP requirement NN I-NP for IN B-PP precise JJ B-NP spacing NN I-NP of IN B-PP the DT O muA NN B-NP and CC O muB NN B-NP elements NNS B-NP is VBZ B-VP due JJ O in IN B-PP part NN B-NP to TO B-PP a DT B-NP directed JJ I-NP DNA NN I-NP bend NN I-NP induced VBN B-VP by IN B-PP PU.1 NN B-NP . . O C\/EBP NN B-NP activators NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP HIV-1 NN B-NP replication NN I-NP and CC O proviral JJ B-NP induction NN I-NP in IN B-PP monocytic JJ B-NP cell NN I-NP lines NNS I-NP . . O Previous JJ B-NP work NN I-NP has VBZ B-VP shown VBN I-VP that IN B-SBAR C\/EBP NN B-NP sites NNS I-NP and CC O C\/EBP NN B-NP transcriptional JJ I-NP activators NNS I-NP are VBP B-VP necessary JJ B-ADJP for IN B-PP HIV-1 NN B-NP LTR NN I-NP activity NN I-NP in IN B-PP monocytes\/macrophages NNS B-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP role NN I-NP that WDT B-NP C\/EBP NN B-NP proteins NNS I-NP play VBP B-VP in IN B-PP induction NN B-NP and CC O replication NN B-NP of IN B-PP HIV-1 NN B-NP . . O Ectopic JJ B-NP expression NN I-NP of IN B-PP the DT B-NP dominant JJ I-NP negative JJ I-NP C\/EBP NN I-NP protein NN I-NP LIP NN I-NP inhibited VBD B-VP HIV-1 NN B-NP mRNA NN I-NP and CC O virus NN B-NP production NN I-NP in IN B-PP activated VBN B-NP U1 NN I-NP cells NNS I-NP COMMA COMMA O demonstrating VBG B-VP that IN B-SBAR C\/EBP NN B-NP proteins NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP provirus NN B-NP induction NN I-NP . . O U1 NN B-NP lines NNS I-NP overexpressing VBG B-VP C\/EBP NN B-NP activator NN I-NP NF-IL-6 NN I-NP produced VBD B-VP more JJR B-NP viral JJ B-NP mRNA NN I-NP and CC O virus NN B-NP particles NNS I-NP following VBG B-PP cellular JJ B-NP activation NN I-NP than IN B-PP control NN B-NP lines NNS I-NP COMMA COMMA O demonstrating VBG B-VP that IN B-SBAR C\/EBP NN B-NP proteins NNS I-NP are VBP B-VP limiting VBG B-ADJP for IN B-PP virus NN B-NP transcription NN I-NP . . O HIV-1 NN B-NP harboring NN I-NP mutations NNS I-NP within IN B-PP two CD B-NP C\/EBP NN I-NP sites NNS I-NP were VBD B-VP crippled VBN B-ADJP in IN B-PP their PRP$ B-NP ability NN I-NP to TO B-VP replicate VB I-VP in IN B-PP U937 NN B-NP promonocytic JJ I-NP cells NNS I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR these DT B-NP sites NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP replication NN B-NP . . O These DT B-NP data NNS I-NP identify VBP B-VP C\/EBP NN B-NP proteins NNS I-NP as IN B-PP regulators NNS B-NP of IN B-PP HIV-1 NN B-NP expression NN I-NP in IN B-PP monocytes\/macrophages NNS B-NP . . O Reversal NN B-NP of IN B-PP apoptosis NN B-NP by IN B-PP the DT B-NP leukaemia-associated JJ I-NP E2A-HLF NN I-NP chimaeric JJ I-NP transcription NN I-NP factor NN I-NP . . O The DT B-NP E2A-HLF NN I-NP ( ( O for IN B-PP hepatic JJ B-NP leukaemia NN I-NP factor NN I-NP ) ) O fusion NN B-NP gene NN I-NP COMMA COMMA O formed VBN B-VP by IN B-PP action NN B-NP of IN B-PP the DT B-NP t(17;19) NN I-NP (q22;p13) NN I-NP chromosomal JJ I-NP translocation NN I-NP COMMA COMMA O drives VBZ B-VP the DT B-NP leukaemic JJ I-NP transformation NN I-NP of IN B-PP early JJ B-NP B-cell NN I-NP precursors NNS I-NP COMMA COMMA O but CC O the DT B-NP mechanism NN I-NP of IN B-PP this DT B-NP activity NN I-NP remains VBZ B-VP unknown JJ B-ADJP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR human JJ B-NP leukaemia NN I-NP cells NNS I-NP carrying VBG B-VP the DT B-NP translocation NN I-NP t(17;19) NN I-NP rapidly RB B-ADVP died VBD B-VP by IN B-PP apoptosis NN B-NP when WRB B-ADVP programmed VBN B-VP to TO I-VP express VB I-VP a DT B-NP dominant-negative JJ I-NP suppressor NN I-NP of IN B-PP the DT B-NP fusion NN I-NP protein NN I-NP E2A-HLF NN I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP chimaeric JJ I-NP oncoprotein NN I-NP probably RB B-ADVP affects VBZ B-VP cell NN B-NP survival NN I-NP rather RB B-CONJP than IN I-CONJP cell NN B-NP growth NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O when WRB B-ADVP introduced VBN B-VP into IN B-PP murine JJ B-NP pro-B JJ I-NP lymphocytes NNS I-NP COMMA COMMA O the DT B-NP oncogenic JJ I-NP E2A-HLF NN I-NP fusion NN I-NP protein NN I-NP reversed VBD B-VP both CC B-NP interleukin-3-dependent JJ I-NP and CC I-NP p53-mediated JJ I-NP apoptosis NN I-NP . . O The DT B-NP close JJ I-NP homology NN I-NP of IN B-PP the DT O basic JJ B-NP region\/leucine NN I-NP zipper NN I-NP ( ( O bZIP NN B-NP ) ) O DNA-binding JJ B-ADJP and CC O dimerization NN B-NP domain NN B-NP of IN B-PP HLF NN B-NP to TO B-PP that DT B-NP of IN B-PP the DT B-NP CES-2 NN I-NP cell-death NN I-NP specification NN I-NP protein NN I-NP of IN B-PP Caenorhabditis NN B-NP elegans NNS I-NP suggests VBZ B-VP a DT B-NP model NN I-NP of IN B-PP leukaemogenesis NN B-NP in IN B-PP which WDT B-NP E2A-HLF NN B-NP blocks VBZ B-VP an DT B-NP early JJ I-NP step NN I-NP within IN B-PP an DT B-NP evolutionarily RB I-NP conserved VBN I-NP cell-death NN I-NP pathway NN I-NP . . O Effects NNS B-NP of IN B-PP IL-10 NN B-NP and CC O IL-4 NN B-NP on IN B-PP LPS-induced JJ B-NP transcription NN I-NP factors NNS I-NP ( ( O AP-1 NN B-NP COMMA COMMA O NF-IL6 NN B-NP and CC O NF-kappa NN B-NP B NN I-NP ) ) O which WDT B-NP are VBP B-VP involved VBN I-VP in IN B-PP IL-6 NN B-NP regulation NN I-NP . . O Interleukin-10 NN B-NP ( ( O IL-10 NN B-NP ) ) O COMMA COMMA O like IN B-PP IL-4 NN B-NP COMMA COMMA O is VBZ B-VP known VBN I-VP to TO I-VP inhibit VB I-VP cytokine NN B-NP expression NN I-NP in IN B-PP activated VBN B-NP human JJ I-NP monocytes NNS I-NP . . O We PRP B-NP showed VBD B-VP that IN B-SBAR both CC O IL-10 NN B-NP and CC O IL-4 NN B-NP inhibit VBP B-VP LPS-induced JJ O IL-6 NN O mRNA NN B-NP and CC O protein NN B-NP expression NN B-NP by IN B-PP inhibiting VBG B-VP the DT B-NP transcription NN I-NP rate NN I-NP of IN B-PP the DT B-NP IL-6 NN I-NP gene NN I-NP . . O The DT B-NP strong JJ I-NP inhibition NN I-NP of IN B-PP the DT B-NP IL-6 NN I-NP transcription NN I-NP rate NN I-NP prompted VBD B-VP us PRP B-NP to TO B-VP study VB I-VP the DT B-NP effect NN I-NP of IN B-PP IL-10 NN B-NP and CC O IL-4 NN B-NP on IN B-PP the DT B-NP expression NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP . . O We PRP B-NP questioned VBD B-VP whether IN B-SBAR or CC O not RB O IL-10 NN B-NP and CC O IL-4 NN B-NP affected VBD B-VP the DT B-NP expression NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP that WDT B-NP are VBP B-VP known VBN I-VP to TO I-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP control NN I-NP of IN B-PP the DT B-NP IL-6 NN I-NP transcription NN I-NP rate NN I-NP COMMA COMMA B-NP namely RB I-NP activator NN B-NP protein-1 NN I-NP ( ( O AP-1 NN B-NP ) ) O COMMA COMMA O nuclear JJ B-NP factor NN I-NP IL-6 NN I-NP ( ( O NF-IL6 NN B-NP ) ) O COMMA COMMA O and CC O nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappaB NN B-NP ) ) O . . O In IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP ( ( O EMSAs NNS B-NP ) ) O we PRP B-NP showed VBD B-VP that IN B-SBAR IL-10 NN B-NP and CC O IL-4 NN B-NP inhibited VBD B-VP LPS-induced JJ B-NP AP-1 NN I-NP binding NN I-NP activity NN I-NP . . O The DT B-NP inhibiting JJ I-NP effect NN I-NP of IN B-PP IL-4 NN B-NP was VBD B-VP slightly RB B-ADJP more RBR I-ADJP pronounced JJ I-ADJP than IN B-PP that DT B-NP of IN B-PP IL-10 NN B-NP . . O Downregulation NN B-NP of IN B-PP LPS-induced JJ B-NP AP-1 NN I-NP was VBD B-VP accompanied VBN I-VP COMMA COMMA O and CC O thus RB O possibly RB B-VP explained VBN I-VP COMMA COMMA O by IN B-PP a DT B-NP reduced VBN I-NP expression NN I-NP at IN B-PP mRNA NN B-NP level NN I-NP of IN B-PP the DT B-NP two CD I-NP major JJ I-NP components NNS I-NP of IN B-PP the DT B-NP AP-1 NN I-NP complex NN I-NP COMMA COMMA B-NP namely RB I-NP c-fos NN B-NP and CC O c-jun NN B-NP as IN B-SBAR determined VBN B-VP by IN B-PP Northern NN B-NP experiments NNS I-NP . . O Binding NN B-NP activity NN I-NP of IN B-PP NF-IL6 NN B-NP was VBD B-VP also RB I-VP strongly RB I-VP inhibited VBN I-VP by IN B-PP IL-4 NN B-NP whereas IN O IL-10 NN B-NP showed VBD B-VP no DT B-NP effect NN I-NP . . O NF-IL6 NN B-NP mRNA NN I-NP levels NNS I-NP were VBD B-VP not RB I-VP affected VBN I-VP by IN B-PP IL-10 NN B-NP or CC O IL-4 NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR IL-4 NN B-NP affects VBZ B-VP binding NN B-NP activity NN I-NP of IN B-PP preexisting VBG B-NP NF-IL6 NN I-NP . . O Neither CC O IL-10 NN B-NP nor CC O IL-4 NN B-NP inhibited VBD B-VP LPS-induced JJ B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP activity NN I-NP . . O In IN B-PP agreement NN I-PP with IN I-PP this DT B-NP finding NN I-NP COMMA COMMA O Northern NN B-NP experiments NNS I-NP where WRB B-ADVP p65 NN B-NP and CC O p105 NN B-NP mRNA NN B-NP levels NNS I-NP were VBD B-VP determined VBN I-VP COMMA COMMA O demonstrated VBD B-VP that IN B-SBAR expression NN B-NP of IN B-PP these DT B-NP components NNS I-NP of IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP transcription NN I-NP factor NN I-NP were VBD B-VP not RB I-VP affected VBN I-VP by IN B-PP IL-10 NN B-NP or CC O IL-4 NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O neither CC O IL-10 NN B-NP nor CC O IL-4 NN B-NP showed VBD B-VP any DT B-NP effect NN I-NP on IN B-PP I-kappa NN B-NP B NN I-NP mRNA NN I-NP expression NN I-NP as IN B-SBAR determined VBN B-VP by IN B-PP Northern NN B-NP experiments NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O IL-10 NN B-NP and CC O IL-4 NN B-NP similarly RB B-ADVP affect VBP B-VP IL-6 NN B-NP expression NN I-NP . . O However RB B-ADVP COMMA COMMA O for IN B-PP IL-4 NN B-NP this DT B-NP was VBD B-VP accompanied VBN I-VP with IN B-PP a DT B-NP reduction NN I-NP of IN B-PP AP-1 NN B-NP and CC O NF-IL6 NN B-NP binding NN B-NP activity NN I-NP whereas IN B-SBAR IL-10 NN B-NP only RB B-ADVP inhibited VBD B-VP AP-1 NN B-NP binding NN I-NP activity NN I-NP . . O Inhibition NN B-NP of IN B-PP transcription NN B-NP factor NN I-NP Stat1 NN I-NP activity NN I-NP in IN B-PP mononuclear JJ B-NP cell NN I-NP cultures NNS I-NP and CC O T NN B-NP cells NNS I-NP by IN B-PP the DT B-NP cyclic JJ I-NP AMP NN I-NP signaling NN I-NP pathway NN I-NP . . O Activation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP results VBZ B-VP in IN B-PP a DT B-NP cascade NN I-NP of IN B-PP gene NN B-NP activation NN I-NP and CC O subsequent JJ B-NP proliferation NN B-NP and CC O differentiation NN B-NP into IN B-PP effector NN B-NP phenotypes NNS I-NP . . O The DT B-NP regulation NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP belonging VBG B-VP to TO B-PP the DT O signal NN B-NP transducer NN I-NP and CC O activator NN B-NP of IN B-PP transcription NN B-NP ( ( O STAT NN B-NP ) ) O family NN B-NP was VBD B-VP analyzed VBN I-VP in IN B-PP PHA-activated JJ B-NP mononuclear JJ I-NP cells NNS I-NP and CC B-PP in IN B-PP purified VBN B-NP T NN I-NP cells NNS I-NP activated VBN B-VP by IN B-PP cross-linking JJ B-NP cell NN I-NP surface NN I-NP CD3 NN I-NP . . O Cell NN B-NP activation NN I-NP resulted VBD B-VP in IN B-PP a DT B-NP delayed VBN I-NP induction NN I-NP of IN B-PP STAT NN B-NP DNA-binding JJ I-NP activity NN I-NP COMMA COMMA O which WDT B-NP was VBD B-VP sustained JJ I-VP for IN B-PP several JJ B-NP days NNS I-NP COMMA COMMA O was VBD B-VP composed VBN I-VP predominantly RB B-ADVP of IN B-PP Stat1 NN B-NP and CC O Stat3 NN B-NP COMMA COMMA O and CC O was VBD B-VP blocked VBN I-VP by IN B-PP cycloheximide NN B-NP and CC O actinomycin NN B-NP D NN I-NP . . O Increased VBN O Stat1 NN B-NP and CC O Stat3 NN B-NP mRNA NN B-NP and CC O protein NN B-NP levels NNS B-NP were VBD B-VP detected VBN I-VP COMMA COMMA O respectively RB B-ADVP 4 CD B-NP and CC I-NP 24 CD I-NP h NN I-NP after IN B-PP activation NN B-NP . . O Stimulation NN B-NP of IN B-PP the DT B-NP cAMP NN I-NP signal NN I-NP transduction NN I-NP pathway NN I-NP COMMA COMMA O which WDT B-NP skews VBZ B-VP cytokine NN B-NP production NN I-NP toward IN B-PP a DT B-NP Th2 NN I-NP pattern NN I-NP COMMA COMMA O resulted VBD B-VP in IN B-PP the DT B-NP preferential JJ I-NP suppression NN I-NP of IN B-PP Stat1 NN B-NP activity NN I-NP . . O cAMP NN B-NP inhibited VBD B-VP the DT B-NP induction NN I-NP of IN B-PP expression NN B-NP of IN B-PP IL-2 NN B-NP receptor NN I-NP components NNS I-NP COMMA COMMA O but CC O did VBD B-VP not RB I-VP inhibit VB I-VP IL-4 NN B-NP receptor NN I-NP alpha-chain NN I-NP and CC O CD69 NN B-NP expression NN B-NP or CC O the DT B-NP induction NN I-NP of IN B-PP activator NN B-NP protein NN I-NP 1 CD I-NP transcription NN I-NP factors NNS I-NP . . O cAMP NN B-NP signaling NN I-NP inhibited VBD B-VP Stat1 NN B-NP at IN B-PP several JJ B-NP different JJ I-NP levels NNS I-NP COMMA COMMA O including VBG B-PP suppression NN B-NP of IN B-PP DNA NN B-NP binding NN I-NP and CC O down-regulation NN B-NP of IN B-PP Stat1 NN B-NP protein NN B-NP and CC O mRNA NN B-NP levels NNS B-NP . . O Our PRP$ B-NP results NNS I-NP demonstrate VBP B-VP the DT B-NP regulation NN I-NP of IN B-PP STAT NN B-NP activity NN I-NP by IN B-PP a DT B-NP signaling NN I-NP pathway NN I-NP that WDT B-NP regulates VBZ B-VP the DT B-NP T NN I-NP cell NN I-NP functional JJ I-NP phenotype NN I-NP and CC O is VBZ B-VP distinct JJ B-ADJP from IN B-PP the DT B-NP cytokine-activated JJ I-NP Janus NN I-NP kinase-STAT NN I-NP signaling NN I-NP pathway NN I-NP . . O oriP NN B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP EBNA NN B-NP gene NN I-NP promoter NN I-NP activity NN I-NP in IN B-PP Epstein-Barr JJ B-NP virus-immortalized JJ I-NP lymphoblastoid JJ I-NP cell NN I-NP lines NNS I-NP . . O During IN B-PP Epstein-Barr JJ B-NP virus NN I-NP latent JJ I-NP infection NN I-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP in FW B-ADVP vitro FW I-ADVP COMMA COMMA O six CD B-NP viral JJ I-NP nuclear JJ I-NP antigens NNS I-NP ( ( O EBNAs NN B-NP ) ) O are VBP B-VP expressed VBN I-VP from IN B-PP one CD B-NP of IN B-PP two CD B-NP promoters NNS I-NP COMMA COMMA O Cp NN B-NP or CC O Wp NN B-NP COMMA COMMA O whose WP$ B-NP activities NNS I-NP are VBP B-VP mutually RB B-ADJP exclusive JJ I-ADJP . . O Upon IN B-PP infection NN B-NP COMMA COMMA O Wp NN B-NP is VBZ B-VP initially RB B-ADVP active JJ B-ADJP COMMA COMMA O followed VBN B-VP by IN B-PP a DT B-NP switch NN I-NP to TO B-PP Cp NN B-NP for IN B-PP the DT B-NP duration NN I-NP of IN B-PP latency NN B-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O the DT B-NP region NN I-NP upstream JJ B-ADVP of IN B-PP Cp NN B-NP was VBD B-VP analyzed VBN I-VP for IN B-PP the DT B-NP presence NN I-NP of IN B-PP cis NN B-NP elements NNS I-NP involved VBN B-VP in IN B-PP regulating VBG B-VP the DT B-NP activities NNS I-NP of IN B-PP the DT B-NP EBNA NN I-NP gene NN I-NP promoters NNS I-NP in IN B-PP established JJ B-NP in FW I-NP vitro FW I-NP immortalized VBN I-NP lymphoblastoid JJ B-NP cell NN I-NP lines NNS I-NP ( ( O LCLs NNS B-NP ) ) O . . O It PRP B-NP was VBD B-VP determined VBN I-VP that IN B-SBAR oriP NN B-NP COMMA COMMA O the DT B-NP origin NN I-NP for IN B-PP episomal JJ B-NP maintenance NN I-NP during IN B-PP latency NN B-NP COMMA COMMA O is VBZ B-VP essential JJ B-ADJP for IN B-PP efficient JJ B-NP transcription NN I-NP initiation NN I-NP from IN B-PP either CC O Cp NN B-NP or CC O Wp NN B-NP in IN B-PP LCLs NN B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP some DT O Burkitt NN B-NP 's POS B-NP lymphoma NN I-NP cell NN I-NP lines NNS I-NP . . O Deletion NN B-NP of IN B-PP the DT B-NP EBNA2-dependent JJ I-NP enhancer NN I-NP located JJ B-ADJP upstream RB I-ADJP of IN B-PP Cp NN B-NP resulted VBD B-VP in IN B-PP a DT B-NP ca. FW I-NP two- CD I-NP to TO I-NP fivefold JJ I-NP reduction NN I-NP in IN B-PP Cp NN B-NP activity NN I-NP in IN B-PP the DT B-NP LCLs NNS I-NP assayed VBN B-VP . . O More RBR B-NP extensive JJ I-NP deletion NN I-NP of IN B-PP sequences NNS B-NP upstream JJ B-ADVP of IN B-PP Cp NN B-NP COMMA COMMA O including VBG B-PP the DT B-NP EBNA2-dependent JJ I-NP enhancer NN I-NP COMMA COMMA O resulted VBD B-VP in IN B-PP nearly RB B-NP complete JJ I-NP loss NN I-NP of IN B-PP Cp NN B-NP activity NN I-NP . . O This DT B-NP loss NN I-NP of IN B-PP activity NN B-NP was VBD B-VP shown VBN I-VP to TO I-VP correlate VB I-VP with IN B-PP deletion NN B-NP of IN B-PP two CD B-NP CCAAT NN I-NP boxes NNS I-NP COMMA COMMA O a DT B-NP proximal JJ I-NP CCAAT NN I-NP box NN I-NP located JJ B-ADJP at IN B-PP bp NN B-NP -61 CD B-NP to TO O -65 CD B-NP and CC O a DT B-NP distal JJ I-NP CCAAT NN I-NP box NN I-NP located JJ B-ADJP at IN B-PP bp NN B-NP -253 CD B-NP to TO O -257 CD B-NP COMMA COMMA O upstream RB B-ADVP of IN B-PP Cp NN B-NP . . O Site-directed JJ B-NP mutagenesis NN I-NP of IN B-PP these DT B-NP cis NN I-NP elements NNS I-NP demonstrated VBD B-VP that IN B-SBAR Cp NN B-NP activity NN I-NP is VBZ B-VP highly RB B-ADJP dependent JJ I-ADJP on IN B-PP the DT B-NP presence NN I-NP of IN B-PP a DT B-NP properly RB I-NP positioned VBN I-NP CCAAT NN I-NP box NN I-NP COMMA COMMA O with IN B-PP the DT B-NP dependence NN I-NP on IN B-PP the DT B-NP distal JJ I-NP CCAAT NN I-NP box NN I-NP apparent JJ B-ADJP only RB B-ADVP when WRB I-ADVP the DT B-NP proximal JJ I-NP CCAAT NN I-NP box NN I-NP was VBD B-VP deleted VBN I-VP or CC O mutated VBN B-VP . . O Deletion NN B-NP of IN B-PP the DT B-NP glucocorticoid NN I-NP response NN I-NP elements NNS I-NP located JJ B-ADJP at IN B-PP ca. FW B-NP bp NN I-NP -850 CD I-NP upstream RB B-ADVP of IN B-PP Cp NN B-NP did VBD B-VP not RB I-VP result VB I-VP in IN B-PP a DT B-NP significant JJ I-NP loss NN I-NP in IN B-PP activity NN B-NP . . O In IN B-PP general JJ B-NP COMMA COMMA O deletions NNS B-NP which WDT B-NP diminished VBD B-VP Cp JJ B-NP activity NN I-NP resulted VBD B-VP in IN B-PP induction NN B-NP of IN B-PP Wp JJ B-NP activity NN I-NP COMMA COMMA O consistent JJ B-ADJP with IN B-PP suppression NN B-NP of IN B-PP Wp JJ B-NP activity NN I-NP by IN B-PP transcriptional JJ B-NP interference NN I-NP from IN B-PP Cp NN B-NP . . O The DT B-NP identification NN I-NP of IN B-PP oriP NN B-NP and CC O the DT B-NP EBNA2-dependent JJ I-NP enhancer NN I-NP as IN B-PP the DT B-NP major JJ I-NP positive JJ I-NP cis NN I-NP elements NNS I-NP involved VBN B-VP in IN B-PP regulating VBG B-VP Cp JJ B-NP activity NN I-NP in IN B-PP LCL NN B-NP suggests VBZ B-VP that IN B-SBAR EBNA NN B-NP gene NN I-NP transcription NN I-NP is VBZ B-VP largely RB I-VP autoregulated VBN I-VP by IN B-PP EBNA NN B-NP 1 CD I-NP and CC O EBNA NN B-NP 2 CD I-NP . . O Various JJ B-NP modes NNS I-NP of IN B-PP basic JJ B-NP helix-loop-helix JJ I-NP protein-mediated JJ I-NP regulation NN I-NP of IN B-PP murine JJ B-NP leukemia NN I-NP virus NN I-NP transcription NN I-NP in IN B-PP lymphoid JJ B-NP cell NN I-NP lines NNS I-NP . . O The DT B-NP transcriptionally RB I-NP regulatory JJ I-NP regions NNS I-NP of IN B-PP the DT B-NP lymphomagenic JJ I-NP Akv NN B-NP and CC O SL3-3 NN B-NP murine JJ B-NP leukemia NN I-NP retroviruses NNS I-NP ( ( O MLVs NNS B-NP ) ) O contain VBP B-VP two CD B-NP types NNS I-NP of IN B-PP E-box NN B-NP consensus NN I-NP motifs NNS I-NP COMMA COMMA O CAGATG NN B-NP . . O One CD B-NP type NN I-NP COMMA COMMA O EA\/S NN B-NP COMMA COMMA O is VBZ B-VP located JJ B-ADJP in IN B-PP the DT B-NP upstream JJ I-NP promoter NN I-NP region NN I-NP COMMA COMMA O and CC O the DT B-NP other JJ I-NP COMMA COMMA O E(gre) NN B-NP COMMA COMMA O is VBZ B-VP located JJ B-ADJP in IN B-PP a DT B-NP tandem JJ I-NP repeat NN I-NP with IN B-PP enhancer NN B-NP properties NNS I-NP . . O We PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP requirements NNS I-NP of IN B-PP the DT B-NP individual JJ I-NP E-boxes NNS I-NP in IN B-PP MLV NN B-NP transcriptional JJ I-NP regulation NN I-NP . . O In IN B-PP lymphoid JJ B-NP cell NN I-NP lines NNS I-NP only RB B-ADVP COMMA COMMA O the DT B-NP E(gre)-binding JJ I-NP protein NN I-NP complexes NNS I-NP included VBD B-VP ALF1 NN B-NP or CC O HEB NN B-NP and CC O E2A NN B-NP basic JJ B-NP helix-loop-helix JJ I-NP proteins NNS I-NP . . O Ectopic JJ O ALF1 NN B-NP and CC O E2A NN B-NP proteins NNS B-NP required VBD B-VP intact JJ B-NP E(gre) NN I-NP motifs NNS I-NP for IN B-PP mediating VBG B-VP transcriptional JJ B-NP activation NN I-NP . . O ALF1 NNP B-NP transactivated VBD B-VP transcription NN B-NP of IN B-PP Akv NN B-NP MLV NN I-NP through IN B-PP the DT B-NP two CD I-NP E(gre) NN I-NP motifs NNS I-NP equally RB B-ADVP COMMA COMMA O whereas IN O E2A NN B-NP protein NN I-NP required VBD B-VP the DT B-NP promoter-proximal JJ I-NP E(gre) NN I-NP motif NN I-NP . . O In IN B-PP T- NN B-NP and CC O B-cell NN B-NP lines NNS B-NP COMMA COMMA O the DT B-NP E(gre) NN I-NP motifs NNS I-NP were VBD B-VP of IN B-PP major JJ B-NP importance NN I-NP for IN B-PP Akv NN B-NP MLV NN I-NP transcriptional JJ I-NP activity NN I-NP COMMA COMMA O while IN B-SBAR the DT B-NP EA\/S NN I-NP motif NN I-NP had VBD B-VP some DT B-NP effect NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O neither CC O E(gre) NN B-NP nor CC O EA\/S NN B-NP motifs NNS B-NP contributed VBD B-VP pronouncedly RB B-ADVP to TO B-PP Akv NN B-NP MLV NN I-NP transcription NN I-NP in IN B-PP NIH NN B-NP 3T3 NN I-NP cells NNS I-NP lacking VBG B-VP DNA-binding JJ O ALF1 NN B-NP or CC O HEB NN B-NP and CC O E2A NN B-NP proteins NNS B-NP . . O The DT B-NP Id1 NN I-NP protein NN I-NP was VBD B-VP found VBN I-VP to TO I-VP repress VB I-VP ALF1 NN B-NP activity NN I-NP in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP . . O Moreover RB B-ADVP COMMA COMMA O ectopic JJ B-NP Id1 NN I-NP repressed VBD B-VP E(gre)-directed JJ O but CC B-CONJP not RB I-CONJP EA\/S-directed JJ B-NP MLV NN I-NP transcription NN I-NP in IN B-PP lymphoid JJ B-NP cell NN I-NP lines NNS I-NP . . O In IN B-PP conclusion NN B-NP COMMA COMMA O E(gre) NN B-NP motifs NNS I-NP and CC O interacting VBG B-NP basic JJ I-NP helix-loop-helix JJ I-NP proteins NNS I-NP are VBP B-VP important JJ B-NP determinants NNS I-NP for IN B-PP MLV NN B-NP transcriptional JJ I-NP activity NN I-NP in IN B-PP lymphocytic JJ B-NP cell NN I-NP lines NNS I-NP . . O The DT B-NP human JJ I-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP posttranscriptional JJ I-NP trans-activator NN I-NP Rex NN I-NP contains VBZ B-VP a DT B-NP nuclear JJ I-NP export NN I-NP signal NN I-NP . . O The DT B-NP Rex NN I-NP protein NN I-NP of IN B-PP human JJ B-NP T-cell NN I-NP leukemia NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP is VBZ B-VP required VBN I-VP for IN B-PP the DT B-NP nuclear JJ I-NP export NN I-NP of IN B-PP unspliced JJ B-NP viral JJ I-NP mRNA NN I-NP and CC B-PP COMMA COMMA I-PP therefore RB I-PP COMMA COMMA O for IN B-PP virus NN B-NP replication NN I-NP . . O In IN B-PP this DT B-NP manuscript NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR Rex NN B-NP shuttles VBZ B-VP between IN B-PP the DT B-NP nucleus NN I-NP and CC O the DT B-NP cytoplasm NN I-NP and CC O that IN B-SBAR its PRP$ B-NP activation NN I-NP domain NN I-NP constitutes VBZ B-VP a DT B-NP nuclear JJ I-NP export NN I-NP signal NN I-NP that WDT B-NP specifies VBZ B-VP efficient JJ B-NP transport NN I-NP to TO B-PP the DT B-NP cytoplasm NN I-NP . . O These DT B-NP findings NNS I-NP are VBP B-VP consistent JJ B-ADJP with IN B-PP a DT B-NP model NN I-NP for IN B-PP Rex-mediated JJ B-NP trans-activation NN I-NP in IN B-PP which WDT B-NP Rex-viral JJ B-NP mRNA NN I-NP complexes NNS I-NP are VBP B-VP targeted VBN I-VP for IN B-PP nuclear JJ B-NP export NN I-NP by IN B-PP the DT B-NP direct JJ I-NP action NN I-NP of IN B-PP the DT B-NP activation NN I-NP domain NN I-NP . . O Multiple JJ B-NP p21ras NN I-NP effector NN I-NP pathways NNS I-NP regulate VBP B-VP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O The DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O Nuclear JJ B-NP Factor NN I-NP of IN I-NP Activated VBN I-NP T NN I-NP cells NNS I-NP ( ( O NFAT NN B-NP ) ) O is VBZ B-VP a DT B-NP major JJ I-NP target NN I-NP for IN B-PP p21ras NN B-NP and CC O calcium NN B-NP signalling NN B-NP pathways NNS I-NP in IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP and CC O is VBZ B-VP induced VBN I-VP by IN B-PP p21ras NN B-NP signals NNS I-NP acting VBG B-VP in IN B-PP synergy NN B-NP with IN B-PP calcium\/calcineurin NN B-NP signals NNS I-NP . . O One CD B-NP p21ras NN I-NP effector NN I-NP pathway NN I-NP involves VBZ B-VP the DT B-NP MAP NN I-NP kinase NN I-NP ERK-2 NN I-NP COMMA COMMA O and CC O we PRP B-NP have VBP B-VP examined VBN I-VP its PRP$ B-NP role NN I-NP in IN B-PP NFAT NN B-NP regulation NN I-NP . . O Expression NN B-NP of IN B-PP dominant JJ B-NP negative JJ I-NP MAPKK-1 NN I-NP prevents VBZ B-VP NFAT NN B-NP induction NN I-NP . . O Constitutively RB B-NP active JJ I-NP MAPKK-1 NN I-NP fully RB B-ADVP activates VBZ B-VP ERK-2 NN B-NP and CC O the DT B-NP transcription NN I-NP factor NN I-NP Elk-1 NN I-NP COMMA COMMA O but CC O does VBZ B-VP not RB I-VP substitute VB I-VP for IN B-PP activated VBN B-NP p21ras NN I-NP and CC O synergize VBP B-VP with IN B-PP calcium\/calcineurin NN B-NP signals NNS I-NP to TO B-VP induce VB I-VP NFAT NN B-NP . . O Expression NN B-NP of IN B-PP dominant JJ B-NP negative JJ I-NP N17Rac NN I-NP also RB B-ADVP prevents VBZ B-VP TCR NN B-NP and CC O p21ras NN B-NP activation NN B-NP of IN B-PP NFAT NN B-NP COMMA COMMA O but CC O without IN B-PP interfering VBG B-VP with IN B-PP the DT B-NP ERK-2 NN I-NP pathway NN I-NP . . O The DT B-NP transcriptional JJ I-NP activity NN I-NP of IN B-PP the DT B-NP NFAT NN I-NP binding NN I-NP site NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP a DT B-NP complex NN I-NP comprising VBG B-VP a DT B-NP member NN I-NP of IN B-PP the DT B-NP NFAT NN I-NP group NN I-NP and CC O AP-1 NN B-NP family NN I-NP proteins NNS I-NP . . O The DT B-NP induction NN I-NP of IN B-PP AP-1 NN B-NP by IN B-PP p21ras NN B-NP also RB B-ADVP requires VBZ B-VP Rac-1 NN B-NP function NN I-NP . . O Activated VBN B-NP Rac-1 NN I-NP could MD B-VP mimic VB I-VP activated VBN B-NP p21ras NN I-NP to TO B-VP induce VB I-VP AP-1 NN B-NP but CC O not RB B-VP to TO I-VP induce VB I-VP NFAT NN B-NP . . O Moreover RB B-ADVP COMMA COMMA O the DT B-NP combination NN I-NP of IN B-PP activated VBN B-NP MAPKK-1 NN B-NP and CC O Rac-1 NN B-NP could MD B-VP not RB I-VP substitute VB I-VP for IN B-PP activated VBN B-NP p21ras NN I-NP and CC O synergize VB B-VP with IN B-PP calcium NN B-NP signals NNS I-NP to TO B-VP induce VB I-VP NFAT NN B-NP . . O Thus RB B-ADVP COMMA COMMA O p21ras NN B-NP regulation NN I-NP of IN B-PP NFAT NN B-NP in IN B-PP T NN B-NP cells NNS I-NP requires VBZ B-VP the DT B-NP activity NN I-NP of IN B-PP multiple JJ B-NP effector NN I-NP pathways NNS I-NP including VBG B-PP those DT B-NP regulated VBN B-VP by IN B-PP MAPKK-1\/ERK-2 NN B-NP and CC O Rac-1 NN B-NP . . O Protein-tyrosine JJ B-NP kinase NN I-NP activation NN I-NP is VBZ B-VP required VBN I-VP for IN B-PP lipopolysaccharide NN B-NP induction NN I-NP of IN B-PP interleukin NN B-NP 1beta NN I-NP and CC O NFkappaB NN B-NP activation NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP NFkappaB NN B-NP nuclear JJ I-NP translocation NN I-NP . . O In IN B-PP human JJ B-NP monocytes NNS I-NP COMMA COMMA O interleukin NN B-NP 1beta NN I-NP protein NN I-NP production NN I-NP and CC O steady JJ B-NP state NN I-NP mRNA NN I-NP levels NNS I-NP are VBP B-VP increased VBN I-VP in IN B-PP response NN I-PP to TO I-PP lipopolysaccharide NN B-NP COMMA COMMA O predominantly RB B-ADVP as IN B-PP a DT B-NP result NN I-NP of IN B-PP increased VBN B-NP transcription NN I-NP of IN B-PP the DT B-NP interleukin NN I-NP 1beta NN I-NP gene NN I-NP . . O Expression NN B-NP of IN B-PP interleukin NN B-NP 1beta NN I-NP and CC O other JJ B-NP cytokines NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP interleukin NN B-NP 6 CD I-NP and CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP COMMA COMMA O has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP dependent JJ B-ADJP on IN B-PP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O NFkappaB NN B-NP . . O Since IN B-SBAR recent JJ B-NP studies NNS I-NP have VBP B-VP shown VBN I-VP that IN B-SBAR lipopolysaccharide-induced JJ B-NP tyrosine NN I-NP kinase NN I-NP activation NN I-NP is VBZ B-VP not RB I-VP required VBN I-VP for IN B-PP NFkappaB NN B-NP nuclear JJ I-NP translocation NN I-NP COMMA COMMA O we PRP B-NP sought VBD B-VP to TO I-VP determine VB I-VP whether IN B-SBAR NFkappaB NN B-NP translocated VBN B-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP tyrosine NN B-NP kinase NN I-NP activity NN I-NP was VBD B-VP active JJ B-ADJP in IN B-PP stimulating VBG B-VP transcription NN B-NP . . O We PRP B-NP have VBP B-VP found VBN I-VP that IN B-SBAR COMMA COMMA O in IN B-PP the DT B-NP human JJ I-NP pro-monocytic JJ I-NP cell NN I-NP line NN I-NP COMMA COMMA O THP-1 NN B-NP COMMA COMMA O the DT B-NP lipopolysaccharide-induced JJ I-NP expression NN I-NP of IN B-PP interleukin NN B-NP 1beta NN I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP tyrosine NN B-NP kinase NN I-NP activation NN I-NP . . O Tyrosine NN B-NP kinases NNS I-NP are VBP B-VP not RB I-VP required VBN I-VP for IN B-PP lipopolysaccharide-mediated JJ B-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP NFkappaB NN B-NP . . O However RB B-ADVP COMMA COMMA O in IN B-PP the DT I-PP absence NN I-PP of IN I-PP tyrosine NN B-NP kinase NN I-NP activity NN I-NP COMMA COMMA O the DT B-NP ability NN I-NP of IN B-PP NFkappaB NN B-NP to TO B-VP stimulate VB I-VP transcription NN B-NP is VBZ B-VP impaired JJ B-ADJP . . O This DT B-NP inhibition NN I-NP of IN B-PP transcription NN B-NP is VBZ B-VP specific JJ B-ADJP for IN B-PP NFkappaB NN B-NP ; : O in IN B-PP the DT I-PP absence NN I-PP of IN I-PP tyrosine NN B-NP kinase NN I-NP activity NN I-NP COMMA COMMA O AP-1-dependent JJ B-NP transcription NN I-NP is VBZ B-VP enhanced VBN I-VP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR COMMA COMMA O while IN B-NP lipopolysaccharide-induced JJ I-NP expression NN O of IN B-NP inflammatory JJ I-NP mediators NNS B-VP requires VBZ B-NP tyrosine NN I-NP kinase NN I-NP activity NN O COMMA COMMA B-NP tyrosine NN I-NP kinase NN I-NP activity NN B-VP is VBZ I-VP not RB B-ADJP obligatory JJ B-PP for IN B-NP lipopolysaccharide NN I-NP signal NN I-NP transduction NN O Granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP preferentially RB B-ADVP activates VBZ B-VP the DT B-NP 94-kD JJ I-NP STAT5A NN I-NP and CC O an DT B-NP 80-kD JJ I-NP STAT5A NN I-NP isoform NN I-NP in IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP monocytes NNS I-NP . . O Granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O induces VBZ B-VP immediate JJ B-NP effects NNS I-NP in IN B-PP monocytes NNS B-NP by IN B-PP activation NN B-NP of IN B-PP the DT O Janus NN B-NP kinase NN I-NP ( ( O JAK2 NN B-NP ) ) O and CC O STAT NN B-NP transcription NN I-NP factor NN I-NP ( ( O STAT5 NN B-NP ) ) O pathway NN B-NP . . O Recent JJ B-NP studies NNS I-NP have VBP B-VP identified VBN I-VP homologues NNS B-NP of IN B-PP STAT5 NN B-NP COMMA COMMA O STAT5A NN B-NP COMMA COMMA O and CC O STAT5B NN B-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP lower JJR B-NP molecular JJ I-NP weight NN I-NP variants NNS I-NP of IN B-PP STAT5 NN B-NP . . O To TO B-VP define VB I-VP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP STAT5 NN I-NP homologues NNS B-NP and CC O lower JJR B-NP molecular JJ I-NP weight NN I-NP variant NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP and CC O monocytes NNS B-NP differentiated VBN B-VP into IN B-PP macrophages NNS B-NP by IN B-PP culture NN B-NP in IN B-PP macrophage-CSF NN B-NP ( ( O M-CSF NN B-NP ) ) O COMMA COMMA O we PRP B-NP measured VBD B-VP the DT B-NP GM-CSF NN I-NP induced JJ I-NP tyrosine NN I-NP phosphorylation NN I-NP of IN B-PP STAT5A NN B-NP COMMA COMMA O STAT5B NN B-NP COMMA COMMA O and CC O any DT B-NP lower JJR I-NP molecular JJ I-NP weight NN I-NP STAT5 NN I-NP isoforms NNS I-NP . . O Freshly RB B-NP isolated VBN I-NP monocytes NNS I-NP expressed VBD B-VP 94-kD JJ B-NP STAT5A NN I-NP COMMA COMMA O 92-kD JJ B-NP STAT5B NN I-NP COMMA COMMA O and CC O an DT B-NP 80-kD JJ I-NP STAT5A NN I-NP molecule NN I-NP . . O Whereas IN B-SBAR 94-kD JJ B-NP STAT5A NN I-NP was VBD B-VP clearly RB I-VP tyrosine NN I-VP phosphorylated JJ I-VP and CC O bound VBD B-VP to TO B-PP the DT B-NP enhancer NN I-NP element NN I-NP COMMA COMMA O the DT B-NP gamma NN I-NP response NN I-NP region NN I-NP ( ( O GRR NN B-NP ) ) O COMMA COMMA O of IN B-PP the DT B-NP Fc NN I-NP gamma NN I-NP RI NN I-NP gene NN I-NP COMMA COMMA O substantially RB B-VP less JJR I-VP tyrosine NN I-VP phosphorylated JJ I-VP STAT5B NN B-NP bound VBD B-VP to TO B-PP the DT B-NP immobilized JJ I-NP GRR NN I-NP element NN I-NP . . O Macrophages NNS B-NP lost VBD B-VP their PRP$ B-NP ability NN I-NP to TO B-VP express VB I-VP the DT B-NP 80-kD JJ I-NP STAT5A NN I-NP protein NN I-NP COMMA COMMA O but CC O retained VBD B-VP their PRP$ B-NP ability NN I-NP to TO B-VP activate VB I-VP STAT5A NN B-NP . . O STAT5A-STAT5A JJ B-NP homodimers NNS I-NP and CC O STAT5A-STAT5B NN B-NP heterodimers NNS I-NP formed VBD B-VP in IN B-PP response NN I-PP to TO I-PP GM-CSF NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O activation NN B-NP of IN B-PP STAT5A NN B-NP predominates VBZ B-VP compared VBN B-PP to TO B-PP STAT5B NN B-NP when WRB B-ADVP assayed VBN B-VP by IN B-PP direct JJ B-NP immunoprecipitation NN I-NP and CC B-PP by IN B-PP evaluation NN B-NP of IN B-PP bound VBN B-NP STATs NNS I-NP to TO B-PP immobilized JJ B-NP GRR NN I-NP . . O Selective JJ B-NP activation NN I-NP of IN B-PP STAT5 NN B-NP homologues NNS I-NP in IN B-CONJP addition NN O to TO O generation NN B-NP of IN B-PP lower JJR B-NP molecular JJ I-NP isoforms NNS I-NP may MD B-VP provide VB I-VP specificity NN B-NP and CC O control NN B-NP to TO B-PP genes NNS B-NP expressed VBN B-VP in IN B-PP response NN I-PP to TO I-PP cytokines NNS B-NP such JJ B-PP as IN I-PP GM-CSF NN B-NP . . O LYSP100-associated JJ B-NP nuclear JJ I-NP domains NNS I-NP ( ( O LANDs NNS B-NP ) ) O : : O description NN B-NP of IN B-PP a DT B-NP new JJ I-NP class NN I-NP of IN B-PP subnuclear JJ B-NP structures NNS I-NP and CC O their PRP$ B-NP relationship NN I-NP to TO B-PP PML NN B-NP nuclear JJ I-NP bodies NNS I-NP . . O The DT B-NP PML NN I-NP gene NN I-NP is VBZ B-VP fused VBN I-VP to TO B-PP the DT O retinoic JJ B-NP acid NN I-NP receptor NN I-NP alpha NN I-NP ( ( O RAR NN B-NP alpha NN I-NP ) ) O gene NN B-NP in IN B-PP t(15;17) NN B-NP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP ( ( O APL NN B-NP ) ) O COMMA COMMA O creating VBG B-VP a DT B-NP PML-RAR NN I-NP alpha NN I-NP fusion NN I-NP oncoprotein NN I-NP . . O The DT B-NP PML NN I-NP gene NN I-NP product NN I-NP has VBZ B-VP been VBN I-VP localized JJ I-VP to TO B-PP subnuclear JJ B-NP dot-like JJ I-NP structures NNS I-NP variously RB B-VP termed VBN I-VP PODs NNS B-NP COMMA COMMA O ND10s NNS B-NP COMMA COMMA O Kr NN B-NP bodies NNS I-NP COMMA COMMA O or CC O PML NN B-NP nuclear JJ I-NP bodies NNS I-NP ( ( O PML NN B-NP NBs NNS I-NP ) ) O . . O The DT B-NP present JJ I-NP study NN I-NP describes VBZ B-VP the DT B-NP cloning NN I-NP of IN B-PP a DT B-NP lymphoid-restricted JJ I-NP gene NN I-NP COMMA COMMA O LYSP100 NN B-NP COMMA COMMA O that WDT B-NP is VBZ B-VP homologous JJ B-ADJP to TO B-PP another DT B-NP protein NN I-NP that WDT B-NP localizes VBZ B-VP to TO B-PP PML NN B-NP NBs NNS I-NP COMMA COMMA O SP100 NN B-NP . . O In IN B-PP addition NN I-PP to TO I-PP SP100 NN B-NP homology NN I-NP regions NNS I-NP COMMA COMMA O one CD B-NP LYSP100 NN I-NP cDNA NN I-NP isoform NN I-NP contains VBZ B-VP a DT B-NP bromodomain NN I-NP and CC O a DT B-NP PHD\/TTC NN I-NP domain NN I-NP COMMA COMMA O which WDT B-NP are VBP B-VP present JJ B-ADJP in IN B-PP a DT B-NP variety NN I-NP of IN B-PP transcriptional JJ B-NP regulatory JJ I-NP proteins NNS I-NP . . O By IN B-PP immunofluorescence NN B-NP COMMA COMMA O LYSP100 NN B-NP was VBD B-VP localized JJ I-VP to TO B-PP nuclear JJ B-NP dots NNS I-NP that WDT B-NP were VBD B-VP surprisingly RB B-ADVP largely RB B-ADJP nonoverlapping JJ I-ADJP with IN B-PP PML NN B-NP NBs NNS I-NP . . O However RB B-ADVP COMMA COMMA O a DT B-NP minority NN I-NP of IN B-PP LYSP100 NN B-NP nuclear JJ I-NP dots NNS I-NP exactly RB B-ADVP colocalized VBD B-VP with IN B-PP PML NN B-NP and CC O SP100 NN B-NP . . O We PRP B-NP term VBP B-VP the DT B-NP LYSP100 NN I-NP structures NNS I-NP " `` O LANDs NNS B-NP COMMA COMMA O " '' O for IN B-PP LYSP100-associated JJ B-NP nuclear JJ I-NP domains NNS I-NP . . O Although IN B-SBAR LYSP100 NN B-NP is VBZ B-VP expressed VBN I-VP only RB B-PP in IN I-PP lymphoid JJ B-NP cells NNS I-NP COMMA COMMA O LANDs NNS B-NP could MD B-VP be VB I-VP visualized VBN I-VP in IN B-PP HeLa NN B-NP cells NNS I-NP by IN B-PP transfection NN B-NP of IN B-PP a DT B-NP LYSP100 NN I-NP cDNA NN I-NP . . O Immunoelectron NN B-NP microscopy NN I-NP revealed VBD B-VP LANDs NNS B-NP to TO B-VP be VB I-VP globular JJ B-NP COMMA COMMA I-NP electron-dense JJ I-NP structures NNS I-NP morphologically RB B-ADJP distinct JJ I-ADJP from IN B-PP the DT B-NP annular JJ I-NP structures NNS I-NP characteristic JJ B-ADJP of IN B-PP PML NN B-NP NBs NNS I-NP . . O LANDs NNS B-NP were VBD B-VP most RBS I-VP often RB I-VP found VBN I-VP in IN B-PP the DT B-NP nucleoplasm NN I-NP COMMA COMMA O but CC O were VBD B-VP also RB I-VP found VBN I-VP at IN B-PP the DT B-NP nuclear JJ I-NP membrane NN I-NP and CC B-PP in IN B-PP the DT B-NP cytoplasm NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR these DT B-NP structures NNS I-NP may MD B-VP traffic VBP I-VP between IN B-PP the DT B-NP cytoplasm NN I-NP and CC O the DT B-NP nucleus NN I-NP . . O By IN B-PP double-immunogold JJ B-NP labeling NN I-NP of IN B-PP PML NN B-NP and CC O LYSP100 NN B-NP COMMA COMMA O some DT B-NP LANDs NNS I-NP were VBD B-VP shown VBN I-VP to TO I-VP contain VB I-VP both CC O PML NN B-NP and CC O LYSP100 NN B-NP . . O Thus RB B-ADVP COMMA COMMA O PML NN B-NP is VBZ B-VP localized JJ I-VP to TO O a DT B-NP second JJ I-NP subnuclear JJ I-NP domain NN I-NP that WDT B-NP is VBZ B-VP morphologically RB B-ADJP and CC I-ADJP biochemically RB I-ADJP distinct JJ I-ADJP from IN B-PP PML NN B-NP NBs NNS I-NP . . O Abnormalities NNS B-NP of IN B-PP p16 NN B-NP COMMA COMMA O p15 NN B-NP and CC O CDK4 NN B-NP genes NNS B-NP in IN B-PP recurrent JJ B-NP malignant JJ I-NP astrocytomas NNS I-NP . . O Abnormalities NNS B-NP in IN B-PP the DT O p16 NN B-NP COMMA COMMA O p15 NN B-NP and CC O CDK4 NN B-NP genes NNS B-NP that WDT B-NP regulate VBP B-VP transition NN B-NP through IN B-PP the DT B-NP G1 NN I-NP phase NN I-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP have VBP B-VP been VBN I-VP implicated VBN I-VP in IN B-PP the DT B-NP malignant JJ I-NP progression NN I-NP of IN B-PP astrocytomas NNS B-NP . . O The DT B-NP results NNS I-NP of IN B-PP the DT B-NP present JJ I-NP study NN I-NP demonstrate VBP B-VP that IN B-SBAR dysfunction NN B-NP of IN B-PP these DT B-NP genes NNS I-NP also RB B-ADVP occurs VBZ B-VP during IN B-PP recurrence NN B-NP of IN B-PP glial JJ B-NP tumors NNS I-NP that WDT B-NP were VBD B-VP highly RB B-ADJP malignant JJ I-ADJP at IN B-PP first JJ B-NP presentation NN I-NP . . O Analysis NN B-NP of IN B-PP 10 CD B-NP matched VBN I-NP pairs NNS I-NP of IN B-PP high JJ B-NP grade NN I-NP malignant JJ I-NP astrocytomas NNS I-NP and CC O their PRP$ B-NP subsequent JJ I-NP recurrences NNS I-NP identified VBD B-VP three CD B-NP distinct JJ I-NP groups NNS I-NP . . O The DT B-NP primary JJ I-NP and CC I-NP recurrent JJ I-NP tumors NNS I-NP in IN B-PP Group NN B-NP A NN I-NP did VBD B-VP not RB I-VP show VB I-VP structural JJ B-NP alterations NNS I-NP in IN B-PP the DT O p16 NN B-NP COMMA COMMA O p15 NN B-NP or CC O CDK4 NN B-NP genes NNS B-NP COMMA COMMA O whereas IN O homozygous JJ B-NP codeletion NN I-NP of IN B-PP p16 NN B-NP and CC O p15 NN B-NP was VBD B-VP observed VBN I-VP in IN B-PP both CC B-NP primary JJ I-NP and CC I-NP recurrent JJ I-NP tumors NNS I-NP in IN B-PP Group NN B-NP B NN I-NP . . O The DT B-NP primary JJ I-NP tumors NNS I-NP in IN B-PP Group NN B-NP C NN I-NP had VBD B-VP a DT B-NP normal JJ I-NP profile NN I-NP of IN B-PP p16 NN B-NP COMMA COMMA O p15 NN B-NP and CC O CDK4 NN B-NP at IN B-PP presentation NN B-NP . . O Upon IN B-PP recurrence NN B-NP COMMA COMMA O however RB B-ADVP COMMA COMMA O the DT B-NP tumors NNS I-NP sustained VBD B-VP either CC O deletion NN B-NP of IN B-PP p16 NN B-NP alone RB B-ADVP or CC O codeletion NN B-NP of IN B-PP both CC O p16 NN B-NP and CC O p15 NN B-NP or CC O amplification NN B-NP of IN B-PP CDK4 NN B-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP molecular JJ I-NP differences NNS I-NP between IN B-PP primary JJ B-NP anaplastic JJ I-NP astrocytomas\/glioblastomas NNS I-NP and CC O their PRP$ B-NP subsequent JJ I-NP recurrences NNS I-NP COMMA COMMA O which WDT B-NP are VBP B-VP clinically RB B-ADVP indistinguishable JJ B-ADJP COMMA COMMA O may MD B-VP provide VB I-VP better JJR B-NP therapeutic JJ I-NP options NNS I-NP for IN B-PP treatment NN B-NP . . O CTL NN B-NP recognition NN I-NP of IN B-PP an DT B-NP altered JJ I-NP peptide NN I-NP associated VBN B-VP with IN B-PP asparagine NN B-NP bond NN I-NP rearrangement NN I-NP . . O Implications NNS B-NP for IN B-PP immunity NN B-NP and CC O vaccine NN B-NP design NN I-NP . . O The DT B-NP extent NN I-NP to TO B-PP which WDT B-NP peptides NNS B-NP containing VBG B-VP chemically RB B-ADVP and CC B-ADVP post-translationally RB B-ADVP modified VBN B-NP amino NN I-NP acid NN I-NP side JJ I-NP chains NNS I-NP are VBP B-VP recognized VBN I-VP by IN B-PP primed JJ B-NP CTL NN I-NP has VBZ B-VP not RB I-VP been VBN I-VP clearly RB I-VP defined VBN I-VP . . O We PRP B-NP report VBP B-VP on IN B-PP the DT B-NP CTL NN I-NP recognition NN I-NP of IN B-PP a DT B-NP MHC NN I-NP class NN I-NP I-restricted JJ I-NP peptide NN I-NP containing VBG B-VP a DT O cyclized JJ B-NP asparagine NN I-NP ( ( O succinimide NN B-NP ) ) O residue NN B-NP . . O This DT B-NP modification NN I-NP of IN B-PP the DT B-NP asparagine NN I-NP side JJ I-NP chain NN I-NP is VBZ B-VP a DT B-NP common JJ I-NP intermediate JJ I-NP structure NN I-NP during IN B-PP deamidation NN B-NP COMMA COMMA O isomerization NN B-NP COMMA COMMA O and CC O bond NN B-NP rearrangements NNS I-NP of IN B-PP amide-containing JJ B-NP amino NN I-NP acids NNS I-NP and CC O also RB O occurs VBZ B-VP as IN B-PP a DT B-NP side JJ I-NP reaction NN I-NP in IN B-PP peptide NN B-NP synthesis NN I-NP . . O The DT B-NP CTL NN I-NP specifically RB B-ADVP recognized VBD B-VP the DT B-NP succinimide-containing JJ I-NP peptide NN I-NP showing VBG B-VP only RB B-NP weak JJ I-NP cross-reactivity NN I-NP at IN B-PP high JJ B-NP concentrations NNS I-NP of IN B-PP the DT B-NP parent NN I-NP peptide NN I-NP containing VBG B-VP unmodified JJ B-NP asparagine NN I-NP . . O Similarly RB B-ADVP COMMA COMMA O CTL NN B-NP raised VBN B-VP against IN B-PP the DT B-NP parent NN I-NP peptide NN I-NP did VBD B-VP not RB I-VP recognize VB I-VP the DT B-NP succinimide JJ I-NP derivative NN I-NP of IN B-PP this DT B-NP peptide NN I-NP . . O Naturally RB B-NP processed VBN I-NP forms NNS I-NP of IN B-PP these DT B-NP structures NNS I-NP are VBP B-VP likely JJ B-ADJP to TO B-VP occur VB I-VP given VBN B-PP the DT B-NP importance NN B-NP and CC O frequency NN B-NP of IN B-PP deamidation NN B-NP both CC O in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP . . O Moreover RB B-ADVP COMMA COMMA O since IN B-SBAR succinimide NN B-NP intermediates NNS I-NP of IN B-PP deamidated VBN B-NP peptides NNS I-NP can MD B-VP occasionally RB I-VP be VB I-VP very RB B-ADJP stable JJ I-ADJP COMMA COMMA O these DT B-NP peptides NNS I-NP have VBP B-VP the DT B-NP potential NN I-NP to TO B-VP act VB I-VP as IN B-PP altered JJ B-NP self-Ags NNS I-NP with IN B-PP significant JJ B-NP implications NNS I-NP for IN B-PP autoimmunity NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O unwanted JJ B-NP and CC I-NP potentially RB I-NP hazardous JJ I-NP specificities NNS I-NP may MD B-VP be VB I-VP elicited VBN I-VP when WRB B-ADVP using VBG B-VP synthetic JJ B-NP peptides NNS I-NP in IN B-PP subunit NN B-NP vaccines NNS I-NP in IN B-PP which WDT B-NP succinimide NN B-NP residues NNS I-NP may MD B-VP form VB I-VP spontaneously RB B-ADVP during IN B-PP storage NN B-NP or CC O chemical JJ B-NP synthesis NN I-NP . . O { ( O NGFI-B\/nur77 NN B-NP family NN I-NP involved VBN B-VP in IN B-PP T-cell NN B-NP apoptosis NN I-NP } ) O NGFI-B\/nur77 NN B-NP is VBZ B-VP a DT B-NP member NN I-NP of IN B-PP the DT B-NP steroid NN I-NP receptor NN I-NP superfamily NN I-NP . . O NGFI-B\/nur77 NN B-NP and CC O its PRP$ B-NP related JJ I-NP genes NNS I-NP constitute VBP B-VP a DT B-NP family NN I-NP and CC O the DT B-NP NGFI-B\/nur77 NN I-NP family NN I-NP consists VBZ B-VP of IN B-PP three CD B-NP subtypes NNS I-NP COMMA COMMA O named VBN B-VP nur77 NN B-NP alpha NN I-NP COMMA COMMA O nur77 NN B-NP beta NN I-NP COMMA COMMA O nur77 NN B-NP gamma NN I-NP . . O We PRP B-NP cloned VBD B-VP human JJ B-NP nur77 NN I-NP beta NN I-NP cDNA NN I-NP COMMA COMMA O called VBN B-VP TINUR NN B-NP . . O Although IN B-SBAR NGFI-B\/nur77 NN B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP TCR-mediated JJ B-NP apoptosis NN I-NP in IN B-PP T-cell NN B-NP hybridomas NNS I-NP COMMA COMMA O the DT B-NP reports NNS I-NP on IN B-PP nur77 NN B-NP knock-out JJ I-NP mice NNS I-NP and CC O nur77 NN B-NP dominant JJ I-NP negative JJ I-NP transgenic JJ I-NP mice NNS I-NP suggest VBP B-VP that IN B-SBAR there EX B-NP is VBZ B-VP a DT B-NP functional JJ I-NP redundancy NN I-NP among IN B-PP NGFI-B\/nur77 NN B-NP family NN I-NP . . O NGFI-B\/nur77 NN B-NP binds VBZ B-VP to TO B-PP the DT B-NP response NN I-NP element NN I-NP by IN B-PP monomer NN B-NP or CC O heterodimer NN B-NP with IN B-PP retinoid NN B-NP X NN I-NP receptor NN I-NP ( ( O RXR NN B-NP ) ) O . . O Assuming VBG B-PP that IN B-SBAR 9-cis-retinoic JJ B-NP acid NN I-NP ( ( O 9-cis-RA NN B-NP ) ) O inhibits VBZ B-VP TCR-mediated JJ B-NP apoptosis NN I-NP COMMA COMMA O nur77 NNS B-NP may MD B-VP cause VB I-VP apoptosis NN B-NP by IN B-PP monomer NN B-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP 9-cis-RA NN B-NP and CC O may MD B-VP inhibit VB I-VP apoptosis NN B-NP by IN B-PP heterodimer NN B-NP with IN B-PP RXR NN B-NP in IN B-PP the DT I-PP presence NN I-PP of IN I-PP 9-cis-RA NN B-NP . . O Interaction NN B-NP of IN B-PP the DT B-NP human JJ I-NP T-cell NN I-NP lymphotropic JJ I-NP virus NN I-NP type NN I-NP 1 CD I-NP tax NN I-NP transactivator NN I-NP with IN B-PP transcription NN B-NP factor NN I-NP IIA NN I-NP . . O The DT B-NP Tax NN I-NP protein NN I-NP of IN B-PP human JJ B-NP T-cell NN I-NP lymphotropic NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HTLV-1 NN B-NP ) ) O is VBZ B-VP a DT B-NP 40-kDa JJ I-NP transcriptional JJ I-NP activator NN I-NP which WDT B-NP is VBZ B-VP critical JJ B-ADJP for IN B-PP HTLV-1 NN B-NP gene NN I-NP regulation NN I-NP and CC O virus-induced JJ B-NP cellular JJ I-NP transformation NN I-NP . . O Tax NN B-NP is VBZ B-VP localized JJ I-VP to TO B-PP the DT B-NP DNA NN I-NP through IN B-PP its PRP$ B-NP interaction NN I-NP with IN B-PP the DT B-NP site-specific JJ I-NP activators NNS I-NP cyclic JJ B-NP AMP-responsive JJ I-NP element-binding JJ I-NP protein NN I-NP COMMA COMMA O NF-kappaB NN B-NP COMMA COMMA O and CC O serum NN B-NP response NN I-NP factor NN I-NP . . O It PRP B-NP has VBZ B-VP been VBN I-VP suggested VBN I-VP that IN B-SBAR the DT B-NP recruitment NN I-NP of IN B-PP Tax NN B-NP to TO B-PP the DT B-NP DNA NN I-NP positions VBZ B-VP Tax NN B-NP for IN B-PP interaction NN B-NP with IN B-PP the DT B-NP basal JJ I-NP transcriptional JJ I-NP machinery NN I-NP . . O On IN B-PP the DT I-PP basis NN I-PP of IN I-PP several JJ B-NP independent JJ I-NP assays NNS I-NP COMMA COMMA O we PRP B-NP now RB B-ADVP report VBP B-VP a DT B-NP physical JJ I-NP and CC I-NP functional JJ I-NP interaction NN I-NP between IN B-PP Tax NN B-NP and CC O the DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O TFIIA NN B-NP . . O First RB B-ADVP COMMA COMMA O Tax NN B-NP was VBD B-VP found VBN I-VP to TO I-VP interact VB I-VP with IN B-PP the DT O 35-kDa JJ O ( ( O alpha NN B-NP ) ) O subunit NN B-NP of IN B-PP TFIIA NN B-NP in IN B-PP the DT B-NP yeast NN I-NP two-hybrid JJ I-NP interaction NN I-NP system NN I-NP . . O Importantly RB B-ADVP COMMA COMMA O two CD B-NP previously RB I-NP characterized VBN I-NP mutants NNS I-NP with IN B-PP point NN B-NP mutations NNS I-NP in IN B-PP Tax NN B-NP COMMA COMMA O M32 NN B-NP ( ( O Y196A NN B-NP COMMA COMMA O K197S NN B-NP ) ) O and CC O M41 NN B-NP ( ( O H287A NN B-NP COMMA COMMA O P288S NN B-NP ) ) O COMMA COMMA O which WDT B-NP were VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP defective JJ B-ADJP in IN B-PP Tax-activated JJ B-NP transcription NN I-NP were VBD B-VP unable JJ B-ADJP to TO B-VP interact VB I-VP with IN B-PP TFIIA NN B-NP in IN B-PP this DT B-NP assay NN I-NP . . O Second RB B-ADVP COMMA COMMA O a DT O glutathione-S-transferase NN B-NP ( ( O GST NN B-NP ) ) O affinity-binding JJ B-NP assay NN I-NP showed VBD B-VP that IN B-SBAR the DT B-NP interaction NN I-NP of IN B-PP holo-TFIIA NN B-NP with IN B-PP GST-Tax NN B-NP was VBD B-VP 20-fold RB B-ADJP higher JJR I-ADJP than IN B-PP that DT B-NP observed VBN B-VP with IN B-PP either CC O the DT B-NP GST-Tax NN I-NP M32 NN I-NP activation NN I-NP mutant NN I-NP or CC O the DT B-NP GST NN I-NP control NN I-NP . . O Third RB B-ADVP COMMA COMMA O a DT B-NP coimmunoprecipitation NN I-NP assay NN I-NP showed VBD B-VP that IN B-SBAR in IN B-PP HTLV-1-infected JJ B-NP human JJ I-NP T NN I-NP lymphocytes NNS I-NP COMMA COMMA O Tax NN B-NP and CC O TFIIA NN B-NP were VBD B-VP associated VBN I-VP . . O Finally RB B-ADVP COMMA COMMA O TFIIA NN B-NP facilitates NNS B-VP Tax NN B-NP transactivation NN I-NP in FW B-ADVP vitro FW I-ADVP and CC B-ADVP in FW B-ADVP vivo FW I-ADVP . . O In FW B-NP vitro FW I-NP transcription NN I-NP studies NNS I-NP showed VBD B-VP reduced VBN B-NP levels NNS I-NP of IN B-PP Tax-activated JJ B-NP transcription NN I-NP in IN B-PP cell NN B-NP extracts NNS I-NP depleted VBN B-VP of IN B-PP TFIIA NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O transfection NN B-NP of IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP with IN B-PP TFIIA NN B-NP expression NN I-NP vectors NNS I-NP enhanced VBD B-VP Tax-activated JJ B-NP transcription NN I-NP of IN B-PP an DT B-NP HTLV-1 NN I-NP long JJ I-NP terminal JJ I-NP repeat-chloramphenicol NN I-NP acetyltransferase NN I-NP reporter NN I-NP construct NN I-NP . . O Our PRP$ B-NP study NN I-NP suggests VBZ B-VP that IN B-SBAR the DT B-NP interaction NN I-NP of IN B-PP Tax NN B-NP with IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP TFIIA NN I-NP may MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP Tax-mediated JJ B-NP transcriptional JJ I-NP activation NN I-NP . . O Peptide NN B-NP vaccination NN I-NP can MD B-VP lead VB I-VP to TO B-PP enhanced VBN B-NP tumor NN I-NP growth NN I-NP through IN B-PP specific JJ B-NP T-cell NN I-NP tolerance NN I-NP induction NN I-NP . . O Vaccination NN B-NP with IN B-PP synthetic JJ B-NP peptides NNS I-NP representing VBG B-VP cytotoxic JJ B-NP T NN I-NP lymphocyte NN I-NP ( ( O CTL NN B-NP ) ) O epitopes NNS B-NP can MD B-VP lead VB I-VP to TO B-PP a DT B-NP protective JJ I-NP CTL-mediated JJ I-NP immunity NN I-NP against IN B-PP tumors NNS B-NP or CC O viruses NNS B-NP . . O We PRP B-NP now RB B-ADVP report VBP B-VP that IN B-SBAR vaccination NN B-NP with IN B-PP a DT B-NP CTL NN I-NP epitope NN I-NP derived VBN B-VP from IN B-PP the DT B-NP human JJ I-NP adenovirus NN I-NP type NN I-NP 5 CD I-NP E1A-region NN I-NP ( ( O Ad5E1A234-243 NN B-NP ) ) O COMMA COMMA O which WDT B-NP can MD B-VP serve VB I-VP as IN B-PP a DT B-NP target NN I-NP for IN B-PP tumor-eradicating JJ B-NP CTL NN I-NP COMMA COMMA O enhances VBZ B-VP rather RB B-CONJP than IN I-CONJP inhibits VBZ B-VP the DT B-NP growth NN I-NP of IN B-PP Ad5E1A-expressing JJ B-NP tumors NNS I-NP . . O This DT B-NP adverse JJ I-NP effect NN I-NP of IN B-PP peptide NN B-NP vaccination NN I-NP was VBD B-VP rapidly RB I-VP evoked VBN I-VP COMMA COMMA O required VBD B-VP low JJ B-NP doses NNS I-NP of IN B-PP peptide NN B-NP ( ( O 10 CD B-NP micrograms NNS I-NP ) ) O COMMA COMMA O and CC O was VBD B-VP achieved VBN I-VP by IN B-PP a DT B-NP mode NN I-NP of IN B-PP peptide NN B-NP delivery NN I-NP that WDT B-NP induces VBZ B-VP protective JJ B-NP T-cell-mediated JJ I-NP immunity NN I-NP in IN B-PP other JJ B-NP models NNS I-NP . . O Ad5E1A-specific JJ B-NP CTL NN I-NP activity NN I-NP could MD B-VP no RB I-VP longer RB I-VP be VB I-VP isolated VBN I-VP from IN B-PP mice NNS B-NP after IN B-PP injection NN B-NP of IN B-PP Ad5E1A-peptide NN B-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR tolerization NN B-NP of IN B-PP Ad5E1A-specific JJ B-NP CTL NN I-NP activity NN I-NP causes VBZ B-VP the DT B-NP enhanced VBN I-NP tumor NN I-NP outgrowth NN I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP peptide NN B-NP vaccination NN I-NP COMMA COMMA O immunization NN B-NP with IN B-PP adenovirus NN B-NP COMMA COMMA O expressing VBG B-VP Ad5E1A NN B-NP COMMA COMMA O induced VBD B-VP Ad5E1A-specific JJ B-NP immunity NN I-NP and CC O prevented VBD B-VP the DT B-NP outgrowth NN I-NP of IN B-PP Ad5E1A-expressing JJ B-NP tumors NNS I-NP . . O These DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR immunization NN B-NP with IN B-PP synthetic JJ B-NP peptides NNS I-NP can MD B-VP lead VB I-VP to TO B-PP the DT B-NP elimination NN I-NP of IN B-PP anti-tumor JJ B-NP CTL NN I-NP responses NNS I-NP . . O These DT B-NP findings NNS I-NP are VBP B-VP important JJ B-ADJP for IN B-PP the DT B-NP design NN I-NP of IN B-PP safe JJ B-NP peptide-based JJ I-NP vaccines NNS I-NP against IN B-PP tumors NNS B-NP COMMA COMMA O allogeneic JJ B-NP organ NN I-NP transplants NNS I-NP COMMA COMMA O and CC O T-cell-mediated JJ B-NP autoimmune JJ I-NP diseases NNS I-NP . . O Transgenic JJ B-NP expression NN I-NP of IN B-PP PML\/RARalpha NN B-NP impairs VBZ B-VP myelopoiesis NN B-NP . . O The DT B-NP translocation NN I-NP found VBN B-VP in IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP rearranges VBZ B-VP the DT B-NP promyelocytic JJ I-NP leukemia NN I-NP gene NN I-NP ( ( O PML NN B-NP ) ) O on IN B-PP chromosome NN B-NP 15 CD I-NP with IN B-PP the DT B-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP alpha NN I-NP ( ( O RARalpha NN B-NP ) ) O on IN B-PP chromosome NN B-NP 17 CD I-NP . . O This DT B-NP yields VBZ B-VP a DT B-NP fusion NN I-NP transcript NN I-NP COMMA COMMA O PML\/RARalpha NN B-NP COMMA COMMA O a DT B-NP transcription NN I-NP factor NN I-NP with IN B-PP reported VBN B-NP dominant JJ I-NP negative JJ I-NP functions NNS I-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP hormone NN B-NP . . O Clinical JJ B-NP remissions NNS I-NP induced VBN B-VP with IN B-PP all-trans JJ O retinoic JJ B-NP acid NN I-NP ( ( O RA NN B-NP ) ) O treatment NN B-NP in IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP are VBP B-VP linked VBN I-VP to TO B-PP PML\/RARalpha NN B-NP expression NN I-NP in IN B-PP leukemic JJ B-NP cells NNS I-NP . . O To TO B-VP evaluate VB I-VP the DT B-NP PML\/RARalpha NN I-NP role NN I-NP in IN B-PP myelopoiesis NN B-NP COMMA COMMA O transgenic JJ B-NP mice NNS I-NP expressing VBG B-VP PML\/RARalpha NN B-NP were VBD B-VP engineered VBN I-VP . . O A DT B-NP full-length JJ I-NP PML\/RARalpha NN I-NP cDNA NN I-NP driven VBN B-VP by IN B-PP the DT B-NP CD11b NN I-NP promoter NN I-NP was VBD B-VP expressed VBN I-VP in IN B-PP transgenic JJ B-NP mice NNS I-NP . . O Expression NN B-NP was VBD B-VP confirmed VBN I-VP in IN B-PP the DT B-NP bone NN I-NP marrow NN I-NP with IN B-PP a DT B-NP reverse JJ I-NP transcription NN I-NP PCR NN I-NP assay NN I-NP . . O Basal JJ O total JJ O white JJ B-NP blood NN I-NP cell NN I-NP and CC O granulocyte NN B-NP counts NNS B-NP did VBD B-VP not RB I-VP appreciably RB I-VP differ VB I-VP between IN B-PP PML\/RARalpha NN O transgenic JJ O and CC O control NN B-NP mice NNS B-NP . . O Cell NN B-NP sorter NN I-NP analysis NN I-NP of IN B-PP CD11b+ JJ B-NP bone NN I-NP marrow NN I-NP cells NNS I-NP revealed VBD B-VP similar JJ B-NP CD11b+ JJ I-NP populations NNS I-NP in IN B-PP transgenic JJ O and CC O control NN B-NP mice NNS B-NP . . O Granulocyte\/macrophage NN B-NP colony-stimulating JJ I-NP factor NN I-NP and CC O kit NN B-NP ligand NN I-NP cotreatment NN I-NP did VBD B-VP not RB I-VP overcome VB I-VP this DT B-NP inhibition NN I-NP . . O Impaired JJ B-NP myelopoiesis NN I-NP in FW B-ADVP vivo FW I-ADVP was VBD B-VP shown VBN I-VP by IN B-PP stressing VBG B-VP these DT B-NP mice NNS I-NP with IN B-PP sublethal JJ B-NP irradiation NN I-NP . . O Following VBG B-PP irradiation NN B-NP COMMA COMMA O PML\/RARalpha NN B-NP transgenic JJ I-NP mice NNS I-NP COMMA COMMA O as IN B-SBAR compared VBN B-VP with IN B-PP controls NNS B-NP COMMA COMMA O more RBR B-ADVP rapidly RB I-ADVP depressed VBD B-VP peripheral JJ B-NP white JJ I-NP blood NN I-NP cell NN I-NP and CC O granulocyte NN B-NP counts NNS B-NP . . O As IN B-SBAR expected VBN B-VP COMMA COMMA O nearly RB B-NP all DT I-NP control NN I-NP mice NNS I-NP ( ( O 94.4 CD B-NP % NN I-NP ) ) O survived VBD B-VP irradiation NN B-NP COMMA COMMA O yet CC O this DT B-NP irradiation NN I-NP was VBD B-VP lethal JJ B-ADJP to TO B-PP 45.8 CD B-NP % NN I-NP of IN B-PP PML\/RARalpha NN B-NP transgenic JJ I-NP mice NNS I-NP . . O Lethality NN B-NP was VBD B-VP associated VBN I-VP with IN B-PP more RBR B-NP severe JJ I-NP leukopenia NN I-NP in IN B-PP transgenic JJ O versus CC O control NN B-NP mice NNS B-NP . . O Retinoic JJ B-NP acid NN I-NP treatment NN I-NP of IN B-PP irradiated JJ B-NP PML\/RARalpha NN I-NP mice NNS I-NP enhanced VBD B-VP granulocyte NN B-NP recovery NN I-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR abnormal JJ B-NP myelopoiesis NN I-NP due IN B-PP to TO I-PP PML\/RARalpha NN B-NP expression NN I-NP is VBZ B-VP an DT B-NP early JJ I-NP event NN I-NP in IN B-PP oncogenic JJ B-NP transformation NN I-NP . . O Defective JJ B-NP transcription NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP is VBZ B-VP associated VBN I-VP with IN B-PP impaired JJ B-NP expression NN I-NP of IN B-PP c-Fos NN B-NP COMMA COMMA O FosB NN B-NP COMMA COMMA O and CC O JunB NN B-NP in IN B-PP anergic JJ B-NP T NN I-NP helper NN I-NP 1 CD I-NP cells NNS I-NP . . O Anergic JJ B-NP CD4+ JJ I-NP Th NN I-NP cells NNS I-NP do VBP B-VP not RB I-VP produce VB I-VP IL-2 NN B-NP when WRB B-ADVP challenged VBN B-VP with IN B-PP Ag-pulsed JJ B-NP accessory JJ I-NP cells NNS I-NP because IN B-PP of IN I-PP a DT B-NP transcriptional JJ I-NP defect NN I-NP . . O In IN B-PP this DT B-NP work NN I-NP COMMA COMMA O we PRP B-NP report VBP B-VP that IN B-SBAR these DT B-NP anergic JJ I-NP T NN I-NP cells NNS I-NP are VBP B-VP defective JJ B-ADJP in IN B-PP their PRP$ B-NP ability NN I-NP to TO B-VP up-regulate VB I-VP protein NN B-NP binding NN I-NP and CC O transactivation NN B-NP at IN B-PP two CD B-NP critical JJ I-NP IL-2 NN I-NP DNA NN I-NP enhancer NN I-NP elements NNS I-NP : : O NF-AT NN B-NP ( ( O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ; : O a DT B-NP sequence NN I-NP that WDT B-NP binds VBZ B-VP a DT O heterotrimeric JJ O NFATp NN B-NP COMMA COMMA O Fos NN B-NP COMMA COMMA O and CC O Jun NN B-NP protein NN B-NP complex NN I-NP ) ) O and CC O Activator NN B-NP Protein-1 NN I-NP ( ( O AP-1 NN B-NP ) ) O ( ( O that WDT B-NP binds VBZ B-VP Fos NN B-NP and CC O Jun NN B-NP heterodimers NNS B-NP ) ) O . . O Western NN B-NP blot NN I-NP analysis NN I-NP of IN B-PP nuclear JJ B-NP extracts NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP impaired JJ I-NP DNA-protein NN I-NP interactions NNS I-NP in IN B-PP anergic JJ B-NP T NN I-NP cells NNS I-NP were VBD B-VP associated VBN I-VP with IN B-PP poor JJ B-NP expression NN I-NP of IN B-PP the DT B-NP inducible JJ I-NP AP-1 NN I-NP family NN I-NP members NNS I-NP c-Fos NN B-NP COMMA COMMA O FosB NN B-NP COMMA COMMA O and CC O JunB NN B-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP reduced VBN I-NP expression NN I-NP of IN B-PP these DT B-NP proteins NNS I-NP was VBD B-VP not RB O the DT B-NP result NN I-NP of IN B-PP a DT B-NP global JJ I-NP TCR\/CD3-signaling JJ I-NP defect NN I-NP because IN B-SBAR CD3 NN B-NP cross-linking NN I-NP induced VBD B-VP an DT B-NP equivalent JJ I-NP increase NN I-NP in IN B-PP intracellular-free JJ B-NP calcium NN I-NP ions NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP NFATp NN B-NP dephosphorylation NN I-NP COMMA COMMA O translocation NN B-NP to TO B-PP the DT B-NP nucleus NN I-NP COMMA COMMA O and CC O DNA NN B-NP binding NN I-NP in IN B-PP both CC B-NP normal JJ I-NP and CC I-NP anergic JJ I-NP T NN I-NP cells NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O defective JJ B-NP IL-2 NN I-NP gene NN I-NP transcription NN I-NP appears VBZ B-VP to TO I-VP be VB I-VP due JJ B-PP COMMA COMMA B-ADVP at IN I-ADVP least JJS B-PP in IN B-NP part NN O COMMA COMMA O to TO B-NP a DT I-NP selective JJ I-NP block NN O in IN B-NP the DT I-NP expression NN O of IN O the DT O AP-1 NN B-NP Fos NN B-NP and CC O Jun NN B-NP family NN I-NP members NNS O in IN B-NP anergic JJ I-NP T NN I-NP cells NNS O Elevated JJ B-NP cyclic JJ I-NP AMP NN I-NP inhibits VBZ B-VP NF-kappaB-mediated JJ B-NP transcription NN I-NP in IN B-PP human JJ B-NP monocytic JJ B-NP cells NNS I-NP and CC O endothelial JJ B-NP cells NNS I-NP . . O The DT B-NP NF-kappaB\/Rel NN I-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP regulates VBZ B-VP the DT B-NP inducible JJ I-NP expression NN I-NP of IN B-PP many JJ B-NP genes NNS I-NP in IN B-PP activated VBN B-NP human JJ I-NP monocytes NNS B-NP and CC O endothelial JJ B-NP cells NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP examined VBD B-VP the DT B-NP molecular JJ I-NP mechanism NN I-NP by IN B-PP which WDT B-NP agents NNS B-NP that WDT B-NP elevate VBP B-VP intracellular JJ B-NP cAMP NN I-NP inhibit VBP B-VP the DT B-NP expression NN I-NP of IN B-PP the DT O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNFalpha NN B-NP ) ) O COMMA COMMA O tissue NN B-NP factor NN I-NP COMMA COMMA O endothelial JJ B-NP leukocyte NN I-NP adhesion NN I-NP molecule-1 NN I-NP COMMA COMMA O and CC O vascular JJ B-NP cell NN I-NP adhesion NN I-NP molecule-1 NN I-NP genes NNS B-NP . . O Both CC O forskolin NN B-NP and CC O dibutyryl NN B-NP cAMP NN I-NP COMMA COMMA O which WDT B-NP elevate VBP B-VP intracellular JJ B-NP cAMP NN I-NP by IN B-PP independent JJ B-NP mechanisms NNS I-NP COMMA COMMA O inhibited VBD B-VP TNFalpha NN B-NP and CC O tissue NN B-NP factor NN I-NP expression NN B-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP transcription NN B-NP . . O Induction NN B-NP of IN B-PP NF-kappaB-dependent JJ B-NP gene NN I-NP expression NN I-NP in IN B-PP transiently RB B-NP transfected VBN I-NP human JJ B-NP monocytic JJ I-NP THP-1 NN I-NP cells NNS I-NP and CC O human JJ B-NP umbilical JJ I-NP vein NN I-NP endothelial JJ I-NP cells NNS I-NP was VBD B-VP inhibited VBN I-VP by IN B-PP elevated JJ B-NP cAMP NN I-NP and CC B-PP by IN B-PP overexpression NN B-NP of IN B-PP the DT B-NP catalytic JJ I-NP subunit NN I-NP of IN B-PP protein NN B-NP kinase NN I-NP A NN I-NP ( ( O PKA NN B-NP ) ) O . . O Elevated JJ B-NP cAMP NN I-NP did VBD B-VP not RB I-VP prevent VB I-VP nuclear JJ B-NP translocation NN I-NP of IN B-PP p50\/p65 NN B-NP and CC O c-Rel\/p65 NN B-NP heterodimers NNS B-NP COMMA COMMA O decrease VB B-VP nuclear JJ B-NP translocation NN I-NP of IN B-PP p65 NN B-NP COMMA COMMA O or CC O significantly RB B-VP modify VB I-VP TNFalpha-induced JJ B-NP phosphorylation NN I-NP of IN B-PP p65 NN B-NP . . O Functional JJ B-NP studies NNS I-NP demonstrated VBD B-VP that IN B-SBAR transcriptional JJ B-NP activation NN I-NP of IN B-PP a DT B-NP plasmid NN I-NP containing VBG B-VP multimerized JJ B-NP kappaB NN I-NP sites NNS I-NP by IN B-PP p65 NN B-NP was VBD B-VP inhibited VBN I-VP by IN B-PP agents NNS B-NP that IN B-NP elevate VBP B-VP cAMP NN B-NP and CC B-PP by IN B-PP overexpression NN B-NP of IN B-PP the DT B-NP catalytic JJ I-NP subunit NN I-NP of IN B-PP PKA NN B-NP . . O This DT B-NP study NN I-NP indicates VBZ B-VP that IN B-SBAR activation NN B-NP of IN B-PP PKA NN B-NP reduces VBZ B-VP the DT B-NP induction NN I-NP of IN B-PP a DT B-NP distinct JJ I-NP set NN I-NP of IN B-PP genes NNS B-NP in IN B-PP monocytes NNS B-NP and CC O endothelial JJ B-NP cells NNS I-NP by IN B-PP inhibiting VBG B-VP NF-kappaB-mediated JJ B-NP transcription NN I-NP . . O Characterization NN B-NP of IN B-PP a DT B-NP new JJ I-NP isoform NN I-NP of IN B-PP the DT O NFAT NN B-NP ( ( O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ) ) O gene NN B-NP family NN I-NP member NN I-NP NFATc NN B-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP J NNP B-NP Biol NNP I-NP Chem NNP I-NP 1996 CD B-NP Dec NNP I-NP 27 CD I-NP ; : O 271 CD B-NP ( ( I-NP 52 CD I-NP ) ) O : : O 33705 CD B-NP } ) O The DT B-NP cyclosporin NN I-NP A NN I-NP ( ( I-NP CsA NN I-NP ) ) I-NP \/FK506-sensitive JJ I-NP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NFAT NN B-NP ) ) O plays VBZ B-VP a DT B-NP key JJ I-NP role NN I-NP in IN B-PP the DT B-NP inducible JJ I-NP expression NN I-NP of IN B-PP cytokine NN B-NP genes NNS I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O Although IN B-SBAR NFAT NN B-NP has VBZ B-VP been VBN I-VP recently RB I-VP shown VBN I-VP to TO I-VP be VB I-VP inducible JJ B-ADJP in IN B-PP several JJ B-NP non-T JJ I-NP immune JJ I-NP cells NNS I-NP COMMA COMMA O the DT B-NP NFAT NN I-NP gene NN I-NP family NN I-NP members NNS I-NP characterized VBN B-VP to TO B-PP date NN B-NP have VBP B-VP been VBN I-VP isolated VBN I-VP only RB B-PP from IN I-PP T NN B-NP cells NNS I-NP . . O To TO B-VP further RBR I-VP characterize VB I-VP NFAT NN B-NP function NN I-NP in IN B-PP human JJ B-NP B NN I-NP cells NNS I-NP and CC O to TO B-VP demonstrate VB I-VP cytokine NN B-NP gene NN I-NP specificity NN I-NP of IN B-PP NFAT NN B-NP proteins NNS I-NP COMMA COMMA O we PRP B-NP report VBP B-VP here RB B-ADVP the DT B-NP isolation NN B-NP and CC O characterization NN B-NP of IN B-PP a DT B-NP cDNA NN I-NP clone NN I-NP from IN B-PP the DT B-NP Raji NN I-NP B NN I-NP cell NN I-NP line NN I-NP . . O The DT B-NP cDNA NN I-NP clone NN I-NP encodes VBZ B-VP a DT B-NP new JJ I-NP isoform NN I-NP COMMA COMMA O NFATc.beta NN B-NP COMMA COMMA O of IN B-PP the DT B-NP NFAT NN I-NP gene NN I-NP family NN I-NP member NN I-NP NFATc NN I-NP ( ( O designated VBN B-VP here RB B-ADVP NFATc.alpha NN B-NP ) ) O . . O The DT B-NP amino NN I-NP acid NN I-NP sequence NN I-NP of IN B-PP NFATc.beta NN B-NP differs VBZ B-VP from IN B-PP that DT B-NP of IN B-PP NFATc.alpha NN B-NP in IN B-PP the DT B-NP first JJ I-NP NH2-terminal JJ I-NP 29 CD I-NP residues NNS I-NP and CC O contains VBZ B-VP an DT B-NP additional JJ I-NP region NN I-NP of IN B-PP 142 CD B-NP residues NNS I-NP at IN B-PP the DT B-NP COOH NN I-NP terminus NN I-NP . . O Northern NN B-NP analysis NN I-NP using VBG B-VP a VBG B-NP probe NN I-NP encompassing VBG B-VP a DT B-NP common JJ I-NP region NN I-NP of IN B-PP both DT B-NP isoforms NNS I-NP showed VBD B-VP two CD B-NP mRNA NN I-NP species NNS I-NP of IN B-PP 2.7 CD B-NP and CC I-NP 4.5 CD I-NP kilobase NN I-NP pairs NNS I-NP COMMA COMMA O while IN B-SBAR an DT B-NP NFATc.beta-specific JJ I-NP probe NN I-NP detected VBD B-VP only RB B-NP the DT I-NP 4.5-kilobase NN I-NP pair NN I-NP mRNA NN I-NP which WDT B-NP was VBD B-VP preferentially RB I-VP expressed VBN I-VP in IN B-PP the DT B-NP spleen NN I-NP . . O Transient JJ B-NP expression NN I-NP of IN B-PP NFATc.beta NN B-NP was VBD B-VP capable JJ B-ADJP of IN B-PP activating VBG B-VP an DT B-NP interleukin-2 NN I-NP NFAT-driven JJ I-NP reporter NN I-NP gene NN I-NP in IN B-PP stimulated VBN B-NP Jurkat NN I-NP cells NNS I-NP in IN B-PP a DT B-NP CsA-sensitive JJ I-NP manner NN I-NP . . O However RB B-ADVP COMMA COMMA O NFATc.beta NN B-NP neither CC O bound VBD B-VP to TO B-PP the DT B-NP kappa3 NN I-NP element NN I-NP ( ( O an DT B-NP NFAT-binding JJ I-NP site NN I-NP ) ) O in IN B-PP the DT B-NP tumor NN I-NP necrosis NN I-NP factor-alpha NN I-NP promoter NN I-NP nor CC O activated VBD B-VP the DT B-NP tumor NN I-NP necrosis NN I-NP factor-alpha NN I-NP promoter NN I-NP in IN B-PP cotransfection NN B-NP assays NN I-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR different JJ B-NP members NNS B-NP or CC O isoforms NNS B-NP of IN B-PP NFAT NN B-NP gene NN I-NP family NN I-NP may MD B-VP regulate VB I-VP inducible JJ B-NP expression NN I-NP of IN B-PP different JJ B-NP cytokine NN I-NP genes NNS I-NP . . O Activation NN B-NP of IN B-PP human JJ B-NP monocytic JJ I-NP cells NNS I-NP by IN B-PP Treponema FW B-NP pallidum FW I-NP and CC O Borrelia FW B-NP burgdorferi FW I-NP lipoproteins NNS B-NP and CC O synthetic JJ B-NP lipopeptides NNS I-NP proceeds VBZ B-VP via IN B-PP a DT B-NP pathway NN I-NP distinct JJ B-ADJP from IN B-PP that DT B-NP of IN B-PP lipopolysaccharide NN B-NP but CC O involves VBZ B-VP the DT B-NP transcriptional JJ I-NP activator NN I-NP NF-kappa NN I-NP B NN I-NP . . O There EX B-NP is VBZ B-VP increasing VBG B-NP evidence NN I-NP that IN B-SBAR lipoproteins NNS B-NP of IN B-PP Treponema FW B-NP pallidum FW I-NP and CC O Borrelia FW B-NP burgdorferi FW I-NP are VBP B-VP key JJ B-NP inflammatory JJ I-NP mediators NNS I-NP during IN B-PP syphilis NN B-NP and CC O Lyme NN B-NP disease NN I-NP . . O A DT B-NP principal JJ I-NP objective NN I-NP of IN B-PP the DT B-NP present JJ I-NP study NN I-NP was VBD B-VP to TO B-VP identify VB I-VP more RBR B-ADVP precisely RB I-ADVP similarities NNS B-NP and CC O divergences NNS B-NP among IN B-PP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O - : O and CC O lipoprotein-lipopeptide-induced JJ B-ADJP immune JJ B-NP cell NN I-NP signaling NN I-NP events NNS I-NP . . O Like IN B-PP LPS NN B-NP COMMA COMMA O purified VBN B-NP native JJ I-NP B. FW I-NP burgdorferi FW I-NP OspA NN I-NP and CC O synthetic JJ B-NP analogs NNS I-NP of IN B-PP OspA NN B-NP COMMA COMMA O OspB NN B-NP COMMA COMMA O and CC O two CD B-NP T. FW I-NP pallidum FW I-NP lipoproteins NNS I-NP ( ( O Tpp47 NN B-NP and CC O Tpp17 NN B-NP ) ) O all DT B-NP induced VBD B-VP NF-kappa NN B-NP B NN I-NP translocation NN I-NP in IN B-PP THP-1 NN B-NP human JJ I-NP monocytoid NN I-NP cells NNS I-NP . . O Acylation NN B-NP of IN B-PP OspA NN B-NP and CC O the DT B-NP synthetic JJ I-NP peptides NNS I-NP was VBD B-VP requisite JJ B-ADJP for IN B-PP cell NN B-NP activation NN I-NP . . O Polymyxin NN B-NP B NN I-NP abrogated VBD B-VP only RB B-NP the DT I-NP response NN I-NP to TO B-PP LPS NN B-NP . . O By IN B-PP using VBG B-VP 70Z\/3-derived JJ B-NP pre-B-cell NN I-NP lines NNS I-NP either CC O lacking VBG B-VP or CC O expressing VBG B-VP human JJ B-NP CD14 NN I-NP ( ( O the DT B-NP LPS NN I-NP receptor NN I-NP ) ) O COMMA COMMA O it PRP B-NP was VBD B-VP observed VBN I-VP that IN B-SBAR expression NN B-NP of IN B-PP human JJ B-NP CD14 NN I-NP imparted VBD B-VP responsiveness NN B-NP to TO B-PP LPS NN B-NP but CC B-PP not RB B-PP to TO I-PP OspA NN B-NP or CC O spirochetal JJ B-NP lipopeptides NNS I-NP ( ( O assessed VBN B-VP by IN B-PP induction NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP and CC O expression NN B-NP of IN B-PP surface NN B-NP immunoglobulin NN I-NP M NN I-NP ) ) O . . O Finally RB B-ADVP COMMA COMMA O the DT B-NP biological JJ I-NP relevance NN I-NP of IN B-PP the DT B-NP observation NN I-NP that IN B-SBAR T. FW B-NP pallidum FW I-NP lipoproteins-lipopeptides NNS I-NP induce VBP B-VP both CC O NF-kappa NN B-NP B NN I-NP and CC O cytokine NN B-NP production NN B-NP in IN B-PP monocytes NNS B-NP was VBD B-VP supported VBN I-VP by IN B-PP the DT B-NP ability NN I-NP of IN B-PP the DT B-NP synthetic JJ I-NP analogs NNS I-NP to TO B-VP promote VB I-VP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP replication NN I-NP in IN B-PP chronically RB B-NP infected JJ I-NP U1 NN I-NP monocytoid NN I-NP cells NNS I-NP ; : O these DT B-NP observations NNS I-NP also RB B-ADVP suggest VBP B-VP a DT B-NP potential JJ I-NP mechanism NN I-NP whereby WRB B-ADVP a DT B-NP syphilitic JJ I-NP chancre NN I-NP can MD B-VP serve VB I-VP as IN B-PP a DT B-NP cofactor NN I-NP for IN B-PP human JJ B-NP immunodeficiency NN I-NP virus NN I-NP transmission NN I-NP . . O The DT B-NP combined JJ I-NP data NNS I-NP lend VBP B-VP additional JJ B-NP support NN I-NP to TO B-PP the DT B-NP proposal NN I-NP that IN B-SBAR spirochetal JJ B-NP lipoproteins NNS I-NP and CC O LPS NN B-NP initiate VBP B-VP monocyte NN B-NP activation NN I-NP via IN B-PP different JJ B-NP cell NN I-NP surface NN I-NP events NNS I-NP but CC O that IN B-SBAR the DT B-NP signaling NN I-NP pathways NNS I-NP ultimately RB B-ADVP converge VBP B-VP to TO I-VP produce VB I-VP qualitatively RB B-NP similar JJ I-NP cellular JJ I-NP responses NNS I-NP . . O Chronic JJ B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP infection NN I-NP of IN B-PP myeloid JJ B-NP cells NNS I-NP disrupts VBZ B-VP the DT B-NP autoregulatory JJ I-NP control NN I-NP of IN B-PP the DT B-NP NF-kappaB\/Rel NN I-NP pathway NN I-NP via IN B-PP enhanced VBN B-NP IkappaBalpha NN I-NP degradation NN I-NP . . O Productive JJ O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP ( ( O HIV-1 NN B-NP ) ) O infection NN B-NP causes VBZ B-VP sustained JJ B-NP NF-kappaB NN I-NP DNA-binding JJ I-NP activity NN I-NP in IN B-PP chronically RB B-NP infected VBN I-NP monocytic JJ I-NP cells NNS I-NP . . O A DT B-NP direct JJ I-NP temporal JJ I-NP correlation NN I-NP exists VBZ B-VP between IN B-PP HIV NN B-NP infection NN I-NP and CC O the DT B-NP appearance NN I-NP of IN B-PP NF-kappaB NN B-NP DNA-binding JJ I-NP activity NN I-NP in IN B-PP myelomonoblastic JJ B-NP PLB-985 NN I-NP cells NNS I-NP . . O HIV-1 NN B-NP infection NN I-NP resulted VBD B-VP in IN B-PP constitutive JJ B-NP COMMA COMMA I-NP low-level JJ I-NP expression NN I-NP of IN B-PP type NN B-NP 1 CD I-NP interferon NN B-NP ( ( O IFN NN B-NP ) ) O at IN B-PP the DT B-NP mRNA NN I-NP level NN I-NP . . O Constitutive JJ B-NP PKR NN I-NP activity NN I-NP was VBD B-VP also RB I-VP detected VBN I-VP in IN B-PP HIV-1-infected JJ B-NP cells NNS I-NP as IN B-PP a DT B-NP result NN I-NP of IN B-PP low-level JJ B-NP IFN NN I-NP production NN I-NP COMMA COMMA O since IN B-SBAR the DT B-NP addition NN I-NP of IN B-PP anti-IFN-alpha\/beta JJ B-NP antibody NN I-NP to TO B-PP the DT B-NP cells NNS I-NP decreased VBD B-VP PKR NN B-NP expression NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O the DT B-NP analysis NN I-NP of IN B-PP IkappaBalpha NN B-NP turnover NN I-NP demonstrated VBD B-VP an DT B-NP increased VBN I-NP degradation NN I-NP of IN B-PP IkappaBalpha NN B-NP in IN B-PP HIV-1-infected JJ B-NP cells NNS I-NP that WDT B-NP may MD B-VP account VB I-VP for IN B-PP the DT B-NP constitutive JJ I-NP DNA NN I-NP binding NN I-NP activity NN I-NP . . O A DT B-NP dramatic JJ I-NP increase NN I-NP in IN B-PP the DT B-NP intracellular JJ I-NP levels NNS I-NP of IN B-PP NF-kappaB NN B-NP subunits NNS I-NP c-Rel NN B-NP and CC O NF-kappaB2 NN B-NP p100 NN I-NP and CC O a DT B-NP moderate JJ I-NP increase NN I-NP in IN B-PP NF-kappaB2 NN B-NP p52 NN I-NP and CC O RelA(p65) NN B-NP were VBD B-VP detected VBN I-VP in IN B-PP HIV-1-infected JJ B-NP cells NNS I-NP COMMA COMMA O whereas IN O NF-kappaB1 NN B-NP p105\/p50 NN I-NP levels NNS I-NP were VBD B-VP not RB I-VP altered VBN I-VP relative JJ B-PP to TO I-PP the DT B-NP levels NNS I-NP in IN B-PP uninfected JJ B-NP cells NNS I-NP . . O We PRP B-NP suggest VBP B-VP that IN B-SBAR HIV-1 NN B-NP infection NN I-NP of IN B-PP myeloid JJ B-NP cells NNS I-NP induces VBZ B-VP IFN NN B-NP production NN I-NP and CC O PKR NN B-NP activity NN I-NP COMMA COMMA O which WDT B-NP in IN B-PP turn NN B-NP contribute VBP B-VP to TO B-PP enhanced VBN B-NP IkappaBalpha NN I-NP phosphorylation NN I-NP and CC O subsequent JJ B-NP degradation NN I-NP . . O Nuclear JJ B-NP translocation NN I-NP of IN B-PP NF-kappaB NN B-NP subunits NNS I-NP may MD B-VP ultimately RB I-VP increase VB I-VP the DT B-NP intracellular JJ I-NP pool NN I-NP of IN B-PP NF-kappaB\/IkappaBalpha NN B-NP by IN B-PP an DT B-NP autoregulatory JJ I-NP mechanism NN I-NP . . O Enhanced VBN B-NP turnover NN I-NP of IN B-PP IkappaBalpha NN B-NP and CC O the DT B-NP accumulation NN I-NP of IN B-PP NF-kappaB\/Rel NN B-NP proteins NNS I-NP may MD B-VP contribute VB I-VP to TO B-PP the DT B-NP chronically RB I-NP activated JJ I-NP state NN I-NP of IN B-PP HIV-1-infected JJ B-NP cells NNS I-NP . . O Transcriptional JJ B-NP analysis NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP gene NN I-NP expression NN I-NP in IN B-PP EBV-positive JJ B-NP gastric JJ I-NP carcinoma NN I-NP : : O unique JJ B-NP viral JJ I-NP latency NN I-NP in IN B-PP the DT B-NP tumour NN I-NP cells NNS I-NP . . O Although IN B-SBAR case-oriented JJ B-NP evidence NN I-NP for IN B-PP an DT B-NP association NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O with IN B-PP gastric JJ B-NP carcinoma NN I-NP has VBZ B-VP been VBN I-VP accumulating VBG I-VP recently RB B-ADVP COMMA COMMA O the DT B-NP interaction NN I-NP ( ( I-NP s NNS I-NP ) ) O between IN B-PP EBV NN B-NP and CC O gastric JJ B-NP epithelial NN I-NP cells NNS I-NP is\/are VBP B-VP largely RB B-ADJP unknown JJ I-ADJP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP examined VBD B-VP seven CD B-NP EBV-positive JJ I-NP gastric JJ I-NP carcinoma NN I-NP tissues NNS I-NP for IN B-PP viral JJ B-NP gene NN I-NP expression NN I-NP at IN B-PP the DT B-NP mRNA NN I-NP level NN I-NP COMMA COMMA O from IN B-PP which WDT B-NP studies NNS B-NP on IN B-PP the DT B-NP EBV NN I-NP oncogenicity NN I-NP in IN B-PP human JJ B-NP epithelial JJ I-NP cells NNS I-NP will MD B-VP benefit VB I-VP . . O Reverse JJ B-NP transcription-PCR NN I-NP analysis NN I-NP showed VBD B-VP that IN B-SBAR all DT B-NP seven CD I-NP EBV-positive JJ I-NP tumour NN I-NP tissues NNS I-NP constitutively RB B-ADVP expressed VBD B-VP EBV NN B-NP nuclear JJ I-NP antigen NN I-NP ( ( O EBNA NN B-NP ) ) O 1 CD B-NP mRNA NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP EBNA2 NN B-NP mRNA NN I-NP . . O The DT B-NP EBNA NN I-NP transcription NN I-NP was VBD B-VP initiated VBN I-VP from IN B-PP one CD B-NP of IN B-PP three CD B-NP EBNA NN I-NP promoters NNS I-NP COMMA COMMA O Qp NN B-NP : : O by IN B-PP contrast NN B-NP COMMA COMMA O both CC O Cp NN B-NP and CC O Wp NN B-NP were VBD B-VP silent JJ B-ADJP COMMA COMMA O thus RB B-ADVP resulting VBG B-VP in IN B-PP the DT B-NP lack NN I-NP of IN B-PP EBNA2 NN B-NP mRNA NN I-NP . . O Latent JJ B-NP membrane NN I-NP protein NN I-NP ( ( O LMP NN B-NP ) ) O 2A NN B-NP mRNA NN I-NP was VBD B-VP detected VBN I-VP in IN B-PP three CD B-NP of IN B-PP seven CD B-NP cases NNS I-NP ; : O however RB B-ADVP COMMA COMMA O neither CC O LMP1 NN B-NP nor CC O LMP2B NN B-NP mRNA NN B-NP was VBD B-VP detected VBN I-VP in IN B-PP any DT B-NP of IN B-PP the DT B-NP tumours NNS I-NP tested VBN B-VP . . O Transcripts NNS B-NP from IN B-PP the DT B-NP BamHI-A NN I-NP region NN I-NP of IN B-PP the DT B-NP viral JJ I-NP genome NN I-NP were VBD B-VP detectable JJ B-ADJP in IN B-PP all DT B-NP cases NNS I-NP . . O BZLF1 NN B-NP mRNA NN I-NP and CC O the DT B-NP product NN I-NP COMMA COMMA O an DT B-NP immediate-early JJ I-NP gene NN I-NP for IN B-PP EBV NN B-NP replication NN I-NP COMMA COMMA O was VBD B-VP not RB I-VP expressed VBN I-VP in IN B-PP any DT B-NP of IN B-PP them PRP B-NP COMMA COMMA O thereby RB B-ADVP suggesting VBG B-VP that IN B-SBAR the DT B-NP tumour JJ I-NP cells NNS I-NP carried VBD B-VP EBV NN B-NP genomes NNS I-NP in IN B-PP a DT B-NP tightly RB I-NP latent JJ I-NP form NN I-NP . . O These DT B-NP findings NNS I-NP further RB B-VP extended VBD I-VP our PRP$ B-NP previous JJ I-NP data NNS I-NP regarding VBG B-PP EBV NN B-NP latency NN I-NP in IN B-PP gastric JJ B-NP carcinoma NN I-NP cells NNS I-NP at IN B-PP the DT B-NP protein NN I-NP level NN I-NP COMMA COMMA O and CC O have VBP B-VP affirmed VBN I-VP that IN B-SBAR the DT B-NP programme NN I-NP of IN B-PP viral JJ B-NP gene NN I-NP expression NN I-NP in IN B-PP the DT B-NP tumour NN I-NP more RBR B-ADVP closely RB I-ADVP resembles VBZ B-VP ' `` O latency NN B-NP I CD I-NP ' '' O represented VBN B-VP by IN B-PP Burkitt NN B-NP 's POS B-NP lymphoma NN O than IN O ' `` B-NP latency NN I-NP II CD B-NP ' '' O represented VBN B-PP by IN B-NP the DT I-NP majority NN O of IN B-NP nasopharyngeal JJ I-NP carcinomas NNS O Sequence-specific JJ B-NP DNA NN I-NP binding NN I-NP of IN B-PP the DT B-NP B-cell-specific JJ I-NP coactivator NN I-NP OCA-B NN I-NP . . O B-cell-specific JJ B-NP transcription NN I-NP of IN B-PP immunoglobulin NN B-NP genes NNS I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP the DT B-NP interaction NN I-NP of IN B-PP a DT B-NP POU NN I-NP domain NN I-NP containing VBG B-VP transcription NN B-NP factor NN I-NP Oct-1 NN B-NP or CC O Oct-2 NN B-NP COMMA COMMA O with IN B-PP the DT B-NP B-cell-specific JJ I-NP coactivator NN I-NP OCA-B NN I-NP ( ( O Bob-1 NN B-NP COMMA COMMA O OBF-1 NN B-NP ) ) O and CC O a DT B-NP prototype NN I-NP octamer NN I-NP element NN I-NP . . O We PRP B-NP find VBP B-VP that IN B-SBAR OCA-B NN B-NP binds VBZ B-VP DNA NN B-NP directly RB B-ADVP in IN B-PP the DT B-NP major JJ I-NP groove NN I-NP between IN B-PP the DT B-NP two CD I-NP subdomains NNS I-NP of IN B-PP the DT B-NP POU NN I-NP domain NN I-NP COMMA COMMA O requiring VBG B-VP both CC O an DT B-NP A NN I-NP at IN B-PP the DT B-NP fifth JJ I-NP position NN I-NP of IN B-PP the DT B-NP octamer NN I-NP element NN I-NP and CC O contact NN B-NP with IN B-PP the DT B-NP POU NN I-NP domain NN I-NP . . O An DT B-NP amino-terminal JJ I-NP fragment NN I-NP of IN B-PP OCA-B NN B-NP binds VBZ B-VP the DT B-NP octamer NN I-NP site NN I-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP a DT B-NP POU NN I-NP domain NN I-NP with IN B-PP the DT B-NP same JJ I-NP sequence NN I-NP specificity NN I-NP . . O Coactivator NN B-NP OCA-B NN I-NP may MD B-VP undergo VB I-VP a DT B-NP POU-dependent JJ I-NP conformational JJ I-NP change NN I-NP that WDT B-NP exposes VBZ B-VP its PRP$ B-NP amino NN I-NP terminus NN I-NP COMMA COMMA O allowing VBG B-VP it PRP B-NP to TO B-VP recognize VB I-VP specific JJ B-NP DNA NN I-NP sequences NNS I-NP in IN B-PP the DT B-NP major JJ I-NP groove NN I-NP within IN B-PP the DT B-NP binding VBG I-NP site NN I-NP for IN B-PP Oct-1 NN B-NP or CC O Oct-2 NN B-NP . . O The DT B-NP recognition NN I-NP of IN B-PP both CC O the DT B-NP POU NN I-NP domain NN I-NP and CC O the DT B-NP octamer NN I-NP sequence NN I-NP by IN B-PP OCA-B NN B-NP provides VBZ B-VP a DT B-NP mechanism NN I-NP for IN B-PP differential JJ B-NP regulation NN I-NP of IN B-PP octamer NN B-NP sites NNS I-NP containing VBG B-VP genes NNS B-NP by IN B-PP the DT B-NP ubiquitous JJ I-NP factor NN I-NP Oct-1 NN I-NP . . O The DT B-NP role NN I-NP of IN B-PP early JJ B-NP growth NN I-NP response NN I-NP gene NN I-NP 1 CD I-NP ( ( O egr-1 NN B-NP ) ) O in IN B-PP regulation NN B-NP of IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O The DT B-NP induction NN I-NP of IN B-PP immediate JJ B-NP early JJ I-NP genes NNS I-NP in IN B-PP cells NNS B-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP is VBZ B-VP critical JJ B-ADJP to TO B-PP determining VBG B-VP the DT B-NP ultimate JJ I-NP outcome NN I-NP of IN B-PP exposure NN B-NP to TO B-PP antigen NN B-NP . . O The DT B-NP importance NN I-NP of IN B-PP many JJ B-NP of IN B-PP these DT B-NP genes NNS I-NP relates VBZ B-VP to TO B-PP the DT B-NP role NN I-NP their PRP$ B-NP transcription NN I-NP factor NN I-NP products NNS I-NP play VBP B-VP in IN B-PP dictating VBG B-VP patterns NNS B-NP of IN B-PP expression NN B-NP of IN B-PP downstream JJ B-NP COMMA COMMA I-NP function-related JJ I-NP genes NNS I-NP . . O Evidence NN B-NP from IN B-PP several JJ B-NP systems NNS I-NP indicates VBZ B-VP that IN B-SBAR the DT B-NP immediate JJ I-NP early JJ I-NP gene NN I-NP COMMA COMMA O egr-1 NN B-NP may MD B-VP be VB I-VP of IN B-PP particular JJ B-NP importance NN I-NP in IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O Recently RB B-ADVP COMMA COMMA O the DT B-NP egr-1 NN I-NP promoter NN I-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP highly RB B-ADJP responsive JJ I-ADJP to TO B-PP the DT B-NP diverse JJ I-NP biochemical JJ I-NP signals NNS I-NP generated VBN B-VP by IN B-PP antigen NN B-NP and CC O cytokines NNS B-NP in IN B-PP cells NNS B-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O an DT B-NP important JJ I-NP role NN I-NP for IN B-PP egr-1 NN B-NP in IN B-PP determining VBG B-VP the DT B-NP differentiation NN I-NP pathway NN I-NP of IN B-PP myeloid JJ B-NP cell NN I-NP precursors NNS I-NP has VBZ B-VP been VBN I-VP recently RB I-VP elaborated VBN I-VP . . O Finally RB B-ADVP COMMA COMMA O potential JJ B-NP targets NNS I-NP of IN B-PP regulation NN B-NP by IN B-PP the DT B-NP zinc-finger NN I-NP transcription NN I-NP factor NN I-NP encoded VBN B-VP by IN B-PP egr-1 NN B-NP include VBP B-VP the DT B-NP interleukin-2 NN B-NP COMMA COMMA O CD44 NN B-NP COMMA COMMA O ICAM-1 NN B-NP COMMA COMMA O and CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP genes NNS I-NP . . O The DT B-NP role NN I-NP of IN B-PP egr-1 NN B-NP in IN B-PP regulation NN B-NP of IN B-PP the DT B-NP immune JJ I-NP response NN I-NP will MD B-VP be VB I-VP discussed VBN I-VP in IN B-PP the DT B-NP context NN I-NP of IN B-PP these DT B-NP recent JJ I-NP studies NNS I-NP . . O Translocation NN B-NP (3;14)(q27;q11) NN I-NP : : O a DT B-NP new JJ I-NP variant JJ I-NP translocation NN I-NP in IN B-PP a DT B-NP patient NN I-NP with IN B-PP non-Hodgkin JJ B-NP 's POS B-NP lymphoma NN I-NP of IN B-PP B-cell NN B-NP type NN I-NP with IN B-PP BCL6 NN B-NP rearrangement NN I-NP . . O We PRP B-NP report VBP B-VP a DT B-NP 65-year-old JJ I-NP woman NN I-NP with IN B-PP non-Hodgkin JJ B-NP 's POS B-NP lymphoma NN I-NP ( ( O NHL NN B-NP ) ) O carrying VBG B-VP a DT B-NP t(3;14)(q27;q11) NN I-NP and CC O BCL6 NN B-NP rearrangement NN I-NP in IN B-PP the DT B-NP affected VBN I-NP cells NNS I-NP . . O She PRP B-NP had VBD B-VP generalized VBN I-VP lymphadenopathy NN B-NP and CC O the DT B-NP bone NN I-NP marrow NN I-NP was VBD B-VP infiltrated VBN I-VP by IN B-PP lymphoma NN B-NP cells NNS I-NP at IN B-PP presentation NN B-NP . . O Histological JJ B-NP diagnosis NN I-NP was VBD B-VP " `` O malignant JJ B-NP lymphoma NN I-NP COMMA COMMA O diffuse JJ B-NP COMMA COMMA O large JJ B-NP cell NN I-NP " '' B-NP type NN I-NP according VBG B-PP to TO B-PP an DT B-NP International NNP I-NP Working NNP I-NP Formulation NNP I-NP . . O Chromosome NN B-NP analysis NN I-NP revealed VBD B-VP a DT B-NP t(3;14)(q27;q11) NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP a DT B-NP new JJ I-NP variant JJ I-NP translocation NN I-NP of IN B-PP t(3;14)(q27;q32) NN B-NP . . O Southern NN B-NP blot NN I-NP analysis NN I-NP showed VBD B-VP rearrangement NN B-NP of IN B-PP BCL6 NN B-NP COMMA COMMA O JH NN B-NP COMMA COMMA O and CC O TCR NN B-NP beta NN I-NP but CC B-PP not RB B-PP of IN I-PP TCR NN B-NP delta NN I-NP . . O Cosmid NN B-NP probe NN I-NP of IN B-PP BCL6 NN B-NP hybridized VBD B-VP to TO B-PP 14q11 NN B-NP and CC O 3q27 NN B-NP by IN B-PP fluorescence NN B-NP in FW I-NP situ FW I-NP hybridization NN I-NP ( ( O FISH NN B-NP ) ) O . . O Although IN B-SBAR the DT B-NP band NN I-NP 14q11 NN I-NP is VBZ B-VP a DT B-NP locus NN I-NP of IN B-PP T-cell NN B-NP receptor NN I-NP alpha- NN B-NP and CC O delta-chains NNS B-NP ( ( O TCR NN B-NP alpha\/delta NN I-NP ) ) O COMMA COMMA O lymphoma NN B-NP cells NNS I-NP expressed VBD B-VP B-cell NN B-NP COMMA COMMA O IgGk NN B-NP phenotype NN B-NP . . O The DT B-NP findings NNS I-NP suggest VBP B-VP that IN B-SBAR a DT B-NP novel JJ I-NP proto-oncogene NN I-NP in IN B-PP the DT B-NP vicinity NN I-NP of IN B-PP TCR NN B-NP alpha\/delta NN I-NP is VBZ B-VP involved VBN I-VP in IN B-PP this DT B-NP translocation NN I-NP . . O Cross NN B-NP talk NN I-NP between IN B-PP cell NN B-NP death NN I-NP and CC O cell NN B-NP cycle NN I-NP progression NN I-NP : : O BCL-2 NN B-NP regulates VBZ B-VP NFAT-mediated JJ B-NP activation NN I-NP . . O BCL-2-deficient JJ B-NP T NN I-NP cells NNS I-NP demonstrate VBP B-VP accelerated VBN B-NP cell NN I-NP cycle NN I-NP progression NN I-NP and CC O increased VBN B-NP apoptosis NN I-NP following VBG B-PP activation NN B-NP . . O Increasing VBG B-VP the DT B-NP levels NNS I-NP of IN B-PP BCL-2 NN B-NP retarded VBD B-VP the DT B-NP G0 NN I-NP --> TO I-NP S NN I-NP transition NN I-NP COMMA COMMA O sustained VBD B-VP the DT B-NP levels NNS I-NP of IN B-PP cyclin-dependent JJ B-NP kinase NN I-NP inhibitor NN I-NP p27Kip1 NN I-NP COMMA COMMA O and CC O repressed VBD B-VP postactivation NN B-NP death NN I-NP . . O Proximal JJ B-NP signal NN I-NP transduction NN I-NP events NNS I-NP and CC O immediate JJ B-NP early JJ I-NP gene NN I-NP transcription NN I-NP were VBD B-VP unaffected JJ B-ADJP . . O However RB B-ADVP COMMA COMMA O the DT B-NP transcription NN B-NP and CC O synthesis NN B-NP of IN B-PP interleukin NN B-NP 2 CD I-NP and CC O other JJ B-NP delayed VBN I-NP early JJ I-NP cytokines NNS I-NP were VBD B-VP markedly RB I-VP attenuated VBN I-VP by IN B-PP BCL-2 NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O a DT B-NP cysteine NN I-NP protease NN I-NP inhibitor NN I-NP that WDT B-NP also RB B-VP blocks VBZ I-VP apoptosis NN B-NP had VBD B-VP no DT B-NP substantial JJ I-NP affect NN I-NP upon IN B-PP cytokine NN B-NP production NN I-NP . . O InterleUkin NN B-NP 2 CD I-NP expression NN I-NP requires VBZ B-VP several JJ B-NP transcription NN I-NP factors NNS I-NP of IN B-PP which WDT B-NP nuclear JJ B-NP translocation NN I-NP of IN B-PP NFAT NN B-NP ( ( O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ) ) O and CC O NFAT-mediated JJ B-NP transactivation NN I-NP were VBD B-VP impaired VBN I-VP by IN B-PP BCL-2 NN B-NP . . O Thus RB B-ADVP COMMA COMMA O select JJ B-NP genetic JJ I-NP aberrations NNS I-NP in IN B-PP the DT B-NP apoptotic JJ I-NP pathway NN I-NP reveal VBP B-VP a DT B-NP cell NN I-NP autonomous JJ I-NP coregulation NN I-NP of IN B-PP activation NN B-NP . . O Activation NN B-NP of IN B-PP Stat NN B-NP 5b NN I-NP in IN B-PP erythroid JJ B-NP progenitors NNS I-NP correlates VBZ B-VP with IN B-PP the DT B-NP ability NN I-NP of IN B-PP ErbB NN B-NP to TO B-VP induce VB I-VP sustained JJ B-NP cell NN I-NP proliferation NN I-NP . . O Self NN B-NP renewal NN I-NP of IN B-PP normal JJ B-NP erythroid JJ I-NP progenitors NNS I-NP is VBZ B-VP induced VBN I-VP by IN B-PP the DT B-NP receptor NN I-NP tyrosine NN I-NP kinase NN I-NP c-ErbB NN I-NP COMMA COMMA O whereas IN O other JJ B-NP receptors NNS I-NP ( ( O c-Kit\/Epo-R NNS B-NP ) ) O regulate VBP B-VP erythroid JJ B-NP differentiation NN I-NP . . O To TO B-VP address VB I-VP possible JJ B-NP mechanisms NNS I-NP that WDT B-NP could MD B-VP explain VB I-VP this DT B-NP selective JJ I-NP activity NN I-NP of IN B-PP c-ErbB NN B-NP COMMA COMMA O we PRP B-NP analyzed VBD B-VP the DT B-NP ability NN I-NP of IN B-PP these DT B-NP receptors NNS I-NP to TO B-VP activate VB I-VP the DT B-NP different JJ I-NP members NNS I-NP of IN B-PP the DT B-NP Stat NN I-NP transcription NN I-NP factor NN I-NP family NN I-NP . . O Ligand NN B-NP activation NN I-NP of IN B-PP c-ErbB NN B-NP induced VBD B-VP the DT B-NP tyrosine NN B-NP phosphorylation NN I-NP COMMA COMMA O DNA-binding NN B-NP COMMA COMMA O and CC O reporter NN B-NP gene NN I-NP transcription NN I-NP of IN B-PP Stat NN B-NP 5b NN I-NP in IN B-PP erythroblasts NNS B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O ligand NN B-NP activation NN I-NP of IN B-PP c-Kit NN B-NP was VBD B-VP unable JJ B-ADJP to TO B-VP induce VB I-VP any DT B-NP of IN B-PP these DT B-NP effects NNS I-NP in IN B-PP the DT B-NP same JJ I-NP cells NNS I-NP . . O Activation NN B-NP of IN B-PP the DT B-NP erythropoietin NN I-NP receptor NN I-NP caused VBD B-VP specific JJ B-NP DNA-binding NN I-NP of IN B-PP Stat NN B-NP 5b NN I-NP COMMA COMMA O but CC O failed VBD B-VP to TO I-VP induce VB I-VP reporter NN B-NP gene NN I-NP transcription NN I-NP . . O These DT B-NP biochemical JJ I-NP findings NNS I-NP correlate VBP B-VP perfectly RB B-ADVP with IN B-PP the DT B-NP selective JJ I-NP ability NN I-NP of IN B-PP c-ErbB NN B-NP to TO B-VP cause VB I-VP sustained JJ B-NP self NN I-NP renewal NN I-NP in IN B-PP erythroid JJ B-NP progenitors NNS I-NP . . O Calcineurin NN B-NP mutants NNS I-NP render VBP B-VP T NN B-NP lymphocytes NNS I-NP resistant JJ B-ADJP to TO B-PP cyclosporin NN B-NP A NN I-NP . . O The DT B-NP immunosuppressants NNS I-NP cyclosporin NN B-NP A NN I-NP ( ( O CsA NN B-NP ) ) O and CC O FK506 NN B-NP have VBP B-VP been VBN I-VP widely RB I-VP used VBN I-VP to TO B-VP prevent VB I-VP and CC O treat VB B-VP graft NN B-NP rejection NN I-NP after IN B-PP human JJ O organ NN B-NP and CC O tissue NN B-NP transplantations NNS B-NP . . O CsA NN B-NP and CC O FK506 NN B-NP associate VBP B-VP with IN B-PP intracellular JJ B-NP binding VBG I-NP proteins NNS I-NP ( ( O i.e. FW B-ADVP COMMA COMMA O CsA NN B-NP with IN B-PP cyclophilin NN B-NP A NN I-NP and CC O FK506 NN B-NP with IN B-PP FKBP12 NN B-NP ) ) O to TO B-VP form VB I-VP protein\/drug NN B-NP complexes NNS I-NP that WDT B-NP suppress VBP B-VP the DT B-NP immune JJ I-NP system NN I-NP by IN B-PP preventing VBG B-VP activation NN B-NP of IN B-PP T NN B-NP cells NNS I-NP in IN B-PP response NN I-PP to TO I-PP antigen NN B-NP presentation NN I-NP . . O The DT B-NP common JJ I-NP target NN I-NP of IN B-PP CsA NN B-NP and CC O FK506 NN B-NP is VBZ B-VP calcineurin NN B-NP COMMA COMMA O a DT B-NP Ca2+\/calmodulin-regulated JJ I-NP COMMA COMMA I-NP serine\/threonine-specific JJ I-NP protein NN I-NP phosphatase NN I-NP that WDT B-NP regulates VBZ B-VP the DT B-NP nuclear JJ I-NP import NN I-NP of IN B-PP a DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O NF-AT NN B-NP COMMA COMMA O required VBN B-VP for IN B-PP expression NN B-NP of IN B-PP T NN B-NP cell NN I-NP activation NN I-NP genes NNS I-NP . . O In IN B-PP previous JJ B-NP studies NNS I-NP COMMA COMMA O we PRP B-NP identified VBD B-VP calcineurin NN B-NP mutations NNS I-NP that WDT B-NP block VBP B-VP binding NN B-NP by IN B-PP the DT B-NP cyclophilin NN I-NP A\/CsA NN I-NP or CC I-NP FKBP12\/FK506 NN I-NP complexes NNS I-NP and CC O thereby RB O render VBP B-VP yeast NN B-NP cells NNS I-NP resistant JJ B-ADJP to TO B-PP the DT B-NP antifungal JJ I-NP effects NNS I-NP of IN B-PP CsA NN B-NP or CC O FK506 NN B-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP corresponding JJ I-NP mutations NNS I-NP in IN B-PP murine JJ B-NP calcineurin NN I-NP render VBP B-VP the DT B-NP T NN I-NP cell NN I-NP receptor NN I-NP signal NN I-NP transduction NN I-NP cascade NN I-NP CsA NN I-NP resistant JJ B-ADJP in IN B-PP human JJ B-NP Jurkat NN I-NP T NN I-NP cells NNS I-NP . . O Our PRP$ B-NP findings NNS I-NP support VBP B-VP the DT B-NP recently RB I-NP determined VBN I-NP calcineurin NN I-NP X-ray NN I-NP crystal NN I-NP structure NN I-NP COMMA COMMA O provide VBP B-VP evidence NN B-NP that IN B-SBAR calcineurin NN B-NP is VBZ B-VP the DT B-NP only RB I-NP CsA-sensitive JJ I-NP component NN I-NP limiting VBG B-VP signaling NN B-NP from IN B-PP the DT B-NP T NN I-NP cell NN I-NP receptor NN I-NP to TO B-PP the DT B-NP nucleus NN I-NP COMMA COMMA O and CC O suggest VBP B-VP a DT B-NP means NN I-NP to TO B-VP render VB I-VP cells NNS B-NP and CC O tissues NNS B-NP resistant JJ B-ADJP to TO B-PP the DT B-NP toxic JJ I-NP side JJ I-NP effects NNS I-NP of IN B-PP CsA NN B-NP and CC O FK506 NN B-NP . . O Retinoid NN B-NP differentiation NN I-NP therapy NN I-NP in IN B-PP promyelocytic JJ B-NP leukemia NN I-NP . . O Acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP ( ( O APL NN B-NP ) ) O is VBZ B-VP a DT B-NP specific JJ I-NP type NN I-NP of IN B-PP acute JJ B-NP myeloid JJ I-NP leukemia NN I-NP characterized VBN B-VP by IN B-PP the DT B-NP morphology NN I-NP of IN B-PP the DT B-NP blast NN I-NP cells NNS I-NP COMMA COMMA O a DT B-NP specific JJ I-NP t(15;17) NN I-NP translocation NN I-NP COMMA COMMA O and CC O risks NNS B-NP of IN B-PP definite JJ B-NP coagulopathy NN I-NP . . O Recently RB B-ADVP this DT B-NP leukemia NN I-NP was VBD B-VP further RB I-VP characterized VBN I-VP by IN B-PP an DT B-NP exquisite JJ I-NP sensitivity NN I-NP to TO B-PP all-trans JJ B-NP retinoic JJ I-NP acid NN I-NP 's POS B-NP differentiation NN I-NP effect NN I-NP and CC O the DT B-NP production NN I-NP of IN B-PP a DT B-NP fusion NN I-NP gene NN I-NP altering VBG B-VP the DT B-NP gene NN I-NP of IN B-PP RARalpha NN B-NP and CC O a DT B-NP novel JJ I-NP gene NN I-NP PML NN I-NP . . O In FW B-NP vivo FW I-NP differentiation NN I-NP therapy NN I-NP with IN B-PP retinoids NNS B-NP in IN B-PP APL NN B-NP patients NNS I-NP follows VBZ B-VP strict JJ B-NP guidelines NNS I-NP related JJ B-ADJP both CC B-PP to TO I-PP the DT B-NP APL NN I-NP cell NN I-NP and CC O the DT B-NP biodisposal NN I-NP of IN B-PP all-trans JJ B-NP retinoic JJ I-NP acid NN I-NP . . O Epstein-Barr JJ B-NP viral JJ I-NP latency NN I-NP is VBZ B-VP disrupted VBN I-VP by IN B-PP the DT B-NP immediate-early JJ I-NP BRLF1 NN I-NP protein NN I-NP through IN B-PP a DT B-NP cell-specific JJ I-NP mechanism NN I-NP . . O Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O COMMA COMMA O the DT B-NP causative JJ I-NP agent NN I-NP of IN B-PP infectious JJ B-NP mononucleosis NN I-NP COMMA COMMA O is VBZ B-VP a DT B-NP human JJ I-NP herpesvirus NN I-NP associated VBN B-VP with IN B-PP epithelial JJ B-NP cell NN I-NP malignancies NNS I-NP ( ( O nasopharyngeal JJ B-NP carcinoma NN I-NP ) ) O as RB B-CONJP well RB I-CONJP as IN I-CONJP B-cell NN B-NP malignancies NNS I-NP . . O Understanding VBG B-VP how WRB B-ADVP viral JJ B-NP latency NN I-NP is VBZ B-VP disrupted VBN I-VP is VBZ B-VP a DT B-NP central JJ I-NP issue NN I-NP in IN B-PP herpesvirus JJ B-NP biology NN I-NP . . O Epithelial JJ B-NP cells NNS I-NP are VBP B-VP the DT B-NP major JJ I-NP site NN I-NP of IN B-PP lytic JJ B-NP EBV NN I-NP replication NN I-NP within IN B-PP the DT B-NP human JJ I-NP host NN I-NP COMMA COMMA O and CC O viral JJ B-NP reactivation NN I-NP occurs VBZ B-VP in IN B-PP EBV-associated JJ B-NP nasopharyngeal JJ I-NP carcinomas NNS I-NP . . O It PRP B-NP is VBZ B-VP known VBN I-VP that IN B-SBAR expression NN B-NP of IN B-PP a DT B-NP single JJ I-NP viral JJ I-NP immediate-early JJ I-NP protein NN I-NP COMMA COMMA O BZLF1 NN B-NP COMMA COMMA O is VBZ B-VP sufficient JJ B-ADJP to TO B-VP initiate VB I-VP the DT B-NP switch NN I-NP from IN B-PP latent JJ B-NP to TO B-PP lytic JJ B-NP infection NN B-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Cellular JJ B-NP regulation NN I-NP of IN B-PP BZLF1 NN B-NP transcription NN I-NP is VBZ B-VP therefore RB I-VP thought VBN I-VP to TO I-VP play VB I-VP a DT B-NP key JJ I-NP role NN I-NP in IN B-PP regulating VBG B-VP the DT B-NP stringency NN I-NP of IN B-PP viral JJ B-NP latency NN I-NP . . O Here RB B-ADVP we PRP B-NP show VBP B-VP that IN B-SBAR COMMA COMMA O unexpectedly RB B-ADVP COMMA COMMA O expression NN B-NP of IN B-PP another DT B-NP viral JJ I-NP immediate-early JJ I-NP protein NN I-NP COMMA COMMA O BRLF1 NN B-NP COMMA COMMA O can MD B-VP disrupt VB I-VP viral JJ B-NP latency NN I-NP in IN B-PP an DT B-NP epithelial JJ I-NP cell-specific JJ I-NP fashion NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O the DT B-NP mechanisms NNS I-NP leading VBG B-VP to TO B-PP disruption NN B-NP of IN B-PP EBV NN B-NP latency NN I-NP appear VBP B-VP to TO I-VP be VB I-VP cell-type NN B-ADJP specific JJ I-ADJP . . O IL4 NN B-NP and CC O IL13 NN B-NP receptors NNS B-NP share VBP B-VP the DT B-NP gamma NN I-NP c NN I-NP chain NN I-NP and CC O activate VBP B-VP STAT6 NN B-NP COMMA COMMA O STAT3 NN B-NP and CC O STAT5 NN B-NP proteins NNS B-NP in IN B-PP normal JJ B-NP human JJ I-NP B NN I-NP cells NNS I-NP . . O IL13 NN B-NP induces VBZ B-VP the DT B-NP same JJ I-NP biological JJ I-NP effects NNS I-NP as IN B-PP IL4 NN B-NP in IN B-PP normal JJ B-NP human JJ I-NP B NN I-NP cells NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR as IN B-PP in IN B-PP the DT B-NP IL4R NN I-NP complex NN I-NP COMMA COMMA O both CC O IL4R NN B-NP alpha NN I-NP and CC O IL2R NN B-NP gamma NN I-NP c NN I-NP are VBP B-VP components NNS B-NP of IN B-PP the DT B-NP IL13R NN I-NP and CC O that IN B-SBAR both DT B-NP cytokines NNS I-NP induced VBD B-VP STAT6 NN B-NP COMMA COMMA O STAT3 NN B-NP and CC O STAT5 NN B-NP activation NN B-NP in IN B-PP B NN B-NP cells NNS I-NP . . O In IN B-PP spite NN I-PP of IN I-PP this DT B-NP similar JJ I-NP downstream JJ I-NP signalling NN I-NP COMMA COMMA O IL4 NN B-NP and CC O IL13 NN B-NP used VBD B-VP a DT B-NP different JJ I-NP set NN I-NP of IN B-PP Janus NN B-NP kinases NNS I-NP : : O IL13 NN B-NP is VBZ B-VP unable JJ B-ADJP to TO B-VP activate VB I-VP JAK1 NN B-NP and CC O JAK3 NN B-NP . . O Attenuated VBN B-NP function NN I-NP of IN B-PP a DT B-NP variant JJ I-NP form NN I-NP of IN B-PP the DT B-NP helix-loop-helix JJ I-NP protein NN I-NP COMMA COMMA O Id-3 NN B-NP COMMA COMMA O generated VBN B-VP by IN B-PP an DT B-NP alternative JJ I-NP splicing NN I-NP mechanism NN I-NP . . O The DT B-NP Id NN I-NP family NN I-NP of IN B-PP helix-loop-helix JJ B-NP proteins NNS I-NP function VBP B-VP as IN B-PP negative JJ B-NP regulators NNS I-NP of IN B-NP DNA NN B-NP binding NN I-NP COMMA COMMA I-NP basic JJ I-NP helix-loop-helix JJ I-NP proteins NNS I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP cell NN B-NP growth NN B-NP and CC O differentiation NN B-NP . . O We PRP B-NP report VBP B-VP here RB B-ADVP on IN B-PP the DT B-NP identification NN I-NP of IN B-PP a DT B-NP 17 CD I-NP kDa NN I-NP variant NN I-NP of IN B-PP the DT B-NP 14 CD I-NP kDa NN I-NP Id-3 NN I-NP protein NN I-NP termed VBN B-VP Id-3L NN B-NP ( ( O long JJ B-NP version NN I-NP ) ) O which WDT B-NP possesses VBZ B-VP a DT B-NP unique JJ I-NP 60 CD I-NP amino NN I-NP acid NN I-NP carboxy-terminus NN I-NP generated VBN B-VP by IN B-PP read VBN B-NP through IN I-NP of IN B-PP a DT B-NP ' `` I-NP coding VBG I-NP intron NN I-NP ' '' O and CC O alternative JJ B-NP splicing NN I-NP . . O Northern NN B-NP analysis NN I-NP revealed VBD B-VP expression NN B-NP of IN B-PP a DT B-NP minor JJ I-NP 1.1 CD I-NP kb NN I-NP Id-3L NN I-NP transcript NN I-NP together RB B-CONJP with IN I-CONJP the DT B-NP predominant JJ I-NP 0.95 CD I-NP kb NN I-NP Id-3 NN I-NP transcript NN I-NP in IN B-PP the DT B-NP majority NN I-NP of IN B-PP adult JJ B-NP human JJ I-NP tissues NNS I-NP analysed VBN B-VP . . O The DT B-NP variant JJ I-NP Id-3L NN I-NP protein NN I-NP is VBZ B-VP functionally RB B-ADJP distinguishable JJ I-ADJP from IN B-PP conventional JJ B-NP Id-3 NN I-NP since IN B-SBAR in IN B-PP in FW B-NP vitro FW I-NP DNA NN I-NP mobility NN I-NP shift NN I-NP assays NNS I-NP COMMA COMMA O it PRP B-NP was VBD B-VP greatly RB B-ADJP impaired JJ I-ADJP in IN B-PP its PRP$ B-NP ability NN I-NP to TO B-VP abrogate VB I-VP binding NN B-NP of IN B-PP the DT B-NP basic JJ I-NP helix-loop-helix JJ I-NP protein NN I-NP COMMA COMMA O E47 NN B-NP COMMA COMMA O to TO B-PP an DT B-NP E NN I-NP box NN I-NP recognition NN I-NP sequence NN I-NP . . O Multifactor JJ B-NP cis-dominant JJ I-NP negative JJ I-NP regulation NN I-NP of IN B-PP IL-2 NN B-NP gene NN I-NP expression NN I-NP in IN B-PP anergized VBN B-NP T NN I-NP cells NNS I-NP . . O The DT B-NP molecular JJ I-NP mechanism NN I-NP underlying VBG B-VP IL-2 NN B-NP transcriptional JJ I-NP blockade NN I-NP in IN B-PP anergic JJ B-NP T NN I-NP cell NN I-NP clones NNS I-NP is VBZ B-VP not RB I-VP fully RB I-VP understood VBN I-VP . . O To TO B-VP examine VB I-VP whether IN B-SBAR an DT B-NP active JJ I-NP negative JJ I-NP regulatory JJ I-NP process NN I-NP occurs VBZ B-VP COMMA COMMA O we PRP B-NP created VBD B-VP a DT B-NP reporter NN I-NP construct NN I-NP containing VBG B-VP as IN B-PP an DT B-NP enhancer NN I-NP four CD B-NP copies NNS I-NP of IN B-PP the DT B-NP NF-AT NN I-NP site NN I-NP and CC O one CD B-NP copy NN I-NP of IN B-PP the DT B-NP octamer NN I-NP site NN I-NP ( ( O 4X NN B-NP NF-AT-Oct NN I-NP ) ) O . . O This DT B-NP construct NN I-NP was VBD O only RB B-ADVP slightly RB I-ADVP reduced VBN B-VP ( ( O 1.3-fold RB B-ADVP ) ) O in IN B-PP its PRP$ B-NP expression NN I-NP when WRB B-ADVP stimulated VBN B-VP under IN B-PP anergic JJ B-NP conditions NNS I-NP COMMA COMMA O while IN B-SBAR a DT B-NP whole JJ I-NP mouse NN I-NP IL-2 NN I-NP enhancer NN I-NP construct NN I-NP showed VBD B-VP a DT B-NP reduction NN I-NP of IN B-PP 4.3-fold JJ B-NP . . O Addition NN B-NP of IN B-PP the DT O -176 CD B-NP to TO O -96 CD B-NP sequence NN B-NP to TO B-PP the DT B-NP 4X NN I-NP NF-AT-Oct NN I-NP construct NN I-NP did VBD B-VP not RB I-VP impart VB I-VP the DT B-NP ability NN I-NP to TO B-VP be VB I-VP affected VBN I-VP by IN B-PP anergy NN B-NP COMMA COMMA O but CC O addition NN B-NP of IN B-PP the DT O -236 CD B-NP to TO O -96 CD B-NP sequence NN B-NP did VBD B-VP COMMA COMMA O demonstrating VBG B-VP that IN B-SBAR anergy NN B-NP is VBZ B-VP an DT B-NP active JJ I-NP inhibitory JJ I-NP process NN I-NP and CC O that IN B-SBAR more JJR B-NP than IN B-PP the DT B-NP presence NN I-NP of IN B-PP the DT B-NP -150 CD I-NP AP-1 NN I-NP binding NN I-NP site NN I-NP ( ( O -152 CD B-NP to TO O -147 CD B-NP ) ) O is VBZ B-VP required VBN I-VP to TO B-VP mediate VB I-VP the DT B-NP effect NN I-NP . . O Mutational JJ B-NP studies NNS I-NP of IN B-PP the DT O -236 CD B-NP to TO O -96 CD B-NP sequence NN B-NP indicated VBD B-VP that IN B-SBAR the DT B-NP presence NN I-NP of IN B-PP both CC O the DT B-NP -130 CD B-NP AP-1-like JJ I-NP site NN I-NP ( ( O -187 CD B-NP to TO O -181 CD B-NP ) ) O and CC O the DT B-NP -150 CD I-NP proximal JJ I-NP AP-1 NN I-NP site NN I-NP were VBD B-VP necessary JJ B-ADJP to TO B-VP observe VB I-VP anergy NN B-NP . . O Because IN B-SBAR the DT B-NP -180 CD I-NP site NN I-NP is VBZ B-VP not RB I-VP required VBN I-VP for IN B-PP trans-activation NN B-NP COMMA COMMA O it PRP B-NP was VBD B-VP possible JJ B-ADJP to TO B-VP confirm VB I-VP by IN B-PP mutation NN B-NP in IN B-PP the DT B-NP normal JJ I-NP mouse NN I-NP IL-2 NN I-NP enhancer NN I-NP that IN B-SBAR this DT B-NP site NN I-NP is VBZ B-VP absolutely RB B-ADJP essential JJ I-ADJP for IN B-PP anergy NN B-NP induction NN I-NP . . O The DT B-NP simplest JJS I-NP model NN I-NP to TO B-VP explain VB I-VP these DT B-NP results NNS I-NP is VBZ B-VP that IN B-SBAR anergy NN B-NP is VBZ B-VP mediated VBN I-VP by IN B-PP a DT B-NP complex NN I-NP of IN B-PP multiple JJ B-NP transcription NN I-NP factors NNS I-NP that WDT B-NP exert VBP B-VP a DT B-NP cis-acting JJ I-NP dominant JJ I-NP negative JJ I-NP regulatory JJ I-NP effect NN I-NP on IN B-PP the DT B-NP trans-activation NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP . . O Characterization NN B-NP of IN B-PP the DT B-NP human JJ I-NP myeloid JJ I-NP cell NN I-NP nuclear JJ I-NP differentiation NN I-NP antigen NN I-NP gene NN I-NP promoter NN I-NP . . O MNDA NN B-NP ( ( O myeloid JJ B-NP cell NN I-NP nuclear JJ I-NP differentiation NN I-NP antigen NN I-NP ) ) O is VBZ B-VP an DT O interferon NN B-NP alpha NN I-NP regulated VBN B-NP nuclear JJ I-NP protein NN I-NP expressed VBN B-VP only RB B-PP in IN I-PP cells NNS B-NP of IN B-PP the DT B-NP human JJ I-NP myelomonocytic JJ I-NP lineage NN I-NP . . O To TO B-VP identify VB I-VP mechanisms NNS B-NP responsible JJ B-ADJP for IN B-PP this DT B-NP lineage-specific JJ I-NP and CC I-NP interferon-regulated JJ I-NP expression NN I-NP COMMA COMMA O the DT B-NP 5' JJ I-NP flanking JJ I-NP sequence NN I-NP of IN B-PP the DT B-NP gene NN I-NP has VBZ B-VP been VBN I-VP characterized VBN I-VP . . O Two CD B-NP interferon-stimulated JJ B-NP response NN I-NP elements NNS I-NP ( ( O ISRE NN B-NP ) ) O flank VBP B-VP a DT B-NP multiple JJ I-NP transcription NN I-NP start NN I-NP site NN I-NP region NN I-NP identifying VBG B-VP MNDA NN B-NP as IN B-PP a DT B-NP TATA-less JJ I-NP interferon-regulated JJ I-NP gene NN I-NP . . O Other JJ B-NP DNA NN I-NP elements NNS I-NP present JJ B-ADJP include VBP B-VP a DT B-NP cluster NN I-NP of IN B-PP Myb NN B-NP sites NNS I-NP COMMA COMMA O several JJ B-NP Ets NNS I-NP COMMA COMMA O an DT B-NP Ets NN I-NP related JJ I-NP PU.1 NN I-NP site NN I-NP and CC O an DT B-NP Sp1 NN I-NP site NN I-NP located JJ B-ADJP within IN B-PP 600 CD B-NP bp NN I-NP of IN B-PP the DT B-NP transcription NN I-NP start NN I-NP sites NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O DNA NN B-NP methylation NN I-NP was VBD B-VP revealed VBN I-VP as IN B-PP one CD B-NP of IN B-PP the DT B-NP possible JJ I-NP factors NNS I-NP in IN B-PP establishing VBG B-VP MNDA NN B-NP expression NN I-NP . . O The DT B-NP 5' JJ I-NP flanking JJ I-NP sequence NN I-NP has VBZ B-VP promoter NN B-NP activity NN I-NP which WDT B-NP is VBZ B-VP elevated VBN I-VP by IN B-PP interferon NN B-NP alpha NN I-NP . . O The DT B-NP findings NNS I-NP indicate VBP B-VP that IN B-SBAR MNDA NN B-NP expression NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP mechanisms NNS B-NP similar JJ B-ADJP to TO B-PP other JJ O myelomonocytic JJ B-NP cell NN I-NP specific JJ B-NP genes NNS I-NP and CC O genes NNS B-NP up-regulated VBN B-VP by IN B-PP interferon NN B-NP alpha NN I-NP . . O Regulation NN B-NP of IN B-PP GM-CSF NN B-NP gene NN I-NP transcription NN I-NP by IN B-PP core-binding JJ B-NP factor NN I-NP . . O GM-CSF NN B-NP gene NN I-NP activation NN I-NP in IN B-PP T NN B-NP cells NNS I-NP is VBZ B-VP known VBN I-VP to TO I-VP involve VB I-VP the DT B-NP transcription NN I-NP factors NNS I-NP nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP COMMA COMMA O AP-1 NN B-NP COMMA COMMA O NFAT NN B-NP COMMA COMMA O and CC O Sp1 NN B-NP . . O Here RB B-ADVP we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP human JJ I-NP GM-CSF NN I-NP promoter NN B-NP and CC O enhancer NN B-NP also RB B-ADVP encompass VBP B-VP binding VBG B-NP sites NNS I-NP for IN B-PP core-binding JJ B-NP factor NN I-NP ( ( O CBF NN B-NP ) ) O . . O Significantly RB B-ADVP COMMA COMMA O the DT B-NP CBF NN I-NP sites NNS I-NP are VBP B-VP in IN B-PP each DT B-NP case NN I-NP contained VBN B-VP within IN B-PP the DT B-NP minimum JJ I-NP essential JJ I-NP core NN I-NP regions NNS I-NP required VBN B-VP for IN B-PP inducible JJ B-NP activation NN I-NP of IN B-PP transcription NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O these DT B-NP core NN I-NP regions NNS I-NP of IN B-PP the DT B-NP enhancer NN B-NP and CC O promoter NN B-NP each DT B-NP encompass VBP B-VP closely RB B-NP linked VBN I-NP binding VBG I-NP sites NNS I-NP for IN B-PP CBF NN B-NP COMMA COMMA O AP-1 NN B-NP COMMA COMMA O and CC O NFATp NN B-NP . . O The DT B-NP GM-CSF NN I-NP promoter NN I-NP CBF NN I-NP site NN I-NP TGTGGTCA NN I-NP is VBZ B-VP located JJ O 51 CD B-ADJP bp NN I-ADJP upstream RB B-ADJP of IN B-PP the DT B-NP transcription NN I-NP start NN I-NP site NN I-NP and CC O also RB O overlaps VBZ B-VP a DT B-NP YY-1 NN I-NP binding NN I-NP site NN I-NP . . O A DT B-NP 2-bp JJ I-NP mutation NN I-NP within IN B-PP the DT B-NP CBF NN I-NP site NN I-NP resulted VBD B-VP in IN B-PP a DT B-NP 2-3-fold JJ I-NP decrease NN I-NP in IN B-PP the DT B-NP activities NNS I-NP of IN B-PP both CC O a DT B-NP 69-bp JJ I-NP proximal JJ I-NP promoter NN I-NP fragment NN I-NP and CC O a DT B-NP 627-bp JJ I-NP full-length NN I-NP promoter NN I-NP fragment NN I-NP . . O Stepwise JJ B-NP deletions NNS I-NP into IN B-PP the DT B-NP proximal JJ I-NP promoter NN I-NP also RB B-ADVP revealed VBD B-VP that IN B-SBAR the DT B-NP CBF NN I-NP site NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP the DT B-NP YY-1 NN I-NP site NN I-NP COMMA COMMA O was VBD B-VP required VBN I-VP for IN B-PP efficient JJ B-NP induction NN I-NP of IN B-PP transcriptional JJ B-NP activation NN I-NP . . O The DT O AML1 NN B-NP and CC O CBF NN B-NP beta NN I-NP genes NNS B-NP that WDT B-NP encode VBP B-VP CBF NN B-NP each DT B-NP have VBP B-VP the DT B-NP ability NN I-NP to TO B-VP influence VB I-VP cell NN B-NP growth NN B-NP and CC O differentiation NN B-NP and CC O have VBP B-VP been VBN B-NP implicated VBN B-VP as IN B-PP proto-oncogenes NNS B-NP in IN B-PP acute JJ B-NP myeloid JJ I-NP leukemia NN I-NP . . O This DT B-NP study NN I-NP adds VBZ B-VP GM-CSF NN B-NP to TO B-PP a DT B-NP growing VBG I-NP list NN I-NP of IN B-PP cytokines NNS B-NP and CC O receptors NNS B-NP that WDT B-NP are VBP B-VP regulated VBN I-VP by IN B-PP CBF NN B-NP and CC O which WDT B-NP control VBP B-VP the DT B-NP growth NN B-NP COMMA COMMA O differentiation NN B-NP COMMA COMMA O and CC O activation NN B-NP of IN B-PP hemopoietic JJ B-NP cells NNS I-NP . . O The DT B-NP GM-CSF NN I-NP locus NN I-NP may MD B-VP represent VB I-VP one CD B-NP of IN B-PP several JJ B-NP target NN I-NP genes NNS I-NP that WDT B-NP are VBP B-VP dysregulated VBN I-VP in IN B-PP acute JJ B-NP myeloid JJ I-NP leukemia NN I-NP . . O Tyloxapol NN B-NP inhibits VBZ B-VP NF-kappa NN B-NP B NN I-NP and CC O cytokine NN B-NP release NN B-NP COMMA COMMA O scavenges VBZ B-VP HOCI NN B-NP COMMA COMMA O and CC O reduces VBZ B-VP viscosity NN B-NP of IN B-PP cystic JJ B-NP fibrosis NN I-NP sputum NN I-NP . . O Cystic JJ B-NP fibrosis NN I-NP ( ( O CF NN B-NP ) ) O patients NNS B-NP develop VB B-VP progressive JJ B-NP cytokine-mediated JJ I-NP inflammatory JJ I-NP lung NN I-NP disease NN I-NP COMMA COMMA O with IN B-PP abundant JJ B-NP production NN I-NP of IN B-PP thick JJ O COMMA COMMA O tenacious JJ O COMMA COMMA O protease- NN B-NP and CC O oxidant-rich JJ B-ADJP purulent JJ B-NP airway NN I-NP secretions NNS I-NP that WDT B-NP are VBP B-VP difficult JJ B-ADJP to TO B-VP clear VB I-VP even RB B-PP with IN I-PP physiotherapy NN B-NP . . O In IN B-PP the DT B-NP search NN I-NP for IN B-PP a DT B-NP potential JJ I-NP treatment NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP tested VBN I-VP tyloxapol NN B-NP COMMA COMMA O an DT B-NP alkylaryl NN I-NP polyether JJ I-NP alcohol NN I-NP polymer NN I-NP detergent NN I-NP previously RB B-VP used VBN I-VP as IN B-PP a DT B-NP mucolytic JJ I-NP agent NN I-NP in IN B-PP adult JJ B-NP chronic JJ I-NP bronchitis NN I-NP . . O Tyloxapol NN B-NP inhibits VBZ B-VP activation NN B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP ( ( O NK-kappa NN B-NP B NN I-NP ) ) O COMMA COMMA O reduces VBZ B-VP resting VBG B-NP secretion NN I-NP of IN B-PP the DT B-NP cytokine NN I-NP interleukin-8 NN B-NP ( ( O IL-8 NN B-NP ) ) O in IN B-PP cultured VBN B-NP human JJ I-NP monocytes NNS I-NP COMMA COMMA O and CC O inhibits VBZ B-VP lipopolysaccharide NN B-NP ( ( I-NP LPS NN I-NP ) ) I-NP -stimulated JJ I-NP release NN I-NP of IN B-PP tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O COMMA COMMA O IL-1 NN B-NP beta NN I-NP COMMA COMMA O IL-6 NN B-NP COMMA COMMA O IL-8 NN B-NP COMMA COMMA O granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O COMMA COMMA O and CC O the DT B-NP eiconsanoids NNS I-NP thromboxane NN B-NP A2 NN I-NP and CC O leukotriene NN B-NP B4 NN I-NP ( ( O LTB4 NN B-NP ) ) O . . O We PRP B-NP have VBP B-VP previously RB I-VP shown VBN I-VP that IN B-SBAR tyloxapol NN B-NP is VBZ B-VP a DT B-NP potent JJ I-NP antioxidant NN I-NP for IN B-PP hydroxyl NN B-NP radicals NNS I-NP ( ( O OH NN B-NP ) ) O . . O Tyloxapol NN B-NP ( ( O 0.05 CD B-NP to TO I-NP 0.1 CD I-NP % NN I-NP wt\/vol NN I-NP ) ) O effectively RB B-ADVP scavenges VBZ B-VP the DT B-NP oxidant JJ I-NP hypochlorous JJ I-NP acid NN I-NP ( ( O HOCl NN B-NP ; : O 1 CD B-NP to TO I-NP 7.5 CD I-NP mM NN I-NP ) ) O in FW B-ADVP vitro FW I-ADVP COMMA COMMA O and CC O protects VBZ B-VP from IN B-PP HOCl-mediated JJ B-NP lung NN I-NP injury NN I-NP in IN B-PP rats NNS B-NP . . O Tyloxapol NN B-NP also RB B-ADVP reduces VBZ B-VP the DT B-NP viscosity NN I-NP of IN B-PP CF NN B-NP sputum NN I-NP ( ( O from IN B-PP 463 CD B-NP +\/- CC I-NP 133 CD I-NP to TO B-PP 128 CD B-NP +\/- CC I-NP 52 CD I-NP centipoise NN B-NP ) ) O . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR tyloxapol NN B-NP is VBZ B-VP potentially RB B-ADVP useful JJ B-ADJP as IN B-PP a DT B-NP new JJ I-NP antiinflammatory JJ I-NP therapy NN I-NP for IN B-PP CF NN B-NP lung NN I-NP disease NN I-NP COMMA COMMA O and CC O could MD B-VP possibly RB I-VP promote VB I-VP clearance NN B-NP of IN B-PP secretions NNS B-NP in IN B-PP the DT B-NP CF NN I-NP airway NN I-NP . . O Abnormality NN B-NP of IN B-PP Oct-1 NN B-NP DNA NN I-NP binding NN I-NP in IN B-PP T NN B-NP cells NNS I-NP from IN B-PP Sjogren NN B-NP 's POS B-NP syndrome NN I-NP patients NNS I-NP . . O Primary JJ B-NP Sjogren NN B-NP 's POS B-NP syndrome NN I-NP ( ( O SS NN B-NP ) ) O is VBZ B-VP an DT B-NP autoimmune JJ I-NP rheumatic JJ I-NP disease NN I-NP characterized VBN B-VP by IN B-PP T NN B-NP cell NN I-NP hypoactivity NN I-NP . . O To TO B-VP understand VB I-VP the DT B-NP diminished VBN I-NP T NN I-NP cell NN I-NP response NN I-NP to TO B-PP activation NN B-NP signals NNS I-NP COMMA COMMA O we PRP B-NP measured VBD B-VP nucleoprotein NN B-NP DNA-binding JJ I-NP activities NNS I-NP regulating VBG B-VP gene NN B-NP expression NN I-NP during IN B-PP T NN B-NP cell NN I-NP activation NN I-NP using VBG B-VP the DT B-NP electrophoretic JJ I-NP mobility NN I-NP shift NN I-NP assay NN I-NP . . O Peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP from IN B-PP 9\/19 CD B-NP SS NN I-NP patients NNS I-NP were VBD B-VP found VBN I-VP to TO I-VP be VB I-VP defective JJ B-ADJP in IN B-PP their PRP$ B-NP ability NN I-NP to TO B-VP bind VB I-VP an DT B-NP october NN I-NP sequence NN I-NP ( ( O Oct-1 NN B-NP ) ) O . . O This DT B-NP Oct-1-binding JJ I-NP phenotype NN I-NP remained VBD B-VP stable JJ B-ADJP in IN B-PP culture NN B-NP for IN B-PP up IN B-NP to TO I-NP 3 CD I-NP days NNS I-NP prior RB B-PP to TO I-PP activation NN B-NP . . O This DT B-NP abnormality NN I-NP was VBD B-VP not RB I-VP seen VBN I-VP in IN B-PP resting VBG B-NP T NN I-NP cells NNS I-NP nor CC O T NN B-NP cells NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP systemic JJ B-NP lupus NN I-NP erythematosus NN I-NP COMMA COMMA O rheumatoid JJ B-NP arthritis NN I-NP ( ( O RA NN B-NP ) ) O COMMA COMMA O or CC O SS NN B-NP accompanied VBN B-VP by IN B-PP RA NN B-NP . . O The DT B-NP SS NN I-NP Oct-1 NN I-NP DNA-binding JJ I-NP abnormality NN I-NP correlated VBD B-VP significantly RB B-ADVP with IN B-PP an DT B-NP inability NN I-NP of IN B-PP cells NNS B-NP to TO B-VP exit VB I-VP the DT B-NP Gzero\/G1 NN I-NP cell NN I-NP cycle NN I-NP phase NN I-NP when WRB B-ADVP stimulated VBN B-VP in FW B-ADVP vitro FW I-ADVP . . O Importantly RB B-ADVP COMMA COMMA O nucleoprotein NN B-NP extracts NNS I-NP showing VBG B-VP decreased VBN B-NP DNA-binding JJ I-NP activity NN I-NP had VBD B-VP normal JJ B-NP amounts NNS I-NP of IN B-PP Oct-1 NN B-NP proteins NNS I-NP as IN B-SBAR determined VBN B-VP by IN B-PP immunoprecipitation NN B-NP COMMA COMMA O implying VBG B-VP a DT B-NP functional JJ I-NP defect NN I-NP in IN B-PP the DT B-NP Oct-1 NN I-NP protein NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O defective JJ B-NP DNA NN I-NP binding NN I-NP was VBD B-VP corrected VBN I-VP by IN B-PP treatment NN B-NP with IN B-PP acid NN B-NP phosphatase NN I-NP . . O Severe JJ B-NP combined JJ I-NP immunodeficiency NN I-NP due IN B-PP to TO I-PP defective JJ B-NP binding NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP of IN B-PP two CD B-NP male JJ I-NP siblings NNS I-NP . . O Peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP ( ( O PBL NN B-NP ) ) O and CC O alloreactive JJ B-NP T NN I-NP cell NN I-NP lines NNS I-NP of IN B-PP two CD B-NP male JJ I-NP infants NNS I-NP born VBN B-VP to TO B-PP consanguinous JJ B-NP parents NNS I-NP and CC O presenting VBG B-VP with IN B-PP severe JJ B-NP combined JJ I-NP immunodeficiency NN I-NP ( ( O SCID NN B-NP ) ) O showed VBD B-VP a DT B-NP pronounced JJ I-NP deficiency NN I-NP in IN B-PP T NN B-NP cell NN I-NP activation NN I-NP . . O Although IN B-SBAR phenotypically RB B-ADJP normal JJ I-ADJP COMMA COMMA O the DT B-NP proliferative JJ I-NP response NN I-NP of IN B-PP the DT B-NP childrens NNS I-NP ' POS B-NP T NN I-NP cells NNS I-NP was VBD B-VP strongly RB I-VP reduced VBN I-VP but CC O could MD B-VP be VB I-VP improved VBN I-VP by IN B-PP the DT B-NP addition NN I-NP of IN B-PP interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O . . O Furthermore RB B-ADVP both DT B-NP childrens NNS I-NP ' POS B-NP T NN I-NP cells NNS I-NP were VBD B-VP unable JJ B-ADJP to TO B-VP produce VB I-VP the DT B-NP cytokines NNS I-NP IL-2 NN B-NP COMMA COMMA O interferon-gamma NN B-NP ( ( O IFN-gamma NN B-NP ) ) O COMMA COMMA O IL-4 NN B-NP and CC O tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O . . O This DT B-NP multiple JJ I-NP cytokine NN I-NP production NN I-NP deficiency NN I-NP could MD B-VP not RB I-VP be VB I-VP restored VBN I-VP by IN B-PP IL-2 NN B-NP or CC O co-stimulatory JJ B-ADJP signals NNS B-NP provided VBN B-VP by IN B-PP antigen-presenting JJ B-NP cells NNS I-NP ( ( O APC NN B-NP ) ) O . . O Moreover RB B-ADVP COMMA COMMA O mRNA NN B-NP for IN B-PP IL-2 NN B-NP and CC O IFN-gamma NN B-NP could MD B-VP not RB I-VP be VB I-VP detected VBN I-VP . . O In IN B-PP contrast NN B-NP COMMA COMMA O expression NN B-NP of IN B-PP the DT B-NP activation-dependent JJ I-NP cell NN I-NP surface NN I-NP markers NNS I-NP CD25 NN B-NP and CC O CD69 NN B-NP was VBD B-VP within IN B-PP normal JJ B-NP limits NNS I-NP . . O To TO B-VP determine VB I-VP whether IN B-SBAR the DT B-NP functional JJ I-NP defect NN I-NP of IN B-PP the DT B-NP patients NNS I-NP ' POS B-NP T NN I-NP cells NNS I-NP was VBD B-VP due JJ B-PP to TO I-PP the DT B-NP absence NN B-NP or CC O abnormal JJ B-NP binding NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP involved VBN B-VP in IN B-PP cytokine NN B-NP gene NN I-NP expression NN I-NP COMMA COMMA O electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP were VBD B-VP used VBN I-VP to TO B-VP examine VB I-VP the DT B-NP DNA NN I-NP binding NN I-NP of IN B-PP AP-1 NN B-NP COMMA COMMA O Oct NN B-NP COMMA COMMA O CREB NN B-NP COMMA COMMA O SP1 NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP and CC O the DT B-NP nuclear JJ I-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O to TO B-PP their PRP$ B-NP respective JJ I-NP response NN I-NP elements NNS I-NP in IN B-PP the DT B-NP promoter NN I-NP of IN B-PP the DT B-NP IL-2 NN I-NP gene NN I-NP . . O Whereas IN B-SBAR AP-1 NN B-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP COMMA COMMA O Oct NN B-NP COMMA COMMA O CREB NN B-NP and CC O SP1 NN B-NP displayed VBD B-VP normal JJ B-NP binding NN I-NP activities NNS I-NP in IN B-PP nuclear JJ B-NP extracts NNS I-NP COMMA COMMA O the DT B-NP binding NN I-NP of IN B-PP NF-AT NN B-NP to TO B-PP its PRP$ B-NP IL-2 NN I-NP promoter NN I-NP response NN I-NP element NN I-NP was VBD B-VP barely RB B-ADJP detectable JJ I-ADJP both CC O before IN B-PP and CC B-PP after IN B-PP T NN B-NP cell NN I-NP stimulation NN I-NP . . O Our PRP$ B-NP results NNS I-NP strongly RB B-ADVP suggest VBP B-VP that IN B-SBAR this DT B-NP NF-AT\/DNA NN I-NP binding NN I-NP defect NN I-NP is VBZ B-VP responsible JJ B-ADJP for IN B-PP the DT B-NP multiple JJ I-NP cytokine NN I-NP deficiency NN I-NP and CC O the DT B-NP SCID NN I-NP phenotype NN I-NP observed VBN B-VP in IN B-PP the DT B-NP two CD I-NP infant JJ I-NP brothers NNS I-NP . . O Requirements NNS B-NP for IN B-PP induction NN B-NP of IN B-PP vitamin NN B-NP D-mediated JJ I-NP gene NN I-NP regulation NN I-NP in IN B-PP normal JJ B-NP human JJ I-NP B NN I-NP lymphocytes NNS I-NP . . O Mature JJ B-NP human JJ I-NP lymphocytes NNS I-NP are VBP B-VP unique JJ B-NP targets NNS I-NP of IN B-PP 1 CD B-NP alphaCOMMA25-dihydroxyvitamin NN I-NP D3 NN I-NP ( ( O 1 CD B-NP alphaCOMMA25(OH)2D3 NN I-NP ) ) O in IN B-PP that IN B-SBAR vitamin NN B-NP D NN I-NP receptors NNS I-NP ( ( O VDR NN B-NP ) ) O are VBP B-VP not RB I-VP constitutively RB I-VP expressed VBN I-VP COMMA COMMA O and CC O specific JJ B-NP cellular JJ I-NP activation NN I-NP signals NNS I-NP are VBP B-VP required VBN I-VP for IN B-PP both DT B-NP the DT I-NP up-regulation NN B-NP of IN B-PP VDR NN B-NP and CC O establishment NN B-NP of IN B-PP reactivity NN B-NP to TO B-PP the DT B-NP lipophilic JJ I-NP ligand NN I-NP . . O Treatment NN B-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP with IN B-PP the DT B-NP cytokine NN I-NP IL-4 NN I-NP ( ( O IL-4 NN B-NP ) ) O COMMA COMMA O in IN B-PP the DT I-PP absence NN I-PP of IN I-PP prior JJ B-NP activation NN I-NP COMMA COMMA O induces VBZ B-VP a DT B-NP weak JJ I-NP up-regulation NN I-NP of IN B-PP VDR NN B-NP expression NN I-NP but CC O fails VBZ B-VP to TO B-VP generate VB I-VP vitamin NN B-NP D-responsive JJ I-NP element NN I-NP ( ( B-NP VDRE NN I-NP ) ) I-NP -reactive JJ I-NP nuclear JJ I-NP protein NN I-NP complexes NNS I-NP or CC O to TO B-VP initiate VB I-VP the DT B-NP genomic JJ I-NP transcription NN I-NP of IN B-PP 25-hydroxyvitamin NN B-NP D3 NN I-NP 24-hydroxylase NN I-NP . . O Stimulation NN B-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP by IN B-PP either CC O ligation NN B-NP of IN B-PP CD40 NN B-NP Ag NN I-NP or CC O cross-linking VBG B-VP the DT B-NP Ig NN I-NP receptor NN I-NP is VBZ B-VP also RB B-ADVP insufficient JJ B-ADJP to TO B-VP render VB I-VP B NN B-NP lymphocytes NNS I-NP responsive JJ B-ADJP to TO B-PP 1 CD B-NP alphaCOMMA25(OH)2D3 NN I-NP . . O However RB B-ADVP COMMA COMMA O this DT B-NP apparent JJ I-NP lack NN I-NP of IN B-PP response NN B-NP to TO B-PP the DT B-NP secosterol NN I-NP can MD B-VP be VB I-VP overcome VBN I-VP by IN B-PP stimulation NN B-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP with IN B-PP a DT B-NP combination NN I-NP of IN B-PP these DT B-NP cellular JJ I-NP activation NN I-NP signals NNS I-NP COMMA COMMA O which WDT B-NP are VBP B-VP sufficient JJ B-ADJP to TO B-VP lead VB I-VP to TO B-PP G1 NN B-NP cell NN I-NP cycle NN I-NP progression NN I-NP . . O In IN B-PP the DT I-PP presence NN I-PP of IN I-PP 1 CD B-NP alphaCOMMA25(OH)2D3 NN I-NP COMMA COMMA O cellular JJ B-NP activation NN I-NP associated VBN B-VP with IN B-PP stimulation NN B-NP of IN B-PP such PDT B-NP a DT I-NP progression NN I-NP appears VBZ B-VP to TO I-VP be VB I-VP sufficient JJ B-ADJP for IN B-PP the DT B-NP up-regulation NN I-NP of IN B-PP VDR NN B-NP message NN I-NP and CC O protein NN B-NP and CC O necessary JJ B-ADJP for IN B-PP the DT B-NP establishment NN I-NP of IN B-PP VDRE NN B-NP binding NN I-NP complexes NNS I-NP and CC O the DT B-NP induction NN I-NP of IN B-PP 24-hydroxylase NN B-NP message NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O biologic JJ B-NP functions NNS I-NP are VBP B-VP modulated VBN I-VP COMMA COMMA O in IN B-PP that IN B-NP the DT B-NP hormone NN I-NP inhibits VBZ B-VP proliferation NN B-NP in IN B-PP a DT B-NP subset NN I-NP of IN B-PP the DT B-NP activated VBN I-NP B NN I-NP cells NNS I-NP . . O These DT B-NP observations NNS I-NP suggest VBP B-VP that IN B-SBAR reactivity NN B-NP to TO B-PP 1 CD B-NP alphaCOMMA25(OH)2D3 NN I-NP is VBZ B-VP tightly RB I-VP regulated VBN I-VP in IN B-PP B NN B-NP lymphocytes NNS I-NP COMMA COMMA O requiring VBG B-VP specific JJ B-NP signals NNS I-NP for IN B-PP its PRP$ B-NP initiation NN I-NP . . O Cell-type-specific JJ B-NP regulation NN I-NP of IN B-PP the DT B-NP human JJ I-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP gene NN I-NP in IN B-PP B NN B-NP cells NNS I-NP and CC O T NN B-NP cells NNS I-NP by IN B-PP NFATp NN B-NP and CC O ATF-2\/JUN NN B-NP . . O The DT O human JJ O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O gene NN B-NP is VBZ B-VP one CD B-NP of IN B-PP the DT B-NP earliest JJS I-NP genes NNS I-NP transcribed VBN B-VP after IN B-PP the DT B-NP stimulation NN I-NP of IN B-PP a DT B-NP B NN I-NP cell NN I-NP through IN B-PP its PRP$ B-NP antigen NN I-NP receptor NN I-NP or CC B-PP via IN B-PP the DT B-NP CD-40 NN I-NP pathway NN I-NP . . O In IN B-PP both DT B-NP cases NNS I-NP COMMA COMMA O induction NN B-NP of IN B-PP TNF-alpha NN B-NP gene NN I-NP transcription NN I-NP can MD B-VP be VB I-VP blocked VBN I-VP by IN B-PP the DT B-NP immunosuppressants NNS I-NP cyclosporin NN B-NP A NN I-NP and CC O FK506 NN B-NP COMMA COMMA O which WDT B-NP suggested VBD B-VP a DT B-NP role NN I-NP for IN B-PP the DT B-NP NFAT NN I-NP family NN I-NP of IN B-PP proteins NNS B-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP gene NN I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O in IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O two CD B-NP molecules NNS I-NP of IN B-PP NFATp NN B-NP bind VBP B-VP to TO B-PP the DT B-NP TNF-alpha NN I-NP promoter NN I-NP element NN I-NP kappa NN I-NP 3 CD I-NP in NN O association NN B-NP with IN B-PP ATF-2 NN B-NP and CC O Jun NN B-NP proteins NNS B-NP bound VBN B-VP to TO B-PP an DT O immediately RB O adjacent JJ O cyclic JJ B-NP AMP NN I-NP response NN I-NP element NN I-NP ( ( O CRE NN B-NP ) ) O site NN B-NP . . O Here RB B-ADVP COMMA COMMA O using VBG B-VP the DT B-NP murine JJ I-NP B-cell NN I-NP lymphoma NN I-NP cell NN I-NP line NN I-NP A20 NN I-NP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP TNF-alpha NN I-NP gene NN I-NP is VBZ B-VP regulated VBN I-VP in IN B-PP a DT B-NP cell-type-specific JJ I-NP manner NN I-NP . . O In IN B-PP A20 NN B-NP B NN I-NP cells NNS I-NP COMMA COMMA O the DT B-NP TNF-alpha NN I-NP gene NN I-NP is VBZ B-VP not RB I-VP regulated VBN I-VP by IN B-PP NFATp NN B-NP bound VBN B-VP to TO B-PP the DT B-NP kappa NN I-NP 3 CD I-NP element NN I-NP . . O Instead RB B-ADVP COMMA COMMA O ATF-2 NN B-NP and CC O Jun NN B-NP proteins NNS B-NP bind VBP B-VP to TO B-PP the DT B-NP composite JJ I-NP kappa NN I-NP 3\/CRE NN I-NP site NN I-NP and CC O NFATp NN B-NP binds VBZ B-VP to TO B-PP a DT B-NP newly RB I-NP identified VBN I-NP second JJ I-NP NFAT NN I-NP site NN I-NP centered JJ B-VP at IN B-PP -76 CD B-NP nucleotides NNS I-NP relative JJ B-PP to TO I-PP the DT B-NP TNF-alpha NN I-NP transcription NN I-NP start NN I-NP site NN I-NP . . O This DT B-NP new JJ I-NP site NN I-NP plays VBZ B-VP a DT B-NP critical JJ I-NP role NN I-NP in IN B-PP the DT B-NP calcium-mediated JJ I-NP COMMA COMMA I-NP cyclosporin NN I-NP A-sensitive JJ I-NP induction NN I-NP of IN B-PP TNF-alpha NN B-NP in IN B-PP both CC O A20 NN B-NP B NN I-NP cells NNS I-NP and CC O Ar-5 NN B-NP cells NNS I-NP . . O Consistent JJ B-ADJP with IN B-PP these DT B-NP results NNS I-NP COMMA COMMA O quantitative JJ B-NP DNase NN I-NP footprinting NN I-NP of IN B-PP the DT B-NP TNF-alpha NN I-NP promoter NN I-NP using VBG B-VP increasing VBG B-NP amounts NNS I-NP of IN B-PP recombinant JJ B-NP NFATp NN I-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP -76 CD I-NP site NN I-NP binds VBZ B-VP to TO B-PP NFATp NN B-NP with IN B-PP a DT B-NP higher JJR I-NP affinity NN I-NP than IN B-PP the DT B-NP kappa NN I-NP 3 CD I-NP site NN I-NP . . O Two CD B-NP other JJ I-NP previously RB I-NP unrecognized JJ I-NP NFATp-binding JJ I-NP sites NNS I-NP in IN B-PP the DT B-NP proximal JJ I-NP TNF-alpha NN I-NP promoter NN I-NP were VBD B-VP also RB I-VP identified VBN I-VP by IN B-PP this DT B-NP analysis NN I-NP . . O Thus RB B-ADVP COMMA COMMA O through IN B-PP the DT B-NP differential JJ I-NP use NN I-NP of IN B-PP the DT B-NP same JJ I-NP promoter NN I-NP element NN I-NP COMMA COMMA O the DT B-NP composite JJ I-NP kappa NN I-NP 3\/CRE NN I-NP site NN I-NP COMMA COMMA O the DT B-NP TNF-alpha NN I-NP gene NN I-NP is VBZ B-VP regulated VBN I-VP in IN B-PP a DT B-NP cell-type-specific JJ I-NP manner NN I-NP in IN B-PP response NN I-PP to TO I-PP the DT B-NP same JJ I-NP extracellular JJ I-NP signal NN I-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP ligand-binding JJ I-NP domain NN I-NP of IN B-PP human JJ B-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP alpha NN I-NP by IN B-PP site-directed JJ B-NP mutagenesis NN I-NP . . O Three CD B-NP subtypes NNS I-NP of IN B-PP retinoic JJ B-NP acid NN I-NP receptors NNS I-NP ( ( O RAR NN B-NP ) ) O COMMA COMMA O termed VBN B-VP RAR NN B-NP alpha NN I-NP COMMA COMMA O RAR NN B-NP beta NN I-NP COMMA COMMA O and CC O RAR NN B-NP gamma NN I-NP COMMA COMMA O have VBP B-VP been VBN I-VP described VBN I-VP . . O They PRP B-NP are VBP B-VP composed VBN I-VP of IN B-PP different JJ B-NP structural JJ I-NP domains NNS I-NP COMMA COMMA O including VBG B-PP distinct JJ B-NP domains NNS I-NP for IN B-PP DNA NN B-NP and CC O ligand NN B-NP binding NN B-NP . . O RARs NNS B-NP specifically RB B-ADVP bind VBP B-VP all-trans-retinoic JJ B-NP acid NN I-NP ( ( O RA NN B-NP ) ) O COMMA COMMA O 9-cis-RA NN B-NP COMMA COMMA O and CC O retinoid JJ B-NP analogs NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP examined VBD B-VP the DT B-NP functional JJ I-NP role NN I-NP of IN B-PP cysteine NN B-NP and CC O arginine NN B-NP residues NNS B-NP in IN B-PP the DT B-NP ligand-binding JJ I-NP domain NN I-NP of IN B-PP hRAR NN B-NP alpha NN I-NP ( ( O hRAR NN B-NP alpha-LBD NN I-NP COMMA COMMA O amino NN B-NP acids NNS I-NP 154 CD B-NP to TO O 462 CD B-NP ) ) O . . O All DT O conserved VBN O cysteine NN B-NP and CC O arginine NN B-NP residues NNS B-NP in IN B-PP this DT B-NP domain NN I-NP were VBD B-VP mutated VBN I-VP by IN B-PP site-directed JJ B-NP mutagenesis NN I-NP COMMA COMMA O and CC O the DT B-NP mutant JJ I-NP proteins NNS I-NP were VBD B-VP characterized VBN I-VP by IN B-PP blocking VBG B-NP reactions NNS I-NP COMMA COMMA O ligand-binding JJ B-NP experiments NNS I-NP COMMA COMMA O transactivation NN B-NP assays NNS I-NP COMMA COMMA O and CC O protease NN B-NP mapping NN I-NP . . O Changes NNS B-NP of IN B-PP any DT B-NP cysteine JJ I-NP residue NN I-NP of IN B-PP the DT B-NP hRAR NN I-NP alpha-LBD NN I-NP had VBD B-VP no DT B-NP significant JJ I-NP influence NN I-NP on IN B-PP the DT B-NP binding NN I-NP of IN B-PP all-trans JJ B-NP RA NN I-NP or CC O 9-cis JJ B-NP RA NN I-NP . . O Interestingly RB B-NP COMMA COMMA O residue JJ B-NP C-235 NN I-NP is VBZ B-VP specifically RB B-ADVP important JJ B-ADJP in IN B-PP antagonist NN B-NP binding NN I-NP . . O With IN B-PP respect NN I-PP to TO I-PP arginine NN B-NP residues NNS I-NP COMMA COMMA O only RB B-NP the DT I-NP two CD I-NP single JJ I-NP mutations NNS I-NP of IN B-PP R-276 NN B-NP and CC O R-394 NN B-NP to TO B-PP alanine NN B-NP showed VBD B-VP a DT B-NP dramatic JJ I-NP decrease NN I-NP of IN B-PP agonist NN B-NP and CC O antagonist NN B-NP binding NN B-NP whereas IN B-SBAR the DT B-NP R272A NN I-NP mutation NN I-NP showed VBD B-VP only RB B-NP a DT I-NP slight JJ I-NP effect NN I-NP . . O For IN B-PP all DT B-NP other JJ I-NP arginine NN I-NP mutations NNS I-NP COMMA COMMA O no DT B-NP differences NNS I-NP in IN B-PP affinity NN B-NP were VBD B-VP detectable JJ B-ADJP . . O The DT B-NP two CD I-NP mutations NNS I-NP R217A NN B-NP and CC O R294A NN B-NP caused VBD B-VP an DT B-NP increased VBN I-NP binding NN I-NP efficiency NN I-NP for IN B-PP antagonists NNS B-NP but CC O no DT B-NP change NN I-NP in IN B-PP agonist NN B-NP binding NN I-NP . . O From IN B-PP these DT B-NP results NNS I-NP COMMA COMMA O we PRP B-NP can MD B-VP conclude VB I-VP that IN B-SBAR electrostatic JJ B-NP interactions NNS I-NP of IN B-PP retinoids NNS B-NP with IN B-PP the DT B-NP RAR NN I-NP alpha-LBD NN I-NP play VBP B-VP a DT B-NP significant JJ I-NP role NN I-NP in IN B-PP ligand NN B-NP binding NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O antagonists NNS B-NP show VBP B-VP distinctly RB B-NP different JJ I-NP requirements NNS I-NP for IN B-PP efficient JJ B-NP binding NN I-NP COMMA COMMA O which WDT B-NP may MD B-VP contribute VB I-VP to TO B-PP their PRP$ B-NP interference NN I-NP in IN B-PP the DT B-NP ligand-inducible JJ I-NP transactivation NN I-NP function NN I-NP of IN B-PP RAR NN B-NP alpha NN I-NP . . O Cloning NN B-NP and CC O characterization NN B-NP of IN B-PP the DT B-NP beta NN I-NP subunit NN I-NP of IN B-PP human JJ B-NP proximal JJ I-NP sequence NN I-NP element-binding JJ I-NP transcription NN I-NP factor NN I-NP and CC O its PRP$ B-NP involvement NN I-NP in IN B-PP transcription NN B-NP of IN B-PP small JJ B-NP nuclear JJ I-NP RNA NN I-NP genes NNS I-NP by IN B-PP RNA NN B-NP polymerases NNS I-NP II CD B-NP and CC O III CD B-NP . . O The DT O proximal JJ B-NP sequence NN I-NP element NN I-NP ( ( B-NP PSE NN I-NP ) ) I-NP -binding JJ I-NP transcription NN I-NP factor NN I-NP ( ( O PTF NN B-NP ) ) O COMMA COMMA O which WDT B-NP binds VBZ B-VP the DT B-NP PSE NN I-NP of IN B-PP both CC O RNA NN B-NP polymerase NN I-NP II- NN I-NP and CC O RNA NN B-ADJP polymerase NN I-ADJP III-transcribed JJ I-ADJP mammalian JJ O small JJ B-NP nuclear JJ I-NP RNA NN I-NP ( ( O snRNA NN B-NP ) ) O genes NNS B-NP COMMA COMMA O is VBZ B-VP essential JJ B-ADJP for IN B-PP their PRP$ B-NP transcription NN I-NP . . O We PRP B-NP previously RB B-ADVP reported VBD B-VP the DT B-NP purification NN I-NP of IN B-PP human JJ B-NP PTF NN I-NP COMMA COMMA O a DT B-NP complex NN I-NP of IN B-PP four CD B-NP subunits NNS I-NP COMMA COMMA O and CC O the DT B-NP molecular JJ B-NP cloning NN I-NP and CC O characterization NN B-NP of IN B-PP PTF NN O gamma NN B-NP and CC O delta NN B-NP subunits NNS B-NP . . O Here RB B-ADVP we PRP B-NP describe VBP B-VP the DT B-NP isolation NN B-NP and CC O expression NN B-NP of IN B-PP a DT B-NP cDNA NN I-NP encoding VBG B-VP PTF NN B-NP beta NN I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP functional JJ B-NP studies NNS I-NP using VBG B-VP anti-PTF JJ B-NP beta NN I-NP antibodies NNS I-NP . . O Native JJ B-NP PTF NN I-NP beta NN I-NP COMMA COMMA O in IN B-PP either CC O protein NN B-NP fractions NNS I-NP or CC O a DT B-NP PTF-Oct-1-DNA NN I-NP complex NN I-NP COMMA COMMA O can MD B-VP be VB I-VP recognized VBN I-VP by IN B-PP polyclonal JJ B-NP antibodies NNS I-NP raised VBN B-VP against IN B-PP recombinant JJ B-NP PTF NN I-NP beta NN I-NP . . O Immunodepletion NN B-NP studies NNS I-NP show VBP B-VP that IN B-SBAR PTF NN B-NP beta NN I-NP is VBZ B-VP required VBN I-VP for IN B-PP transcription NN B-NP of IN B-PP both DT B-NP classes NNS I-NP of IN B-PP snRNA NN B-NP genes NNS I-NP in FW B-ADVP vitro FW I-ADVP . . O In IN B-PP addition NN B-NP COMMA COMMA O immunoprecipitation NN B-NP analyses NNS I-NP demonstrate VBP B-VP that IN B-SBAR substantial JJ B-NP and CC I-NP similar JJ I-NP molar JJ I-NP amounts NNS I-NP of IN B-PP TATA-binding JJ B-NP protein NN I-NP ( ( O TBP NN B-NP ) ) O and CC O TFIIIB90 NN B-NP can MD B-VP weakly RB I-VP associate VBP I-VP with IN B-PP PTF NN B-NP at IN B-PP low JJ B-NP salt NN I-NP conditions NNS I-NP COMMA COMMA O but CC O this DT B-NP association NN I-NP is VBZ B-VP dramatically RB I-VP reduced VBN I-VP at IN B-PP high JJ B-NP salt NN I-NP concentrations NNS I-NP . . O Along IN B-PP with IN I-PP our PRP$ B-NP previous JJ I-NP demonstration NN I-NP of IN B-PP both DT B-NP physical JJ I-NP interactions NNS I-NP between IN B-PP PTF NN B-NP gamma NN I-NP \/ : O PTF NN B-NP delta NN I-NP and CC O TBP NN B-NP and CC O the DT B-NP involvement NN I-NP of IN B-PP TFIIIB90 NN B-NP in IN B-PP the DT B-NP transcription NN I-NP of IN B-PP class NN B-NP III CD I-NP snRNA NN I-NP genes NNS I-NP COMMA COMMA O these DT B-NP results NNS I-NP are VBP B-VP consistent JJ B-ADJP with IN B-PP the DT B-NP notion NN I-NP that IN B-SBAR a DT B-NP TBP-containing JJ I-NP complex NN I-NP related JJ B-ADJP to TO B-PP TFIIIB NN B-NP is VBZ B-VP required VBN I-VP for IN B-PP the DT B-NP transcription NN I-NP of IN B-PP class NN B-NP III CD I-NP snRNA NN I-NP genes NNS I-NP COMMA COMMA O and CC O acts VBZ B-VP through IN B-PP weak JJ B-NP interaction NN I-NP with IN B-PP the DT B-NP four-subunit JJ I-NP PTF NN I-NP . . O Induction NN B-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP by IN B-PP phosphorylated VBN B-NP CREB NN I-NP proteins NNS I-NP during IN B-PP B-cell NN B-NP activation NN I-NP and CC O rescue NN B-NP from IN B-PP apoptosis NN B-NP . . O Engagement NN B-NP of IN B-PP surface NN B-NP immunoglobulin NN I-NP on IN B-PP mature JJ B-NP B NN I-NP cells NNS I-NP leads VBZ B-VP to TO B-PP rescue NN B-NP from IN B-PP apoptosis NN B-NP and CC B-PP to TO B-PP proliferation NN B-NP . . O Levels NNS B-NP of IN B-PP bcl-2 NN B-NP mRNA NN B-NP and CC O protein NN B-NP increase VBP B-VP with IN B-PP cross-linking NN B-NP of IN B-PP surface NN B-NP immunoglobulin NN I-NP . . O We PRP B-NP have VBP B-VP located JJ I-VP the DT B-NP major JJ I-NP positive JJ I-NP regulatory JJ I-NP region NN I-NP for IN B-PP control NN B-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP in IN B-PP B NN B-NP cells NNS I-NP in IN B-PP the DT B-NP 5'-flanking JJ I-NP region NN I-NP . . O The DT B-NP positive JJ I-NP region NN I-NP can MD B-VP be VB I-VP divided VBN I-VP into IN B-PP an DT B-NP upstream JJ I-NP and CC O a DT B-NP downstream JJ I-NP regulatory JJ B-NP region NN I-NP . . O The DT B-NP downstream JJ I-NP regulatory JJ I-NP region NN I-NP contains VBZ B-VP a DT B-NP cyclic JJ I-NP AMP-responsive JJ I-NP element NN I-NP ( ( O CRE NN B-NP ) ) O . . O We PRP B-NP show VBP B-VP by IN B-PP antibody NN B-NP supershift NN I-NP experiments NNS I-NP and CC O UV NN B-NP cross-linking NN I-NP followed VBN B-VP by IN B-PP denaturing VBG B-NP polyacrylamide NN I-NP gel NN I-NP electrophoresis NN I-NP that IN B-SBAR both CC O CREB NN B-NP and CC O ATF NN B-NP family NN B-NP members NNS I-NP bind VBP B-VP to TO B-PP this DT B-NP region NN I-NP in FW B-ADVP vitro FW I-ADVP . . O Mutations NNS B-NP of IN B-PP the DT B-NP CRE NN I-NP site NN I-NP that WDT B-NP result VBP B-VP in IN B-PP loss NN B-NP of IN B-PP CREB NN B-NP binding NN I-NP also RB B-ADVP lead VBP B-VP to TO B-PP loss NN B-NP of IN B-PP functional JJ B-NP activity NN I-NP of IN B-PP the DT B-NP bcl-2 NN I-NP promoter NN I-NP in IN B-PP transient-transfection NN B-NP assays NNS I-NP . . O The DT B-NP presence NN I-NP of IN B-PP an DT B-NP active JJ I-NP CRE NN I-NP site NN I-NP in IN B-PP the DT B-NP bcl-2 NN I-NP promoter NN I-NP implies VBZ B-VP that IN B-SBAR the DT B-NP regulation NN I-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP is VBZ B-VP linked VBN I-VP to TO B-PP a DT B-NP signal NN I-NP transduction NN I-NP pathway NN I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Treatment NN B-NP of IN B-PP the DT B-NP mature JJ I-NP B-cell NN I-NP line NN I-NP BAL-17 NN I-NP with IN B-PP either CC O anti-immunoglobulin JJ B-NP M NN I-NP or CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP leads VBZ B-VP to TO B-PP an DT B-NP increase NN I-NP in IN B-PP bcl-2 NN B-NP expression NN I-NP that WDT B-NP is VBZ B-VP mediated VBN I-VP by IN B-PP the DT B-NP CRE NN I-NP site NN I-NP . . O Treatment NN B-NP of IN B-PP the DT B-NP more RBR I-NP immature JJ I-NP B-cell NN I-NP line NN I-NP COMMA COMMA O Ramos NN B-NP COMMA COMMA O with IN B-PP phorbol NN B-NP esters NNS I-NP rescues VBZ B-VP the DT B-NP cells NNS I-NP from IN B-PP calcium-dependent JJ B-NP apoptosis NN I-NP . . O bcl-2 NN B-NP expression NN I-NP is VBZ B-VP increased VBN I-VP following VBG B-PP phorbol NN B-NP ester NN I-NP treatment NN I-NP COMMA COMMA O and CC O the DT B-NP increased VBN I-NP expression NN I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP CRE NN I-NP site NN I-NP . . O These DT B-NP stimuli NNS I-NP result VBP B-VP in IN B-PP phosphorylation NN B-NP of IN B-PP CREB NN B-NP at IN B-PP serine NN B-NP 133 CD I-NP . . O The DT B-NP phosphorylation NN I-NP of IN B-PP CREB NN B-NP that WDT B-NP results VBZ B-VP in IN B-PP activation NN B-NP is VBZ B-VP mediated VBN I-VP by IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP rather RB B-CONJP than IN I-CONJP by IN B-PP protein NN B-NP kinase NN I-NP A NN I-NP . . O Although IN B-SBAR the DT B-NP CRE NN I-NP site NN I-NP is VBZ B-VP necessary JJ B-ADJP COMMA COMMA O optimal JJ B-NP induction NN I-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP requires VBZ B-VP participation NN B-NP of IN B-PP the DT B-NP upstream JJ I-NP regulatory JJ I-NP element NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR phosphorylation NN B-NP of IN B-PP CREB NN B-NP alters VBZ B-VP its PRP$ B-NP interaction NN I-NP with IN B-PP the DT B-NP upstream JJ I-NP regulatory JJ I-NP element NN I-NP . . O The DT B-NP CRE NN I-NP site NN I-NP in IN B-PP the DT B-NP bcl-2 NN I-NP promoter NN I-NP appears VBZ B-VP to TO I-VP play VB I-VP a DT B-NP major JJ I-NP role NN I-NP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP during IN B-PP the DT B-NP activation NN I-NP of IN B-PP mature JJ B-NP B NN I-NP cells NNS I-NP and CC B-PP during IN B-PP the DT B-NP rescue NN I-NP of IN B-PP immature JJ B-NP B NN I-NP cells NNS I-NP from IN B-PP apoptosis NN B-NP . . O It PRP B-NP is VBZ B-VP possible JJ B-ADJP that IN B-SBAR the DT B-NP CRE NN I-NP site NN I-NP is VBZ B-VP responsible JJ B-ADJP for IN B-PP induction NN B-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP in IN B-PP other JJ B-NP cell NN I-NP types NNS I-NP COMMA COMMA O particularly RB B-NP those DT I-NP in IN B-PP which WDT B-NP protein NN B-NP kinase NN I-NP C NN I-NP is VBZ B-VP involved VBN I-VP . . O Interleukin-6 NN B-NP promotes VBZ B-VP multiple JJ B-NP myeloma NN I-NP cell NN I-NP growth NN I-NP via IN B-PP phosphorylation NN B-NP of IN B-PP retinoblastoma NN B-NP protein NN I-NP . . O Interleukin-6 NN B-NP ( ( O IL-6 NN B-NP ) ) O mediates VBZ B-VP autocrine NN B-NP and CC I-NP paracrine NN I-NP growth NN I-NP of IN B-PP multiple JJ B-NP myeloma NN I-NP ( ( O MM NN B-NP ) ) O cells NNS B-NP and CC O inhibits VBZ B-VP tumor NN B-NP cell NN I-NP apoptosis NN I-NP . . O Abnormalities NNS B-NP of IN B-PP retinoblastoma NN B-NP protein NN I-NP ( ( O pRB NN B-NP ) ) O and CC O mutations NNS B-NP of IN B-PP RB NN B-NP gene NN I-NP have VBP B-VP been VBN I-VP reported VBN I-VP in IN B-PP up IN B-NP to TO I-NP 70 CD I-NP % NN I-NP of IN B-PP MM NN B-NP patients NNS I-NP and CC O 80 CD B-NP % NN I-NP of IN B-PP MM-derived JJ B-NP cell NN I-NP lines NNS I-NP . . O Because IN B-SBAR dephosphorylated VBN O ( ( O activated VBN B-ADJP ) ) O pRB NN B-NP blocks VBZ B-VP transition NN B-NP from IN B-PP G1 NN B-NP to TO B-PP S NN B-NP phase NN B-NP of IN B-PP the DT B-NP cell NN I-NP cycle NN I-NP whereas IN O phosphorylated VBN O ( ( O inactivated VBN B-ADJP ) ) O pRB NN B-NP releases VBZ B-VP this DT B-NP growth NN I-NP arrest NN I-NP COMMA COMMA O we PRP B-NP characterized VBD B-VP the DT B-NP role NN I-NP of IN B-PP pRB NN B-NP in IN B-PP IL-6-mediated JJ B-NP MM NN I-NP cell NN I-NP growth NN I-NP . . O Both CC B-NP phosphorylated VBN I-NP and CC I-NP dephosphorylated VBN I-NP pRB NN I-NP were VBD B-VP expressed VBN I-VP in IN B-PP all DT B-NP serum-starved JJ B-NP MM NN I-NP patient NN I-NP cells NNS I-NP and CC O MM-derived JJ B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O but CC O pRB NN B-NP was VBD B-VP predominantly RB B-ADVP in IN B-PP its PRP$ B-NP phosphorylated JJ I-NP form NN I-NP . . O In IN B-PP MM NN B-NP cells NNS I-NP that WDT B-NP proliferated VBD B-VP in IN B-PP response NN I-PP to TO I-PP IL-6 NN B-NP COMMA COMMA O exogenous JJ B-NP IL-6 NN I-NP downregulated VBD B-VP dephosphorylated VBN B-NP pRB NN I-NP and CC O decreased VBD B-VP dephosphorylated VBN B-NP pRB-E2F NN I-NP complexes NNS I-NP . . O Importantly RB B-ADVP COMMA COMMA O culture NN B-NP of IN B-PP MM NN B-NP cells NNS I-NP with IN B-PP RB NN B-NP antisense JJ I-NP COMMA COMMA I-NP but CC I-NP not RB I-NP RB NN I-NP sense NN I-NP COMMA COMMA O oligonucleotide NN B-NP ( ( O ODN NN B-NP ) ) O triggered VBD B-VP IL-6 NN B-NP secretion NN B-NP and CC O proliferation NN B-NP in IN B-PP MM NN B-NP cells NNS I-NP ; : O however RB B-ADVP COMMA COMMA O proliferation NN B-NP was VBD B-VP only RB I-VP partially RB I-VP inhibited VBN I-VP by IN B-PP neutralizing VBG B-VP anti-IL-6 JJ B-NP monoclonal JJ B-NP antibody NN I-NP ( ( O MoAb NN B-NP ) ) O . . O In IN B-PP contrast NN I-PP to TO I-PP MM NN B-NP cells NNS I-NP COMMA COMMA O normal JJ B-NP splenic JJ I-NP B NN I-NP cells NNS I-NP express VBP B-VP dephosphorylated VBN B-NP pRB NN I-NP . . O Although IN B-SBAR CD40 NN B-NP ligand NN I-NP ( ( O CD40L NN B-NP ) ) O triggers VBZ B-VP a DT B-NP shift NN I-NP from IN B-PP dephosphorylated VBN B-NP to TO B-PP phosphorylated VBN B-NP pRB NN B-NP and CC O proliferation NN B-NP of IN B-PP B NN B-NP cells NNS I-NP COMMA COMMA O the DT B-NP addition NN I-NP of IN B-PP exogenous JJ B-NP IL-6 NN I-NP to TO B-PP CD40L-treated JJ B-NP B NN I-NP cells NNS I-NP does VBZ B-VP not RB I-VP alter VB I-VP either CC O pRB NN B-NP or CC O proliferation NN B-NP COMMA COMMA O as IN B-SBAR observed VBN B-VP in IN B-PP MM NN B-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR phosphorylated VBN B-NP pRB NN I-NP is VBZ B-VP constitutively RB I-VP expressed VBN I-VP in IN B-PP MM JJ B-NP cells NNS I-NP and CC O that IN B-SBAR IL-6 NN B-NP further RB B-ADVP shifts VBZ B-VP pRB NN B-NP from IN B-PP its PRP$ B-NP dephosphorylated JJ I-NP to TO B-PP its PRP$ B-NP phosphorylated JJ I-NP form NN B-NP COMMA COMMA O thereby RB B-ADVP promoting VBG B-VP MM NN B-NP cell NN I-NP growth NN I-NP via IN B-PP two CD B-NP mechanisms NNS I-NP ; : O by IN B-PP decreasing VBG B-VP the DT B-NP amount NN I-NP of IN B-PP E2F NN B-NP bound VBN B-VP by IN B-PP dephosphorylated VBN B-NP pRB NN I-NP due IN B-PP to TO I-PP reduced VBN B-NP dephosphorylated VBN I-NP pRB NN I-NP COMMA COMMA O thereby RB B-ADVP releasing VBG B-VP growth NN B-NP arrest NN I-NP ; : B-PP and CC I-PP by IN B-PP upregulating VBG B-VP IL-6 NN B-NP secretion NN I-NP by IN B-PP MM NN B-NP cells NNS I-NP and CC O related JJ B-NP IL-6-mediated JJ I-NP autocrine JJ I-NP tumor NN I-NP cell NN I-NP growth NN I-NP . . O JNK NN B-NP ( ( O c-Jun NN B-NP NH2-terminal JJ I-NP kinase NN I-NP ) ) O is VBZ B-VP a DT B-NP target NN I-NP for IN B-PP antioxidants NNS B-NP in IN B-PP T NN B-NP lymphocytes NNS I-NP . . O AP-1 NN B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP behave VB I-VP as IN B-PP a DT B-NP redox-sensitive JJ I-NP transcription NN I-NP factor NN I-NP that WDT B-NP can MD B-VP be VB I-VP activated VBN I-VP by IN B-PP both CC B-NP oxidant JJ I-NP and CC I-NP antioxidant JJ I-NP stimuli NNS I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP mechanisms NNS I-NP involved VBN B-VP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP AP-1 NN B-NP by IN B-PP antioxidants NNS B-NP are VBP B-VP largely RB B-ADJP unknown JJ I-ADJP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP structurally RB I-NP unrelated JJ I-NP antioxidant JJ I-NP agents NNS I-NP pyrrolidine NN B-NP dithiocarbamate NN I-NP ( ( O PDTC NN B-NP ) ) O COMMA COMMA O butylated VBN B-NP hydroxyanisole NN I-NP COMMA COMMA O and CC O Nacetylcysteine NN B-NP activated VBD B-VP JNK NN B-NP ( ( O c-Jun NN B-NP NH2-terminal JJ I-NP kinase NN I-NP ) ) O in IN B-PP Jurkat NN B-NP T NN I-NP cells NNS I-NP . . O This DT B-NP activation NN I-NP differed VBD B-VP substantially RB B-ADVP from IN B-PP that DT B-NP mediated VBN B-VP by IN B-PP phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( O PMA NN B-NP ) ) O and CC O Ca2+ NN B-NP ionophore NN I-NP or CC O produced VBN B-VP by IN B-PP costimulation NN B-NP with IN B-PP antibodies NNS B-NP against IN B-PP the DT B-NP T NN B-NP cell NN I-NP receptor-CD3 NN I-NP complex NN I-NP and CC O to TO O CD28 NN B-NP . . O The DT B-NP activation NN I-NP of IN B-PP JNK NN B-NP by IN B-PP classical JJ B-NP T NN I-NP cell NN I-NP stimuli NNS I-NP was VBD B-VP transient JJ B-ADJP COMMA COMMA O whereas IN O that DT B-NP mediated VBN B-VP by IN B-PP PDTC NN B-NP and CC O butylated VBN B-NP hydroxyanisole NN I-NP ( ( O but CC B-CONJP not RB I-CONJP N-acetylcysteine NN B-NP ) ) O was VBD B-VP sustained JJ B-ADJP . . O The DT B-NP kinetics NNS I-NP of IN B-PP JNK NN B-NP activation NN I-NP correlated VBD B-VP with IN B-PP the DT B-NP expression NN I-NP of IN B-PP c-jun NN B-NP which WDT B-NP was VBD B-VP transient JJ B-ADJP after IN B-PP stimulation NN B-NP with IN B-PP PMA NN B-NP plus CC O ionophore NN B-NP and CC O prolonged VBD B-VP in IN B-PP response NN I-PP to TO I-PP PDTC NN B-NP COMMA COMMA O which WDT B-NP also RB B-ADVP transiently RB B-VP induced VBD I-VP c-fos NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O JNK NN B-NP activation NN I-NP by IN B-PP PMA NN B-NP plus CC O ionophore NN B-NP was VBD B-VP sensitive JJ B-ADJP to TO B-PP inhibitors NNS B-NP of IN B-PP signaling NN B-NP pathways NNS I-NP involving VBG B-VP Ca2+ NN B-NP COMMA COMMA O protein NN B-NP kinase NN I-NP C NN I-NP COMMA COMMA O and CC O tyrosine NN B-NP phosphorylation NN B-NP COMMA COMMA O which WDT B-NP failed VBD B-VP to TO I-VP inhibit VB I-VP the DT B-NP activation NN I-NP mediated VBN B-VP by IN B-PP PDTC NN B-NP . . O Transfection NN B-NP of IN B-PP trans-dominant JJ B-NP negative JJ I-NP expression NN I-NP vectors NNS I-NP of IN B-PP ras NN B-NP and CC O raf NN B-NP COMMA COMMA O together RB B-CONJP with IN I-CONJP AP-1-dependent JJ B-NP reporter NN I-NP constructs NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP Western NN B-NP blot NN I-NP analysis NN I-NP using VBG B-VP anti-ERK JJ O ( ( O extracellular JJ B-NP signal-regulated JJ I-NP kinase NN I-NP ) ) O antibodies NNS B-NP COMMA COMMA O indicated VBD B-VP that IN B-SBAR the DT B-NP Ras\/Raf/ERK NN I-NP pathway NN I-NP did VBD B-VP not RB I-VP appear VB I-VP to TO I-VP mediate VB I-VP the DT B-NP effect NN I-NP of IN B-PP the DT B-NP antioxidant NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP combined JJ I-NP treatment NN I-NP with IN B-PP PDTC NN B-NP and CC O PMA NN B-NP COMMA COMMA O two CD B-NP agents NNS I-NP that WDT B-NP synergize VBP B-VP on IN B-PP AP-1 NN B-NP activation NN I-NP COMMA COMMA O resulted VBD B-VP in IN B-PP the DT B-NP persistent JJ I-NP phosphorylation NN I-NP of IN B-PP ERK-2 NN B-NP . . O In IN B-PP conclusion NN B-NP COMMA COMMA O our PRP$ B-NP results NNS I-NP identify VBP B-VP JNK NN B-NP as IN B-PP a DT B-NP target NN I-NP of IN B-PP antioxidant JJ B-NP agents NNS I-NP which WDT B-NP can MD B-VP be VB I-VP regulated VBN I-VP differentially RB B-ADVP under IN B-PP oxidant JJ B-NP and CC I-NP antioxidant JJ I-NP conditions NNS I-NP . . O Cytomegalovirus NN B-NP modulates VBZ B-VP interleukin-6 NN B-NP gene NN I-NP expression NN I-NP . . O Complications NNS B-NP after IN B-PP lung NN B-NP transplantation NN I-NP include VBP B-VP the DT B-NP development NN I-NP of IN B-PP rejection NN B-NP and CC O an DT B-NP increased VBN I-NP incidence NN I-NP of IN B-PP infection NN B-NP COMMA COMMA O particularly RB B-PP with IN I-PP cytomegalovirus NN B-NP ( ( O CMV NN B-NP ) ) O . . O Several JJ B-NP recent JJ I-NP studies NNS I-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR interleukin NN B-NP ( ( I-NP IL NN I-NP ) ) I-NP -6 CD I-NP may MD B-VP be VB I-VP used VBN I-VP to TO B-VP detect VB I-VP both CC O infection NN B-NP and CC O rejection NN B-NP after IN B-PP lung NN B-NP transplantation NN I-NP . . O In IN O addition NN B-NP COMMA COMMA O IL-6 NN B-NP may MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP the DT B-NP development NN I-NP of IN B-PP bronchiolitis NN B-NP obliterans NNS I-NP after IN B-PP transplantation NN B-NP . . O Because IN B-SBAR CMV NN B-NP is VBZ B-VP also RB I-VP associated VBN I-VP with IN B-PP the DT B-NP development NN I-NP of IN B-PP bronchiolitis NN B-NP obliterans NNS I-NP after IN B-PP transplantation NN B-NP COMMA COMMA O we PRP B-NP determined VBD B-VP whether IN B-SBAR CMV NN B-NP induces VBZ B-VP IL-6 NN B-NP gene NN I-NP expression NN I-NP . . O We PRP B-NP demonstrated VBD B-VP that IN B-SBAR CMV NN B-NP infection NN I-NP increased VBD B-VP both CC O IL-6 NN B-NP protein NN I-NP and CC O mRNA NN B-NP in IN B-PP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP . . O We PRP B-NP also RB B-ADVP demonstrated VBD B-VP that IN B-SBAR the DT B-NP CMV NN I-NP immediate JJ I-NP early JJ I-NP 1 CD I-NP gene NN I-NP product NN I-NP increased VBD B-VP expression NN B-NP of IN B-PP the DT B-NP IL-6 NN I-NP promoter NN I-NP . . O This DT B-NP effect NN I-NP of IN B-PP the DT B-NP CMV NN I-NP immediate JJ I-NP early JJ I-NP 1 CD I-NP gene NN I-NP product NN I-NP was VBD B-VP dependent JJ B-ADJP upon IN B-PP the DT B-NP presence NN I-NP of IN B-PP specific JJ B-NP transcription NN I-NP factor NN I-NP binding NN I-NP sites NNS I-NP in IN B-PP the DT B-NP IL-6 NN I-NP promoter NN I-NP . . O These DT B-NP studies NNS I-NP demonstrate VBP B-VP that IN B-SBAR CMV NN B-NP may MD B-VP be VB I-VP an DT B-NP important JJ I-NP cofactor NN I-NP in IN B-PP the DT B-NP development NN I-NP of IN B-PP rejection NN B-NP and CC O infection NN B-NP after IN B-PP transplantation NN B-NP through IN B-PP its PRP$ B-NP effects NNS I-NP on IN B-PP IL-6 NN B-NP . . O E3 NN B-NP COMMA COMMA O a DT B-NP hematopoietic-specific JJ I-NP transcript NN I-NP directly RB B-VP regulated VBN I-VP by IN B-PP the DT B-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP alpha NN I-NP . . O Retinoic JJ B-NP acid NN I-NP ( ( I-NP RA NN I-NP ) ) I-NP -induced JJ I-NP maturation NN I-NP mediated VBN B-VP by IN B-PP the DT B-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP alpha NN I-NP ( ( O RAR NN B-NP alpha NN I-NP ) ) O has VBZ B-VP been VBN I-VP implicated VBN I-VP in IN B-PP myeloid JJ B-NP development NN I-NP . . O We PRP B-NP have VBP B-VP used VBN I-VP differential JJ B-NP hybridization NN I-NP analysis NN I-NP of IN B-PP a DT B-NP cDNA NN I-NP library NN I-NP constructed VBN B-VP from IN B-PP the DT B-NP murine JJ I-NP RA-inducible JJ I-NP MPRO NN I-NP promyelocyte NN I-NP cell NN I-NP line NN I-NP to TO B-VP identify VB I-VP immediate-early JJ B-NP genes NNS I-NP induced VBN B-VP by IN B-PP RA NN B-NP during IN B-PP granulocytic JJ B-NP differentiation NN I-NP . . O E3 NN B-NP COMMA COMMA O one CD B-NP of IN B-PP nine CD B-NP sequences NNS I-NP identified VBN B-VP COMMA COMMA O was VBD B-VP upregulated VBN I-VP in IN B-PP an DT B-NP immediate-early JJ I-NP manner NN I-NP COMMA COMMA O with IN B-PP transcript NN B-NP levels NNS I-NP peaking VBG B-VP after IN B-PP 60 CD B-NP minutes NNS I-NP exposure NN B-NP to TO B-PP RA NN B-NP . . O E3 NN B-NP transcripts NNS I-NP were VBD B-VP RA-inducible JJ B-ADJP in IN B-PP HL60 NN B-NP cells NNS I-NP COMMA COMMA O but CC O not RB B-PP in IN I-PP an DT B-NP RA-resistant JJ I-NP subclone NN I-NP COMMA COMMA O HL60R NN B-NP COMMA COMMA O that WDT B-NP harbors VBZ B-VP a DT B-NP mutated VBN I-NP RAR NN I-NP alpha NN I-NP gene NN I-NP . . O However RB B-ADVP COMMA COMMA O when WRB B-ADVP HL60R NN B-NP cells NNS I-NP were VBD B-VP transduced VBN I-VP with IN B-PP a DT B-NP functional JJ I-NP copy NN I-NP of IN B-PP the DT B-NP RAR NN I-NP alpha NN I-NP gene NN I-NP COMMA COMMA O RA NN B-NP induced VBD B-VP a DT B-NP 10-fold JJ I-NP increase NN I-NP in IN B-PP E3 NN B-NP mRNA NN I-NP levels NNS I-NP . . O E3 NN B-NP transcripts NNS I-NP are VBP B-VP present JJ B-ADJP in IN B-PP the DT B-NP myeloid JJ I-NP COMMA COMMA I-NP B-lymphoid JJ I-NP COMMA COMMA I-NP and CC I-NP erythroid JJ I-NP lineages NNS I-NP COMMA COMMA O absent JJ B-ADJP in IN B-PP nonhematopoietic JJ B-NP cells NNS I-NP COMMA COMMA O and CC O encode VBP B-VP a DT B-NP highly RB I-NP hydrophobic JJ I-NP COMMA COMMA I-NP potentially RB I-NP phosphorylated VBN I-NP polypeptide NN I-NP of IN B-PP unknown JJ B-NP function NN I-NP with IN B-PP significant JJ B-NP homology NN I-NP to TO B-PP a DT B-NP putative JJ I-NP protein NN I-NP expressed VBN B-VP in IN B-PP myeloid JJ B-NP cells NNS I-NP . . O The DT B-NP murine JJ I-NP E3 NN I-NP promoter NN I-NP harbors VBZ B-VP a DT B-NP single JJ I-NP bipartite JJ I-NP retinoic JJ I-NP acid NN I-NP response NN I-NP element NN I-NP which WDT B-NP in IN B-PP transient NN B-NP transfection NN I-NP assays NNS I-NP conferred VBD B-VP RA NN B-NP sensitivity NN I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR E3 NN B-NP is VBZ B-VP a DT B-NP hematopoietic-specific JJ I-NP gene NN I-NP that WDT B-NP is VBZ B-VP an DT B-NP immediate JJ I-NP target NN I-NP for IN B-PP the DT B-NP activated VBN I-NP RAR NN I-NP alpha NN I-NP during IN B-PP myelopoiesis NN B-NP . . O Interstitial JJ B-NP deletion NN I-NP constitutes VBZ B-VP the DT B-NP major JJ I-NP mechanism NN I-NP for IN B-PP loss NN B-NP of IN B-PP heterozygosity NN B-NP on IN B-PP chromosome NN B-NP 20q NN I-NP in IN B-PP polycythemia NN B-NP vera NN I-NP . . O An DT B-NP acquired VBN I-NP deletion NN I-NP of IN B-PP the DT B-NP long JJ I-NP arm NN I-NP of IN B-PP chromosome NN B-NP 20 CD I-NP is VBZ B-VP a DT B-NP recurrent JJ I-NP abnormality NN I-NP in IN B-PP myeloproliferative JJ B-NP disorders NNS I-NP COMMA COMMA O particularly RB B-NP polycythemia NN B-NP vera NN I-NP and CC O myelodysplastic JJ B-ADJP syndromes NNS B-NP . . O The DT B-NP association NN I-NP of IN B-PP 20q NN B-NP deletions NNS I-NP with IN B-PP myeloid JJ B-NP " `` I-NP stem NN I-NP cell NN I-NP " '' I-NP disorders NNS I-NP suggests VBZ B-VP that IN B-SBAR the DT B-NP deletions NNS I-NP mark VBP B-VP the DT B-NP site NN I-NP of IN B-PP one CD B-NP or CC I-NP more JJR I-NP genes NNS I-NP COMMA COMMA O loss NN B-NP or CC O inactivation NN B-NP of IN B-PP which WDT B-NP plays VBZ B-VP a DT B-NP role NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP normal JJ B-NP hematopoietic JJ I-NP progenitors NNS I-NP . . O We PRP B-NP have VBP B-VP recently RB I-VP performed VBN I-VP a DT B-NP detailed JJ I-NP molecular JJ I-NP analysis NN I-NP of IN B-PP 20q JJ B-NP deletions NNS I-NP in IN B-PP peripheral JJ B-NP blood NN I-NP ( ( O PB NN B-NP ) ) O granulocytes NNS B-NP and CC O defined VBN B-VP a DT B-NP commonly RB I-NP deleted VBN I-NP region NN I-NP of IN B-PP 16 CD B-NP to TO I-NP 21 CD I-NP centimorgan NN B-NP ( ( O cM NN B-NP ) ) O . . O To TO B-VP further RBR I-VP reduce VB I-VP the DT B-NP size NN I-NP of IN B-PP the DT B-NP common JJ I-NP deleted VBN I-NP region NN I-NP we PRP B-NP have VBP B-VP searched VBN I-VP for IN B-PP small JJ B-NP deletions NNS I-NP or CC O mitotic JJ B-NP recombination NN I-NP events NNS I-NP COMMA COMMA O neither DT B-NP of IN B-PP which WDT B-NP would MD B-VP be VB I-VP detected VBN I-VP by IN B-PP conventional JJ B-NP cytogenetics NNS I-NP . . O We PRP B-NP have VBP B-VP studied VBN I-VP 48 CD B-NP patients NNS I-NP with IN B-PP polycythemia NN B-NP vera NN I-NP and CC O four CD B-NP patients NNS I-NP with IN B-PP idiopathic JJ B-NP myelofibrosis NN I-NP . . O In IN B-PP each DT B-NP case NN I-NP COMMA COMMA O cytogenetic JJ B-NP analysis NN I-NP had VBD B-VP either RB I-VP failed VBN I-VP or CC O had VBD B-VP shown VBN I-VP no DT B-NP abnormalities NNS I-NP of IN B-PP chromosome NN B-NP 20 CD I-NP . . O Seventeen CD B-NP microsatellite NN I-NP markers NNS I-NP that WDT B-NP span VBP B-VP the DT B-NP common JJ I-NP deleted VBN I-NP region NN I-NP were VBD B-VP used VBN I-VP to TO B-VP search VB I-VP for IN B-PP loss NN B-NP of IN B-PP heterozygosity NN B-NP in IN B-PP granulocyte NN B-NP DNA NN I-NP . . O No DT B-NP instance NN I-NP of IN B-PP microsatellite NN B-NP instability NN I-NP was VBD B-VP observed VBN I-VP in IN B-PP a DT B-NP total NN I-NP of IN B-PP 880 CD B-NP comparisons NNS I-NP of IN B-PP granulocyte NN B-NP and CC O T-cell NN B-NP DNA NN B-NP . . O Granulocyte NN B-NP DNA NN I-NP from IN B-PP four CD B-NP patients NNS I-NP exhibited VBD B-VP allele NN B-NP loss NN I-NP on IN B-PP 20q NN B-NP . . O In IN B-PP each DT B-NP case NN I-NP the DT B-NP allele NN I-NP loss NN I-NP was VBD B-VP caused VBN I-VP by IN B-PP an DT B-NP interstitial JJ I-NP deletion NN I-NP because IN B-SBAR heterozygosity NN B-NP at IN B-PP distal JJ B-NP markers NNS I-NP was VBD B-VP retained VBN I-VP and CC O because IN B-SBAR quantitative JJ B-NP Southern NN I-NP blotting NN I-NP demonstrated VBD B-VP hemizygosity NN B-NP . . O Loss NN B-NP of IN B-PP heterozygosity NN B-NP in IN B-PP PB NN B-NP granulocytes NNS I-NP would MD B-VP be VB I-VP masked VBN I-VP by IN B-PP the DT B-NP presence NN I-NP of IN B-PP significant JJ B-NP numbers NNS I-NP of IN B-PP normal JJ B-NP granulocytes NNS I-NP not RB B-VP derived VBN I-VP from IN B-PP the DT B-NP malignant JJ I-NP clone NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O the DT B-NP human JJ I-NP androgen NN I-NP receptor NN I-NP assay NN I-NP ( ( O HUMARA NN B-NP ) ) O was VBD B-VP used VBN I-VP to TO B-VP determine VB I-VP granulocyte NN B-NP clonality NN I-NP . . O In IN B-PP 21 CD B-NP of IN I-NP 27 CD I-NP informative JJ I-NP female NN I-NP patients NNS I-NP the DT B-NP majority NN I-NP of IN B-PP the DT B-NP granulocytes NNS I-NP were VBD B-VP clonally RB B-ADJP derived VBN I-ADJP . . O In IN B-PP 5 CD B-NP patients NNS I-NP the DT B-NP granulocytes NNS I-NP appeared VBD B-VP polyclonal JJ B-ADJP and CC O in IN B-PP 1 CD B-NP patient NN I-NP unilateral JJ B-NP X NN I-NP inactivation NN I-NP was VBD B-VP observed VBN I-VP in IN B-PP both CC O granulocytes NNS B-NP and CC O T JJ B-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR COMMA COMMA O in IN B-PP the DT B-NP vast JJ I-NP majority NN I-NP of IN B-PP patients NNS B-NP presented VBN B-VP here RB B-ADVP COMMA COMMA O the DT B-NP failure NN I-NP to TO B-VP detect VB I-VP loss NN B-NP of IN B-PP heterozygosity NN B-NP can MD B-VP not RB I-VP be VB I-VP attributed VBN I-VP to TO B-PP the DT B-NP presence NN I-NP of IN B-PP normal JJ B-NP polyclonal JJ I-NP granulocytes NNS I-NP . . O Our PRP$ B-NP results NNS I-NP therefore RB B-ADVP show VBP B-VP that IN B-SBAR allele NN B-NP loss NN I-NP on IN B-PP chromosome NN B-NP 20q NN I-NP in IN B-PP polycythemia NN B-NP vera NN I-NP does VBZ B-VP not RB I-VP commonly RB I-VP involve VB I-VP mitotic JJ B-NP recombination NN I-NP or CC O chromosome NN B-NP loss NN I-NP and CC O that IN B-SBAR microsatellite NN B-NP instability NN I-NP is VBZ B-VP a DT B-NP rare JJ I-NP event NN I-NP in IN B-PP this DT B-NP disorder NN I-NP . . O Transcriptional JJ B-NP control NN I-NP of IN B-PP steroid-regulated JJ B-NP apoptosis NN I-NP in IN B-PP murine JJ B-NP thymoma NN I-NP cells NNS I-NP . . O Early JJ B-NP studies NNS I-NP in IN B-PP murine JJ B-NP T NN I-NP cell NN I-NP lines NNS I-NP indicated VBD B-VP that IN B-SBAR transcriptional JJ B-NP transactivation NN I-NP functions NNS I-NP encoded VBN B-VP in IN B-PP the DT O glucocorticoid NN B-NP receptor NN I-NP ( ( O GR NN B-NP ) ) O N-terminal JJ B-NP domain NN I-NP are VBP B-VP required VBN I-VP for IN B-PP glucocorticoid-mediated JJ B-NP apoptosis NN I-NP . . O However RB B-ADVP COMMA COMMA O more RBR B-NP recent JJ I-NP studies NNS I-NP in IN B-PP human JJ B-NP T NN I-NP cell NN I-NP lines NNS I-NP have VBP B-VP suggested VBN I-VP that IN B-SBAR the DT B-NP N-terminal JJ I-NP domain NN I-NP is VBZ B-VP not RB O necessary JJ B-ADJP for IN B-PP steroid-regulated JJ B-NP apoptosis NN I-NP and CC O that IN B-SBAR GR-mediated JJ B-NP transrepression NN I-NP may MD B-VP be VB I-VP the DT B-NP more RBR I-NP critical JJ I-NP mechanism NN I-NP . . O To TO B-VP better RBR I-VP understand VB I-VP the DT B-NP contribution NN I-NP of IN B-PP the DT B-NP GR NN I-NP N-terminal JJ I-NP transactivation NN I-NP domain NN I-NP in IN B-PP mediating VBG B-VP murine JJ B-NP thymocyte NN I-NP apoptosis NN I-NP COMMA COMMA O we PRP B-NP stably RB B-ADVP transfected VBD B-VP GR NN B-NP COMMA COMMA O GR NN B-NP variants NNS I-NP COMMA COMMA O and CC O the DT B-NP androgen NN I-NP receptor NN I-NP ( ( O AR NN B-NP ) ) O into IN B-PP receptor-negative JJ B-NP S49 NN I-NP murine JJ I-NP thymoma NN I-NP cells NNS I-NP . . O GR NN B-NP expression NN I-NP levels NNS I-NP were VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP rate-limiting JJ B-ADJP for IN B-PP initiating VBG B-VP the DT B-NP apoptotic JJ I-NP pathway NN I-NP COMMA COMMA O and CC O a DT B-NP positive JJ I-NP correlation NN I-NP between IN B-PP steroid NN B-NP sensitivity NN I-NP and CC O GR-mediated JJ B-NP induction NN I-NP of IN B-PP an DT O integrated VBN O mouse NN B-NP mammary JJ I-NP tumor NN I-NP virus NN I-NP ( ( O MMTV NN B-NP ) ) O LTR NN B-NP reporter NN I-NP gene NN I-NP was VBD B-VP observed VBN I-VP . . O Analysis NN B-NP of IN B-PP GR NN B-NP chimeric JJ I-NP receptors NNS I-NP containing VBG B-VP the DT O potent JJ O VP16 NN B-NP and CC O E1A NN B-NP viral JJ B-NP transactivation NN I-NP domains NNS I-NP in IN B-PP place NN I-PP of IN I-PP the DT B-NP GR NN I-NP N NN I-NP terminus NN I-NP revealed VBD B-VP that IN B-SBAR even RB B-NP low JJ I-NP level NN I-NP expression NN I-NP of IN B-PP these DT B-NP receptors NNS I-NP resulted VBD B-VP in IN B-PP both CC O enhanced VBN B-NP steroid NN I-NP sensitivity NN I-NP and CC O MMTV NN B-NP induction NN I-NP COMMA COMMA O thus RB B-VP supporting VBG I-VP a DT B-NP role NN I-NP for IN B-PP transactivation NN B-NP in IN B-PP apoptosis NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O we PRP B-NP found VBD B-VP that IN B-SBAR AR NN B-NP can MD B-VP initiate VB I-VP apoptosis NN B-NP in IN B-PP S49 NN B-NP cells NNS I-NP after IN B-PP treatment NN B-NP with IN B-PP 5 CD B-NP alpha-dihydrotestosterone NN I-NP COMMA COMMA O despite IN B-PP its PRP$ B-NP relative JJ I-NP inability NN I-NP to TO B-VP induce VB I-VP high JJ B-NP level NN I-NP expression NN I-NP of IN B-PP MMTV NN B-NP . . O To TO B-VP investigate VB I-VP this DT B-NP further RBR B-ADVP COMMA COMMA O we PRP B-NP examined VBD B-VP the DT B-NP steroid-regulated JJ I-NP expression NN I-NP of IN B-PP an DT B-NP endogenous JJ I-NP thymocyte-specific JJ I-NP gene NN I-NP called VBN B-VP GIG18 NN B-NP . . O We PRP B-NP found VBD B-VP that IN B-SBAR GIG18 NN B-NP was VBD B-VP rapidly RB I-VP induced VBN I-VP to TO B-PP comparable JJ B-NP levels NNS I-NP by IN B-PP both CC O AR NN B-NP and CC O GR NN B-NP COMMA COMMA O demonstrating VBG B-VP that IN B-SBAR AR NN B-NP can MD B-VP indeed RB I-VP function VB I-VP as IN B-PP a DT B-NP transcriptional JJ I-NP activator NN I-NP in IN B-PP S49 NN B-NP cells NNS I-NP and CC O COMMA COMMA O moreover RB O COMMA COMMA O that IN B-SBAR GIG18 NN B-NP induction NN I-NP may MD B-VP be VB I-VP a DT B-NP marker NN I-NP of IN B-PP early JJ B-NP apoptotic JJ I-NP events NNS I-NP in IN B-PP steroid-treated JJ B-NP cells NNS I-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP support VBP B-VP our PRP$ B-NP conclusion NN I-NP that IN B-SBAR transcriptional JJ B-NP transactivation NN I-NP is VBZ B-VP a DT B-NP necessary JJ I-NP signaling NN I-NP component NN I-NP of IN B-PP S49 NN B-NP cell NN I-NP apoptosis NN I-NP COMMA COMMA O although IN B-SBAR an DT B-NP additional JJ I-NP role NN I-NP for IN B-PP GR-mediated JJ B-NP transrepression NN I-NP can MD B-VP not RB I-VP be VB I-VP excluded VBN O Suppression NN B-NP of IN B-PP c-jun NN B-NP by IN B-PP antisense JJ B-NP oligonucleotides NNS I-NP inhibits VBZ B-VP cell NN B-NP adhesion NN I-NP but CC B-CONJP not RB I-CONJP respiratory JJ B-NP burst NN I-NP during IN B-PP phorbol NN B-NP ester-induced JJ I-NP differentiation NN I-NP of IN B-PP U937 NN B-NP human JJ I-NP monoblastic JJ I-NP cells NNS I-NP . . O We PRP B-NP studied VBD B-VP the DT B-NP role NN I-NP of IN B-PP the DT B-NP immediate JJ I-NP early JJ I-NP gene NN I-NP c-jun NN I-NP in IN B-PP cell NN B-NP proliferation NN I-NP and CC O phorbol NN B-NP 12-myristate NN I-NP 13-acetate NN I-NP ( ( I-NP PMA NN I-NP ) ) I-NP -induced JJ I-NP differentiation NN I-NP in IN B-PP U937 NN B-NP human JJ I-NP monoblastic JJ I-NP cells NNS I-NP COMMA COMMA O using VBG B-VP c-jun-specific JJ O antisense JJ O ( ( O AS JJ B-ADJP ) ) O phosphorothioate NN B-NP oligonucleotides NNS I-NP . . O In IN B-PP selecting VBG B-VP the DT B-NP most RBS I-NP specific JJ I-NP and CC I-NP potent JJ I-NP oligonucleotide JJ I-NP sequence NN I-NP COMMA COMMA O we PRP B-NP performed VBD B-VP extensive JJ B-NP analyses NNS I-NP for IN B-PP the DT B-NP binding NN I-NP specificity NN I-NP between IN B-PP all DT B-NP candidates NNS I-NP of IN B-PP c-jun NN B-NP AS JJ I-NP oligonucleotides NNS I-NP and CC O the DT B-NP whole JJ I-NP sequences NNS I-NP in IN B-PP GenBank NN B-NP database NN I-NP COMMA COMMA O using VBG B-VP a DT B-NP computer NN I-NP program NN I-NP . . O Among IN B-PP the DT B-NP 20 CD I-NP selected VBN I-NP oligonucleotides NNS I-NP COMMA COMMA O two CD B-NP potent JJ I-NP 15-mer JJ I-NP AS JJ I-NP oligonucleotides NNS I-NP ( ( O C-JUN NN B-NP AS JJ I-NP oligonucleotides NNS I-NP ) ) O exhibited VBD B-VP significant JJ B-NP inhibition NN I-NP of IN B-PP cell NN B-NP growth NN I-NP in IN B-PP a DT B-NP dose-dependent JJ I-NP manner NN I-NP between IN B-NP 2 CD I-NP and CC I-NP 10 CD I-NP microM NN I-NP . . O Reverse JJ B-NP transcription-PCR NN I-NP and CC O Western NN B-NP blot NN I-NP analysis NN I-NP demonstrated VBD B-VP that IN B-SBAR 10 CD B-NP microM NN I-NP of IN B-PP C-JUN NN B-NP AS JJ I-NP oligonucleotides NNS I-NP reduced VBD B-VP c-jun NN B-NP expression NN I-NP at IN B-PP both CC O the DT O mRNA NN B-NP and CC O protein NN B-NP levels NNS B-NP . . O More RBR B-ADVP importantly RB I-ADVP COMMA COMMA O C-JUN NN B-NP AS JJ I-NP oligonucleotides NNS I-NP showed VBD B-VP distinct JJ B-NP effects NNS I-NP on IN B-PP two CD B-NP markers NNS I-NP of IN B-PP PMA-induced JJ B-NP differentiation NN I-NP ; : O the DT B-NP C-JUN NN I-NP AS JJ I-NP oligonucleotides NNS I-NP inhibited VBD B-VP cell NN B-NP adhesion NN I-NP COMMA COMMA O whereas IN O they PRP B-NP did VBD B-VP not RB I-VP affect VB I-VP another DT B-NP marker NN I-NP of IN B-PP differentiation NN B-NP COMMA COMMA O respiratory JJ B-NP burst NN I-NP ( ( O measured VBN B-VP by IN B-PP nitro NN B-NP blue JJ I-NP tetrazolium NN I-NP reduction NN I-NP assay NN I-NP ) ) O . . O These DT B-NP results NNS I-NP suggest VBP B-VP a DT B-NP critical JJ I-NP role NN I-NP of IN B-PP c-jun NN B-NP in IN B-PP both CC O cell NN B-NP proliferation NN I-NP and CC O PMA-induced JJ B-NP cell NN I-NP adhesion NN I-NP but CC B-PP not RB B-PP in IN I-PP PMA-induced JJ B-NP respiratory JJ I-NP burst NN I-NP in IN B-PP U937 NN B-NP cells NNS I-NP . . O Human JJ B-NP TAFII NN I-NP 105 CD I-NP is VBZ B-VP a DT B-NP cell NN I-NP type-specific JJ I-NP TFIID NN I-NP subunit NN I-NP related JJ B-ADJP to TO B-PP hTAFII130 NN B-NP . . O We PRP B-NP previously RB B-ADVP characterized VBD B-VP Drosophila NN B-NP and CC O human JJ B-NP TAF NN I-NP subunits NNS B-NP that WDT B-NP make VBP B-VP up RP B-PRT the DT B-NP core NN I-NP TFIID NN I-NP complex NN I-NP found VBN B-VP in IN B-PP all DT B-NP cells NNS I-NP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP report VBP B-VP that IN B-SBAR differentiated VBN B-NP B NN I-NP cells NNS I-NP contain VBP B-VP a DT B-NP novel JJ I-NP substoichiometric JJ I-NP TAF NN I-NP of IN B-PP 105 CD B-NP kDa NN I-NP not RB B-VP found VBN I-VP associated VBN I-VP with IN B-PP TFIID NN B-NP isolated VBN B-VP from IN B-PP other JJ B-NP cell NN I-NP types NNS I-NP . . O The DT B-NP cDNA NN I-NP encoding NN I-NP hTAFII105 NN I-NP reveals VBZ B-VP a DT B-NP highly RB I-NP conserved VBN I-NP C-terminal JJ I-NP domain NN I-NP shared VBN B-VP by IN B-PP hTAFII130 NN B-NP and CC O oTAFII110 NN B-NP COMMA COMMA O while IN B-SBAR the DT B-NP N-terminal JJ I-NP coactivator NN I-NP domain NN I-NP has VBZ B-VP diverged VBN I-VP significantly RB B-ADVP . . O All DT B-NP cells NNS I-NP tested VBN B-VP express VBP B-VP TAFII105 NN B-NP mRNA NN I-NP COMMA COMMA O but CC O only RB B-NP B NN I-NP cells NNS I-NP contain VBP B-VP significant JJ B-NP levels NNS I-NP of IN B-PP protein NN B-NP associated VBN B-VP with IN B-PP TFIID NN B-NP . . O Transient JJ B-NP overexpression NN I-NP of IN B-PP hTAFII105 NN B-NP selectively RB B-ADVP squelches VBZ B-VP the DT B-NP transcription NN I-NP of IN B-PP some DT B-NP genes NNS I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O These DT B-NP properties NNS I-NP suggest VBP B-VP that IN B-SBAR TAFII105 NN B-NP is VBZ B-VP a DT B-NP cell NN I-NP type-specific JJ I-NP subunit NN I-NP of IN B-PP TFIID NN B-NP that WDT B-NP may MD B-VP be VB I-VP responsible JJ B-ADJP for IN B-PP mediating VBG B-VP transcription NN B-NP by IN B-PP a DT B-NP subset NN I-NP of IN B-PP activators NNS B-NP in IN B-PP B NN B-NP cells NNS I-NP . . O Uneven JJ B-NP X NN I-NP inactivation NN I-NP in IN B-PP a DT B-NP female JJ I-NP monozygotic JJ I-NP twin JJ I-NP pair NN I-NP with IN B-PP Fabry NN B-NP disease NN I-NP and CC O discordant JJ B-NP expression NN I-NP of IN B-PP a DT B-NP novel JJ I-NP mutation NN I-NP in IN B-PP the DT B-NP alpha-galactosidase NN I-NP A NN I-NP gene NN I-NP . . O We PRP B-NP describe VBP B-VP two CD O female JJ O monozygotic JJ O ( ( O MZ JJ B-ADJP ) ) O twins NNS B-NP heterozygous JJ B-ADJP for IN B-PP Fabry NN B-NP disease NN I-NP COMMA COMMA O an DT B-NP X NN I-NP linked VBN I-NP disorder NN I-NP resulting VBG B-VP from IN B-PP the DT B-NP deficient JJ I-NP activity NN I-NP of IN B-PP alpha-galactosidase NN B-NP A NN I-NP . . O While IN B-SBAR one CD B-NP of IN B-PP the DT B-NP twins NNS I-NP was VBD B-VP clinically RB B-ADVP affected VBN B-ADJP COMMA COMMA O the DT B-NP other JJ I-NP was VBD B-VP asymptomatic JJ B-ADJP . . O Enzymatic JJ B-NP assay NN I-NP of IN B-PP alpha-galactosidase NN B-NP in IN B-PP blood NN B-NP leucocytes NNS I-NP COMMA COMMA O skin NN B-NP fibroblasts NNS I-NP COMMA COMMA O Epstein-Barr JJ B-NP virus NN I-NP transformed VBD B-NP lymphoid JJ I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O and CC O hair NN B-NP follicles NNS I-NP of IN B-PP the DT B-NP twins NNS I-NP and CC O their PRP$ B-NP parents NNS I-NP confirmed VBD B-VP the DT B-NP heterozygous JJ I-NP status NN I-NP of IN B-PP the DT B-NP twins NNS I-NP and CC O indicated VBD B-VP that IN B-SBAR Fabry NN B-NP disease NN I-NP had VBD B-VP occurred VBN I-VP as IN B-PP a DT B-NP result NN I-NP of IN B-PP a DT B-NP de FW I-NP novo FW I-NP mutation NN I-NP . . O The DT B-NP son NN I-NP of IN B-PP the DT B-NP unaffected JJ I-NP twin NN I-NP sister NN I-NP was VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP hemizygous JJ B-ADJP . . O Molecular JJ B-NP analysis NN I-NP of IN B-PP the DT B-NP alpha-galactosidase NN I-NP A NN I-NP gene NN I-NP permitted VBD B-VP the DT B-NP identification NN I-NP of IN B-PP an DT O as RB B-ADVP yet RB I-ADVP undescribed JJ B-NP point NN I-NP mutation NN I-NP at IN B-PP position NN B-NP 10182 CD I-NP of IN B-PP exon NN B-NP 5 CD I-NP which WDT B-NP causes VBZ B-VP an DT O Asp NN B-NP to TO O Asn NN B-NP substitution NN B-NP at IN B-PP codon NN B-NP 231 CD I-NP . . O Single JJ B-NP strand NN I-NP conformation NN I-NP polymorphism NN I-NP ( ( O SSCP NN B-NP ) ) O analysis NN B-NP again RB B-ADVP showed VBD B-VP the DT B-NP heterozygous JJ I-NP status NN I-NP of IN B-PP the DT B-NP twins NNS I-NP and CC O a DT B-NP normal JJ I-NP pattern NN I-NP in IN B-PP their PRP$ B-NP parents NNS I-NP . . O The DT B-NP basis NN I-NP for IN B-PP the DT B-NP discordant JJ I-NP expression NN I-NP of IN B-PP this DT B-NP d FW I-NP novo FW I-NP mutation NN I-NP in IN B-PP the DT B-NP twins NNS I-NP was VBD B-VP investigated VBN I-VP by IN B-PP studying VBG B-VP their PRP$ B-NP X NN I-NP inactivation NN I-NP status NN I-NP . . O Analysis NN B-NP of IN B-PP the DT O inactive JJ B-NP X NN I-NP specific JJ B-NP methylation NN I-NP at IN B-PP the DT B-NP androgen NN I-NP receptor NN I-NP gene NN I-NP showed VBD B-VP unbalanced JJ B-NP inactivation NN I-NP in IN B-PP the DT B-NP twins NNS I-NP ' POS B-NP fibroblasts NNS I-NP and CC B-PP in IN B-PP opposite JJ B-NP directions NNS I-NP . . O While IN B-SBAR the DT B-NP maternally RB I-NP derived VBN I-NP X NN I-NP chromosome NN I-NP was VBD B-VP preferentially RB B-ADJP active JJ I-ADJP in IN B-PP the DT B-NP asymptomatic JJ I-NP twin NN I-NP COMMA COMMA O the DT B-NP paternal JJ I-NP X NN I-NP chromosome NN I-NP was VBD B-VP active JJ B-ADJP in IN B-PP the DT B-NP other JJ I-NP COMMA COMMA I-NP affected VBN I-NP twin NN I-NP and CC O was VBD B-VP found VBN I-VP in IN B-PP her PRP$ B-NP hemizygotic JJ I-NP nephew NN I-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP paternal JJ I-NP X NN I-NP chromosome NN I-NP carries VBZ B-VP the DT B-NP de FW I-NP novo FW I-NP alpha-galactosidase NN I-NP A NN I-NP mutation NN I-NP and CC O that IN B-SBAR uneven JJ B-NP X NN I-NP inactivation NN I-NP is VBZ B-VP the DT B-NP underlying VBG I-NP mechanism NN I-NP for IN B-PP disease NN B-NP expression NN I-NP in IN B-PP this DT B-NP novel JJ I-NP female NN I-NP MZ JJ I-NP twin NN I-NP pair NN I-NP . . O This DT B-NP is VBZ B-VP the DT B-NP first JJ I-NP documented VBN I-NP case NN I-NP of IN B-PP female JJ B-NP twins NNS I-NP discordant JJ B-ADJP for IN B-PP Fabry NN B-NP disease NN I-NP . . O Signaling NN B-NP by IN B-PP IL-2 NN B-NP and CC O related JJ B-NP cytokines NNS I-NP : : O JAKs NNS B-NP COMMA COMMA O STATs NNS B-NP COMMA COMMA O and CC O relationship NN B-NP to TO B-PP immunodeficiency NN B-NP . . O Cytokines NNS B-NP that WDT B-NP bind VBP B-VP to TO B-PP the DT O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O receptor NN B-NP common JJ I-NP gamma NN B-NP chain NN I-NP ( ( O gamma NN B-NP c NN I-NP ) ) O COMMA COMMA O including VBG B-PP IL-2 NN B-NP COMMA COMMA O IL-4 NN B-NP COMMA COMMA O IL-7 NN B-NP COMMA COMMA O IL-9 NN B-NP COMMA COMMA O and CC O IL-15 NN B-NP COMMA COMMA O are VBP B-VP important JJ B-ADJP for IN B-PP the DT B-NP growth NN B-NP and CC O differentiation NN B-NP of IN B-PP T NN B-NP and CC O B NN B-NP lymphocytes NNS B-NP COMMA COMMA O natural JJ B-NP killer NN I-NP cells NNS I-NP COMMA COMMA O macrophages NNS B-NP COMMA COMMA O and CC O monoctyes NNS B-NP . . O These DT B-NP cytokines NNS I-NP have VBP B-VP overlapping VBG B-NP biological JJ I-NP effects NNS I-NP that WDT B-NP in IN B-PP part NN B-NP result VBP B-VP from IN B-PP the DT B-NP use NN I-NP of IN B-PP the DT B-NP shared VBN I-NP receptor NN I-NP subunit NN I-NP gamma NN I-NP c NN I-NP . . O Recently RB B-ADVP it PRP B-NP has VBZ B-VP become VBN I-VP clear JJ B-ADJP that IN B-SBAR these DT B-NP cytokines NNS I-NP activate VBP B-VP a DT B-NP number NN I-NP of IN B-PP important JJ B-NP intracellular JJ I-NP signaling VBG I-NP molecules NNS I-NP COMMA COMMA O including VBG B-PP the DT B-NP Janus NN I-NP kinases NNS I-NP JAK1 NN B-NP and CC O JAK3 NN B-NP and CC O members NNS B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP family NN I-NP of IN B-PP signal NN B-NP transducers NNS B-NP and CC O activators NNS B-NP of IN B-PP transcription NN B-NP ( ( O STATs NNS B-NP ) ) O . . O The DT B-NP discovery NN I-NP of IN B-PP these DT B-NP signaling NN I-NP pathways NNS I-NP has VBZ B-VP led VBN I-VP to TO B-PP important JJ B-NP new JJ I-NP insights NNS I-NP into IN B-PP their PRP$ B-NP role NN I-NP in IN B-PP lymphocyte NN B-NP maturation NN I-NP COMMA COMMA O as IN B-SBAR it PRP B-NP has VBZ B-VP emerged VBN I-VP that IN B-SBAR mutations NNS B-NP in IN B-PP the DT B-NP genes NNS I-NP encoding VBG B-VP both CC O gamma NN B-NP c NN I-NP and CC O JAK3 NN B-NP result VBP B-VP in IN B-PP similar JJ B-NP forms NNS I-NP of IN B-PP severe JJ B-NP combined JJ I-NP immunodeficiency NN I-NP ( ( O SCID NN B-NP ) ) O . . O In IN B-PP this DT B-NP review NN I-NP we PRP B-NP examine VBP B-VP the DT B-NP structure NN B-NP and CC O function NN B-NP of IN B-PP cytokine NN B-NP receptors NNS I-NP and CC O the DT B-NP signaling NN I-NP pathways NNS I-NP involved VBN B-VP in IN B-PP their PRP$ B-NP regulation NN I-NP of IN B-PP gene NN B-NP expression NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O we PRP B-NP discuss VBP B-VP recent JJ B-NP advances NNS I-NP that WDT B-NP have VBP B-VP led VBN I-VP to TO B-PP a DT B-NP better JJR I-NP understanding NN I-NP of IN B-PP how WRB B-ADVP cytokines NNS B-NP elicit VBP B-VP intracellular JJ B-NP responses NNS I-NP COMMA COMMA O as RB B-PP well RB I-PP as IN I-PP their PRP$ B-NP role NN I-NP in IN B-PP normal JJ B-NP lymphoid JJ I-NP development NN I-NP . . O Eosinophil NN B-NP priming NN I-NP by IN B-PP cytokines NNS B-NP : : O from IN B-PP cellular JJ B-NP signal NN I-NP to TO B-PP in FW B-NP vivo FW I-NP modulation NN I-NP . . O Eosinophils NNS B-NP play VBP B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP effector NN I-NP phase NN I-NP of IN B-PP allergic JJ B-NP inflammation NN I-NP . . O This DT B-NP review NN I-NP will MD B-VP focus VB I-VP on IN B-PP the DT B-NP conversion NN I-NP of IN B-PP the DT B-NP unprimed JJ I-NP eosinophil NN I-NP phenotype NN I-NP in IN B-PP the DT B-NP peripheral JJ I-NP blood NN I-NP of IN B-PP normal JJ B-NP individuals NNS I-NP to TO B-PP the DT B-NP primed JJ I-NP phenotype NN I-NP found VBN B-VP in IN B-PP the DT B-NP peripheral JJ I-NP blood NN B-NP and CC O tissues NNS B-NP of IN B-PP allergic JJ B-NP patients NNS I-NP COMMA COMMA O a DT B-NP phenomenon NN I-NP called VBN B-VP priming NN B-NP . . O Recent JJ B-NP data NNS I-NP on IN B-PP the DT B-NP signals NNS I-NP initiated VBN B-VP after IN B-PP cytokine NN B-NP receptor NN I-NP activation NN I-NP on IN B-PP eosinophils NNS B-NP will MD B-VP be VB I-VP reviewed VBN I-VP . . O Molecular JJ B-NP mechanisms NNS I-NP of IN B-PP steroid NN B-NP action NN I-NP : : O a DT B-NP novel JJ I-NP type NN I-NP of IN B-PP cross-talk NN B-NP between IN B-PP glucocorticoids NNS B-NP and CC O NF-kappa NN B-NP B NN I-NP transcription NN I-NP factors NNS I-NP . . O Despite IN B-PP the DT B-NP widespread JJ I-NP use NN I-NP of IN B-PP glucocorticoids NNS B-NP in IN B-PP the DT B-NP treatment NN I-NP of IN B-PP diseases NNS B-NP characterized VBN B-VP by IN B-PP inflammation NN B-NP COMMA COMMA O the DT B-NP molecular JJ I-NP mechanism NN I-NP ( ( I-NP s NNS I-NP ) ) O by IN B-PP which WDT B-NP these DT B-NP hormones NNS I-NP exert VBP B-VP this DT B-NP beneficial JJ I-NP effect NN I-NP in IN B-PP patients NNS B-NP with IN B-PP asthma NN B-NP remains VBZ B-VP to TO I-VP be VB I-VP elucidated VBN I-VP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP have VBP B-VP studied VBN I-VP the DT B-NP transcriptional JJ I-NP regulation NN I-NP of IN B-PP intercellular JJ B-NP adhesion NN I-NP molecule-1 NN I-NP ( ( O ICAM-1 NN B-NP ) ) O as IN B-SBAR adhesion NN B-NP molecules NNS I-NP are VBP B-VP likely JJ B-ADJP to TO B-VP play VB I-VP a DT B-NP causal JJ I-NP role NN I-NP in IN B-PP inflammation NN B-NP in IN B-PP promoting VBG B-VP cell-cell JJ B-NP and CC I-NP cell-matrix JJ I-NP interactions NNS I-NP . . O We PRP B-NP observed VBD B-VP that IN B-SBAR in IN B-PP a DT B-NP monocytic JJ I-NP ( ( O U937 NN B-NP ) ) O and CC O a DT B-NP bronchial JJ I-NP epithelial NN I-NP ( ( O H292 NN B-NP ) ) O cell-line JJ B-NP dexamethasone NN B-NP strongly RB B-ADVP suppressed VBD B-VP basal JJ B-NP and CC I-NP induced VBN I-NP ICAM-1 NN I-NP expression NN I-NP . . O Subsequent JJ B-NP analysis NN I-NP of IN B-PP the DT B-NP human JJ I-NP ICAM-1 NN I-NP promoter NN I-NP has VBZ B-VP revealed VBN I-VP that IN B-SBAR both CC O 12-O-tetradecanoylphorbol NN B-NP 13-acetate NN I-NP ( ( O TPA NN B-NP ) ) O and CC O tumour NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O upregulate VBP B-VP ICAM-1 NN B-NP expression NN I-NP through IN B-PP the DT B-NP presence NN I-NP of IN B-PP a DT O nuclear JJ B-NP factor NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O target NN B-NP sequence NN I-NP ( ( O TGGAAATTCC NN B-NP ) ) O . . O No DT B-NP glucocorticoid NN I-NP recognition NN I-NP sequences NNS I-NP are VBP B-VP present JJ B-ADJP in IN B-PP this DT B-NP promoter NN I-NP region NN I-NP and CC O dexamethasone NN B-NP is VBZ B-VP still RB B-ADVP able JJ B-ADJP to TO B-VP repress VB I-VP transcription NN B-NP when WRB B-ADVP the DT B-NP multimerized JJ I-NP NF-kappa NN I-NP B NN I-NP sequence NN I-NP is VBZ B-VP transactivated VBN I-VP by IN B-PP TNF-alpha NN B-NP upon IN B-PP transfection NN B-NP in IN B-PP 293 CD B-NP cells NNS I-NP . . O We PRP B-NP propose VBP B-VP that IN B-SBAR direct JJ B-NP interaction NN I-NP between IN B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP and CC O nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP factors NNS I-NP is VBZ B-VP at IN B-ADVP least JJS I-ADVP a DT B-NP partial JJ I-NP explanation NN I-NP for IN B-PP the DT B-NP effects NNS I-NP of IN B-PP this DT B-NP hormone NN I-NP in IN B-PP inflammatory JJ B-NP diseases NNS I-NP . . O The DT B-NP suppression NN I-NP of IN B-PP T NN B-NP cell NN I-NP function NN I-NP and CC O NF(kappa)B NN B-NP expression NN I-NP by IN B-PP serine NN B-NP protease NN I-NP inhibitors NNS I-NP is VBZ B-VP blocked VBN I-VP by IN B-PP N-acetylcysteine NN B-NP . . O Direct JJ B-NP evidence NN I-NP that IN B-SBAR N-acetylcysteine NN B-NP ( ( O NAC NN B-NP ) ) O enhances VBZ B-VP the DT B-NP immune JJ I-NP response NN I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP T NN I-NP cells NNS I-NP at IN B-PP the DT B-NP level NN I-NP of IN B-PP NF(kappa)B NN B-NP is VBZ B-VP presented VBN I-VP . . O In IN B-PP addition NN B-NP COMMA COMMA O NAC NN B-NP blocks VBZ B-VP the DT B-NP suppression NN I-NP of IN B-PP T NN B-NP cell NN I-NP mitogenesis NN I-NP and CC O cytokine NN B-NP production NN I-NP by IN B-PP protease NN B-NP inhibitors NNS I-NP such JJ B-PP as IN I-PP N-tosylphenylalanine NN B-NP chloromethyl NN I-NP ketone NN I-NP ( ( O TPCK NN B-NP ) ) O . . O The DT B-NP proliferative JJ I-NP responses NNS I-NP of IN B-PP purified VBN B-NP CD4+ JJ I-NP or CC I-NP CD8+ JJ I-NP T NN I-NP cells NNS I-NP are VBP B-VP suppressed VBN I-VP more RBR B-ADVP strongly RB I-ADVP by IN B-PP TPCK NN B-NP when WRB B-ADVP anti-CD28 NN B-NP rather RB B-CONJP than IN I-CONJP the DT B-NP phorbol NN I-NP ester NN I-NP PMA NN I-NP is VBZ B-VP used VBN I-VP as IN B-PP the DT B-NP mitogenic JJ I-NP coactivator NN I-NP . . O Cytokine NN B-NP ( ( O IL-2 NN B-NP COMMA COMMA O IL-6 NN B-NP COMMA COMMA O INF-gamma NN B-NP ) ) O production NN B-NP is VBZ B-VP inhibited VBN I-VP 95-100 CD B-NP % NN I-NP by IN B-PP concentrations NNS B-NP of IN B-PP TPCK NN B-NP that WDT B-NP totally RB B-VP suppress VB I-VP the DT B-NP mitogenesis NN I-NP of IN B-PP CD4+ JJ B-NP or CC I-NP CD8+ JJ I-NP cells NNS I-NP . . O Using VBG B-VP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP COMMA COMMA O we PRP B-NP find VBP B-VP that IN B-SBAR TPCK NN B-NP virtually RB B-ADVP abolishes VBZ B-VP ( ( O to TO B-PP less JJR B-NP than IN I-NP 1 CD I-NP % NN I-NP ) ) O the DT B-NP levels NNS I-NP of IN B-PP NF(kappa)B NN B-NP ( ( O but CC B-CONJP not RB I-CONJP Oct-1 NN B-NP ) ) O found VBN B-VP in IN B-PP nuclear JJ O and CC O whole JJ B-NP cell NN I-NP extracts NNS B-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O Strikingly RB B-ADVP COMMA COMMA O the DT B-NP immunosuppressive JJ I-NP effects NNS I-NP of IN B-PP TPCK NN B-NP are VBP B-VP blocked VBN I-VP when WRB B-ADVP T NN B-NP cells NNS I-NP are VBP B-VP pretreated VBN I-VP for IN B-PP 15 CD B-NP min NN I-NP with IN B-PP 5 CD B-NP mM NN I-NP NAC NN I-NP . . O NAC NN B-NP not RB B-CONJP only RB I-CONJP blocks VBZ B-VP the DT B-NP effect NN I-NP of IN B-PP TPCK NN B-NP but CC O enhances VBZ B-VP mitogenesis NN B-NP and CC O cytokine NN B-NP production NN I-NP ( ( O > JJR B-ADVP 2.5-fold RB I-ADVP in IN B-PP some DT B-NP cases NNS I-NP ) ) O upon IN B-PP activation NN B-NP of IN B-PP unsuppressed JJ B-NP T NN I-NP cells NNS I-NP . . O Our PRP$ B-NP data NNS I-NP support VBP B-VP the DT B-NP notion NN I-NP that IN B-SBAR NF NN B-NP ( ( O kappa NN B-NP ) ) O B NN B-VP and CC B-NP I NN I-NP ( ( O kappa NN B-NP ) ) I-NP B NN I-NP proteases NNS B-NP play VBP B-NP obligate JJ B-VP roles NNS B-NP in IN B-NP T NN B-VP cell NN I-VP activation NN B-ADVP and CC B-PP mitogenesis NN B-NP COMMA COMMA O IL-12-induced JJ B-NP activation NN I-NP of IN B-PP NK NN B-NP and CC O T NN B-NP cells NNS B-NP occurs VBZ B-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP immediate-early JJ B-NP activation NN I-NP gene NN I-NP expression NN I-NP . . O The DT B-NP responses NNS I-NP of IN B-PP lymphocytes NNS B-NP to TO B-PP IL-2 NN B-NP and CC O IL-12 NN B-NP COMMA COMMA O involving VBG B-VP proliferation NN B-NP COMMA COMMA O differentiation NN B-NP COMMA COMMA O and CC O cytokine NN B-NP production NN I-NP COMMA COMMA O are VBP B-VP only RB I-VP partially RB I-VP overlapping VBG I-VP COMMA COMMA O and CC O may MD B-VP depend VB I-VP on IN B-PP induced VBN B-NP differential JJ I-NP expression NN I-NP of IN B-PP specific JJ B-NP sets NNS I-NP of IN B-PP genes NNS B-NP . . O Using VBG B-VP reverse-transcription JJ B-NP PCR NN I-NP differential JJ I-NP display NN I-NP COMMA COMMA O we PRP B-NP isolated VBD B-VP an DT B-NP mRNA NN I-NP species NNS I-NP expressed VBN B-VP in IN B-PP IL-2- NN B-NP but CC O not RB B-ADJP IL-12-stimulated JJ I-ADJP NK NN B-NP cells NNS I-NP . . O This DT B-NP was VBD B-VP identified VBN I-VP as IN B-PP the DT B-NP mRNA NN I-NP encoding VBG B-VP the DT B-NP transcription NN I-NP factor NN I-NP egr-1 NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP expressed VBN I-VP with IN B-PP fast JJ B-NP kinetics NNS I-NP in IN B-PP T NN B-NP and CC O NK NN B-NP cells NNS B-NP upon IN B-PP IL-2 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP IL-12 NN B-NP COMMA COMMA O stimulation NN B-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP accumulation NN I-NP of IN B-PP mRNA-encoding JJ B-NP members NNS I-NP of IN B-PP the DT B-NP AP-1 NN I-NP transcription NN I-NP factor NN I-NP family NN I-NP demonstrated VBD B-VP that IN B-SBAR c-fos NN B-NP and CC O junB NN B-NP are VBP B-VP also RB I-VP expressed VBN I-VP upon IN B-PP stimulation NN B-NP of IN B-PP NK NN B-NP and CC O T NN B-NP cells NNS B-NP with IN B-PP IL-2 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP IL-12 NN B-NP COMMA COMMA O whereas IN O expression NN B-NP of IN B-PP c-jun NN B-NP and CC O junD NN B-NP is VBZ B-VP not RB I-VP modified VBN I-VP by IN B-PP either DT B-NP cytokine NN I-NP . . O Accordingly RB B-ADVP COMMA COMMA O increased VBN B-NP AP-1 NN I-NP DNA-binding JJ I-NP activity NN I-NP and CC O AP-1-dependent JJ B-NP transcriptional JJ I-NP activity NN I-NP were VBD B-VP detected VBN I-VP exclusively RB B-ADVP in IN B-PP IL-2-stimulated JJ B-NP cells NNS I-NP . . O Analysis NN B-NP of IN B-PP the DT B-NP expression NN I-NP of IN B-PP genes NNS B-NP reported VBN B-VP to TO I-VP regulate VB I-VP cytokine-induced JJ B-NP proliferation NN I-NP demonstrated VBD B-VP that IN B-SBAR both CC O IL-2 NN B-NP and CC O IL-12 NN B-NP induce VBP B-VP c-myc NN B-NP mRNA NN I-NP accumulation NN I-NP in IN B-PP NK NN B-NP and CC O T NN B-NP cells NNS B-NP COMMA COMMA O whereas IN O only RB B-NP IL-2 NN I-NP induces VBZ B-VP bcl-2 NN B-NP expression NN I-NP . . O Our PRP$ B-NP data NNS I-NP provide VBP B-VP the DT B-NP first JJ I-NP demonstration NN I-NP that IN B-SBAR IL-12-mediated JJ B-NP activation NN I-NP of IN B-PP T NN B-NP and CC O NK NN B-NP cells NNS B-NP does VBZ B-VP not RB I-VP involve VB I-VP expression NN B-NP of IN B-PP members NNS B-NP of IN B-PP the DT B-NP immediate-early JJ I-NP activation NN I-NP genes NNS I-NP family NN I-NP ( ( O egr-1 NN B-NP COMMA COMMA O c-fos NN B-NP COMMA COMMA O and CC O junB NN B-NP ) ) O COMMA COMMA O AP-1 NN B-NP transcriptional JJ I-NP activity NN I-NP COMMA COMMA O or CC O bcl-2 NN B-NP expression NN I-NP . . O This DT B-NP indicates VBZ B-VP that IN B-SBAR functional JJ B-NP differences NNS I-NP observed VBN B-VP in IN B-PP IL-2- NN B-NP and CC O IL-12-stimulated JJ B-ADJP cells NNS B-NP may MD O depend VB O COMMA COMMA B-ADVP at IN I-ADVP least JJS B-PP in IN B-NP part NN B-VP COMMA COMMA O on IN B-NP differential JJ I-NP gene NN I-NP regulation NN O A DT B-NP critical JJ I-NP role NN I-NP of IN B-PP Sp1- NN B-NP and CC O Ets-related JJ B-ADJP transcription NN B-NP factors NNS I-NP in IN B-PP maintaining VBG B-VP CTL-specific JJ B-NP expression NN I-NP of IN B-PP the DT B-NP mouse NN I-NP perforin NN I-NP gene NN I-NP . . O This DT B-NP study NN I-NP was VBD B-VP designed VBN I-VP to TO B-VP determine VB I-VP the DT B-NP potential JJ I-NP cis-elements NNS I-NP involved VBN B-VP in IN B-PP transcriptional JJ B-NP regulation NN I-NP of IN B-PP the DT B-NP mouse NN I-NP perforin NN I-NP gene NN I-NP . . O DNase NN B-NP I CD I-NP hypersensitive JJ I-NP site NN I-NP ( ( O DHS NN B-NP ) ) O mapping NN B-NP revealed VBD B-VP that IN B-SBAR the DT B-NP perforin NN I-NP locus NN I-NP contained VBD B-VP six CD B-NP DHS NN I-NP within IN B-PP 7.0 CD B-NP kb NN I-NP of IN B-PP the DT B-NP 5' JJ I-NP upstream JJ I-NP sequence NN I-NP ( ( O -7.0 CD B-NP kb NN I-NP ) ) O and CC O two CD B-NP DHS NN I-NP in IN B-PP intron NN B-NP 2 CD I-NP . . O The DT B-NP six CD B-NP 5' JJ I-NP upstream JJ I-NP and CC O one CD B-NP intronic JJ I-NP DHS NN B-NP were VBD B-VP detected VBN I-VP in IN B-PP only RB B-NP perforin-expressing JJ I-NP lymphocytes NNS I-NP . . O Chloramphenicol NN B-NP acetyltransferase NN I-NP ( ( O CAT NN B-NP ) ) O activities NNS B-NP directed VBN B-VP by IN B-PP 5' JJ B-NP upstream JJ I-NP promoter NN I-NP were VBD B-VP detected VBN I-VP preferentially RB B-ADVP in IN B-PP perforin-expressing JJ B-NP cell NN I-NP lines NNS I-NP . . O A DT B-NP construct NN I-NP termed VBN B-VP PFP5a NN B-NP containing VBG B-VP -795 CD B-NP bp NN I-NP exhibited VBD B-VP the DT B-NP highest JJS I-NP CAT NN I-NP activity NN I-NP COMMA COMMA O and CC O PFP9a20 NN B-NP containing VBG B-VP only RB B-NP -73 CD I-NP bp NN I-NP also RB B-ADVP produced VBD B-VP significantly RB B-NP high JJ I-NP CAT NN I-NP activity NN I-NP in IN B-PP CTLL-R8 NN B-NP cells NNS I-NP . . O The DT B-NP proximal JJ I-NP region NN I-NP in IN B-PP PFP9a20 NN B-NP contained VBD B-VP two CD B-NP potential JJ I-NP Sp1 NN I-NP binding NN I-NP sites NNS I-NP ( ( O GC NN B-NP box NN I-NP and CC O GT NN B-NP box NN I-NP ) ) O and CC O one CD B-NP Ets NN I-NP binding NN I-NP site NN I-NP ( ( O EBS NN B-NP ) ) O . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assay NN I-NP showed VBD B-VP that IN B-SBAR each DT B-NP of IN B-PP the DT B-NP cis-elements NNS I-NP bound VBD B-VP specific JJ B-NP protein NN I-NP factors NNS I-NP . . O When WRB B-ADVP single-point JJ B-NP mutation NN I-NP was VBD B-VP introduced VBN I-VP to TO B-PP each DT B-NP GC NN B-NP box NN I-NP COMMA COMMA O EBS NN B-NP COMMA COMMA O and CC O GT NN B-NP box NN I-NP in IN B-PP PFP9a20 NN B-NP COMMA COMMA O at IN B-NP least JJS I-NP 3-fold RB I-NP less JJR I-NP CAT NN I-NP activity NN I-NP was VBD B-VP observed VBN I-VP in IN B-PP CTLL-R8 NN B-NP cells NNS I-NP . . O To TO B-VP confirm VB I-VP the DT B-NP importance NN I-NP of IN B-PP the DT B-NP three CD I-NP cis-acting JJ I-NP elements NNS I-NP in IN B-PP the DT B-NP perforin NN I-NP gene NN I-NP expression NN I-NP COMMA COMMA O point NN B-NP mutation NN I-NP was VBD B-VP introduced VBN I-VP again RB B-ADVP to TO B-PP each DT B-NP proximal JJ I-NP GC NN B-NP box NN I-NP COMMA COMMA O EBS NN B-NP COMMA COMMA O and CC O GT NN B-NP box NN I-NP of IN B-PP PFP5a NN B-NP . . O The DT B-NP point NN I-NP mutations NNS I-NP resulted VBD B-VP in IN B-PP a DT B-NP 2.5- CD I-NP to TO I-NP 3-fold JJ I-NP reduction NN I-NP of IN B-PP CAT NN B-NP activity NN I-NP . . O The DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR a DT B-NP combination NN I-NP of IN B-PP the DT B-NP three CD I-NP proximal JJ I-NP cis-acting JJ I-NP elements NNS I-NP may MD B-VP constitute VB I-VP a DT B-NP minimal JJ I-NP region NN I-NP responsible JJ B-ADJP for IN B-PP CTL-specific JJ B-NP expression NN I-NP of IN B-PP perforin NN B-NP . . O Soluble JJ B-NP factors NNS I-NP secreted VBN B-VP by IN B-PP activated VBN B-NP T-lymphocytes NNS I-NP modulate VBP B-VP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP immunosuppressive JJ I-NP cytokine NN I-NP TGF-beta NN I-NP 2 CD I-NP in IN B-PP glial JJ B-NP cells NNS I-NP . . O Coordination NN B-NP of IN B-PP the DT B-NP immune JJ I-NP response NN I-NP to TO B-PP injury NN B-NP or CC O disease NN B-NP in IN B-PP the DT B-NP brain NN I-NP is VBZ B-VP postulated VBN I-VP to TO I-VP involve VB I-VP bi-directional JJ B-NP discourse NN I-NP between IN B-PP the DT B-NP immune JJ I-NP system NN I-NP and CC O the DT B-NP central JJ I-NP nervous JJ I-NP system NN I-NP . . O This DT B-NP cross JJ I-NP communication NN I-NP involves VBZ B-VP soluble JJ B-NP mediators NNS I-NP COMMA COMMA O including VBG B-PP various JJ B-NP growth NN I-NP factors NNS I-NP COMMA COMMA O cytokines NNS B-NP COMMA COMMA O and CC O neuropeptides NNS B-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP supernatant NN I-NP from IN B-PP activated VBN B-NP T-lymphocytes NNS I-NP is VBZ B-VP able JJ B-ADJP to TO B-VP induce VB I-VP the DT B-NP transcription NN I-NP of IN B-PP a DT B-NP potent JJ I-NP cytokine NN I-NP COMMA COMMA O TGF-beta NN B-NP 2 CD I-NP in IN B-PP glial JJ B-NP cells NNS I-NP . . O The DT B-NP activating VBG I-NP stimulus NN I-NP invokes VBZ B-VP signaling NN B-NP mechanisms NNS I-NP distinct JJ B-ADJP from IN B-PP known JJ O kinase NN B-NP or CC O protease NN B-NP pathways NNS B-NP . . O Activation NN B-NP of IN B-PP TGF-beta NN B-NP 2 CD I-NP transcription NN I-NP correlates VBZ B-VP with IN B-PP the DT B-NP loss NN I-NP of IN B-PP binding NN B-NP activity NN I-NP for IN B-PP an DT B-NP 80 CD I-NP kDA NN I-NP glial JJ I-NP labile NN I-NP repressor NN I-NP protein NN I-NP COMMA COMMA O GLRP NN B-NP COMMA COMMA O to TO B-PP a DT B-NP responsive JJ I-NP region NN I-NP within IN B-PP the DT B-NP TFG-beta NN I-NP 2 CD I-NP promoter NN I-NP . . O Although IN B-SBAR GLRP NN B-NP shares VBZ B-VP some DT B-NP characteristics NNS I-NP with IN B-PP the DT B-NP inducible JJ I-NP transcription NN I-NP factor NN I-NP AP-1 NN I-NP COMMA COMMA O it PRP B-NP appears VBZ B-VP to TO I-VP be VB I-VP distinct JJ B-ADJP from IN B-PP known JJ B-NP AP-1 NN I-NP family NN I-NP members NNS I-NP . . O These DT B-NP data NNS I-NP along IN B-PP with IN I-PP previous JJ B-NP observations NNS I-NP demonstrating VBG B-VP the DT B-NP potent JJ I-NP immunosuppressive JJ I-NP activity NN I-NP of IN B-PP TGF-beta NN B-NP 2 CD I-NP COMMA COMMA O support VBP B-VP a DT B-NP model NN I-NP for IN B-PP a DT B-NP feedback NN I-NP mechanism NN I-NP between IN B-PP the DT B-NP activated VBN I-NP T-lymphocytes NNS B-NP and CC O astrocytes NNS B-NP via IN B-PP TGF-beta NN B-NP 2 CD I-NP to TO B-VP regulate VB I-VP the DT B-NP immune JJ I-NP response NN I-NP . . O Dual JJ B-NP action NN I-NP of IN B-PP retinoic JJ B-NP acid NN I-NP on IN B-PP human JJ B-NP embryonic\/fetal JJ I-NP hematopoiesis NN I-NP : : O blockade NN B-NP of IN B-PP primitive JJ B-NP progenitor NN I-NP proliferation NN I-NP and CC O shift NN B-NP from IN B-PP multipotent\/erythroid/monocytic JJ B-NP to TO B-PP granulocytic JJ B-NP differentiation NN B-NP program NN I-NP . . O In IN B-PP preliminary JJ B-NP studies NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP analyzed VBN I-VP the DT O hematopoietic JJ B-NP growth NN I-NP factor NN I-NP ( ( O HGF NN B-NP ) ) O requirement NN B-NP of IN B-PP hematopoietic JJ B-NP progenitor NN I-NP cells NNS I-NP ( ( O HPCs NNS B-NP ) ) O purified VBN B-VP from IN B-PP embryonic-fetal JJ B-NP liver NN I-NP ( ( O FL NN B-NP ) ) O and CC O grown VBN B-VP in IN B-PP fetal JJ O calf NN O serum-supplemented JJ O ( ( O FCS+ NN B-ADJP ) ) O clonogenic JJ B-NP culture NN I-NP . . O The DT B-NP key JJ I-NP role NN I-NP of IN B-PP erythropoietin NN B-NP ( ( O Epo NN B-NP ) ) O for IN B-PP colony NN B-NP formation NN I-NP by IN B-PP early JJ B-NP erythroid JJ I-NP progenitors NNS I-NP ( ( O burst-forming JJ B-NP units-erythroid JJ I-NP { ( O BFU-E NN B-NP } ) O ) ) O has VBZ B-VP been VBN I-VP confirmed VBN I-VP . . O Furthermore RB B-ADVP COMMA COMMA O in IN B-PP the DT I-PP absence NN I-PP of IN I-PP exogenous JJ B-NP HGFs NNS I-NP COMMA COMMA O FL NN B-NP monocytic JJ I-NP progenitors NNS I-NP ( ( O colony-forming JJ B-NP unit NN I-NP monocyte NN I-NP { ( O CFU-M NN B-NP } ) O ) ) O generate VBP B-VP large JJ B-NP colonies NNS I-NP exclusively RB B-VP composed VBN I-VP of IN B-PP monocytes-macrophages NNS B-NP ; : O these DT B-NP colonies NNS I-NP are VBP B-VP absent JJ B-ADJP in IN B-PP FCS- NN B-NP clonogenic JJ I-NP culture NN I-NP . . O On IN B-PP this DT B-NP basis NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP role NN I-NP of IN B-PP all-trans JJ B-NP retinoic JJ I-NP acid NN I-NP ( ( O ATRA NN B-NP ) ) O and CC O its PRP$ B-NP isomer NN I-NP 9-cis JJ I-NP RA NN I-NP in IN B-PP FL NN B-NP hematopoiesis NN I-NP . . O Vitamin NN B-NP D3- NN I-NP and CC O retinoic JJ B-ADJP acid-induced JJ I-ADJP monocytic JJ B-NP differentiation NN I-NP : : O interactions NNS B-NP between IN B-PP the DT B-NP endogenous JJ B-NP vitamin NN I-NP D3 NN I-NP receptor NN I-NP COMMA COMMA O retinoic JJ B-NP acid NN I-NP receptors NNS I-NP COMMA COMMA O and CC O retinoid NN B-NP X NN I-NP receptors NNS I-NP in IN B-PP U-937 NN B-NP cells NNS I-NP . . O Retinoic JJ B-NP acid NN I-NP ( ( O RA NN B-NP ) ) O and CC O 1COMMA25 CD B-NP alpha-dihydroxycholecalciferol NN I-NP ( ( O VitD3 NN B-NP ) ) O are VBP B-VP potent JJ B-NP regulators NNS I-NP of IN B-PP hematopoletic JJ B-NP differentiation NN I-NP . . O Yet RB O COMMA COMMA O little JJ B-NP is VBZ B-VP known VBN I-VP as IN B-PP to TO I-PP how WRB B-ADVP the DT O RA NN B-NP and CC O VitD3 NN B-NP receptor NN B-NP network NN I-NP operates VBZ B-VP in IN B-PP hematopoietic JJ B-NP cells NNS I-NP COMMA COMMA O and CC O whether IN B-SBAR receptor NN B-NP interactions NNS I-NP can MD B-VP explain VB I-VP the DT B-NP interplay NN I-NP between IN B-PP the DT O RA- NN B-NP and CC O VitD3-signaling JJ B-ADJP pathways NNS B-NP during IN B-PP differentiation NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP analyzed VBD B-VP the DT B-NP expression NN B-NP COMMA COMMA O DNA NN B-NP binding NN I-NP COMMA COMMA O and CC O transcriptional JJ B-NP activity NN I-NP of IN B-PP the DT O endogenous JJ O RA NN B-NP and CC O VitD3 NN B-NP receptors NNS B-NP { ( O retinoic JJ B-NP acid NN I-NP receptors NNS I-NP ( ( O RARs NNS B-NP ) ) O COMMA COMMA O retinoid NN B-NP X NN I-NP receptors NNS I-NP ( ( O RXRs NNS B-NP ) ) O COMMA COMMA O and CC O VitD3 NN B-NP receptor NN I-NP ( ( O VDR NN B-NP ) ) O } ) O in IN B-PP the DT B-NP U-937 NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O in IN B-PP which WDT B-NP RA NN B-NP and CC O VitD3 NN B-NP induce VBP B-VP distinct JJ B-NP monocytic JJ I-NP differentiation NN I-NP pathways NNS I-NP . . O VitD3 NN B-NP induction NN I-NP resulted VBD B-VP in IN B-PP the DT B-NP formation NN I-NP of IN B-PP VDR\/RXR NN B-NP DNA-binding JJ I-NP complexes NNS I-NP on IN B-PP both CC O VitD3 NN B-NP response NN I-NP elements NNS I-NP and CC O RA NN B-NP response NN I-NP elements NNS I-NP ( ( O RAREs NNS B-NP ) ) O . . O However RB B-ADVP COMMA COMMA O transcriptional JJ B-NP activation NN I-NP was VBD B-VP only RB I-VP observed VBN I-VP from IN B-PP a DT B-NP VitD3 NN I-NP response NN I-NP element-driven JJ I-NP reporter NN I-NP construct NN I-NP . . O Several JJ B-NP DNA-binding JJ I-NP complexes NNS I-NP were VBD B-VP detected VBN I-VP on IN B-PP RAREs NNS B-NP in IN B-PP undifferentiated JJ B-NP cells NNS I-NP . . O Stimulation NN B-NP by IN B-PP RA NN B-NP resulted VBD B-VP in IN B-PP increased VBN B-NP RAR NN I-NP beta\/RXR NN I-NP DNA NN I-NP binding NN I-NP COMMA COMMA O activated VBN B-NP RARE-dependent JJ I-NP transcription NN I-NP COMMA COMMA O and CC O increased VBN B-NP expression NN I-NP of IN B-PP RAR-beta NN B-NP . . O Concomitant JJ B-NP stimulation NN I-NP by IN B-PP VitD3 NN B-NP inhibited VBD B-VP the DT B-NP RA-stimulated JJ I-NP formation NN I-NP of IN B-PP RAR NN B-NP beta\/RXR NN I-NP heterodimers NNS I-NP COMMA COMMA O favoring VBG B-VP VDR\/RXR NN B-NP binding NN I-NP to TO B-PP the DT B-NP RARE NN I-NP . . O Also RB B-ADVP COMMA COMMA O VitD3 NN B-NP inhibited VBD B-VP the DT B-NP expression NN I-NP of IN B-PP CD23 NN B-NP and CC O CD49f NN B-NP COMMA COMMA O characteristic JJ B-NP markers NNS I-NP of IN B-PP retinoid-induced JJ B-NP U-937 NN I-NP cell NN I-NP differentiation NN I-NP . . O In IN O contrast NN B-NP COMMA COMMA O neither CC O the DT B-NP RA-stimulated JJ I-NP COMMA COMMA I-NP RARE-mediated JJ I-NP transcription NN I-NP nor CC O the DT B-NP induced VBN I-NP RAR-beta NN I-NP expression NN I-NP was VBD B-VP suppressed VBN I-VP by IN B-PP VitD3 NN B-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR VitD3 NN B-NP selectively RB B-ADVP inhibited VBD B-VP the DT B-NP retinoid-induced JJ I-NP differentiation NN I-NP program NN I-NP but CC B-CONJP not RB I-CONJP the DT B-NP RARE-mediated JJ I-NP signal NN I-NP . . O These DT B-NP results NNS I-NP demonstrate VBP B-VP a DT B-NP complex JJ I-NP role NN I-NP for IN B-PP VitD3 NN B-NP in IN B-PP modifying VBG B-VP the DT B-NP retinoid NN I-NP differentiation NN I-NP pathway NN I-NP and CC O may MD B-VP have VB I-VP implications NNS B-NP for IN B-PP differentiation-inducing JJ B-NP therapy NN I-NP of IN B-PP hematopoietic JJ B-NP tumors NNS I-NP . . O Regulation NN B-NP of IN B-PP interferon-gamma NN B-NP gene NN I-NP expression NN I-NP . . O Interferon-gamma NN B-NP ( ( O IFN-gamma NN B-NP ) ) O COMMA COMMA O also RB B-VP known VBN I-VP as IN B-PP type NN B-NP II CD I-NP interferon NN I-NP COMMA COMMA O is VBZ B-VP an DT B-NP important JJ I-NP immunoregulatory JJ I-NP gene NN I-NP that WDT B-NP has VBZ B-VP multiple JJ B-NP effects NNS I-NP on IN B-PP the DT B-NP development NN B-NP COMMA COMMA O maturation NN B-NP COMMA COMMA O and CC O function NN B-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP . . O In IN B-PP this DT B-NP review NN I-NP COMMA COMMA O I PRP B-NP describe VBP B-VP how WRB B-ADVP DNA NN B-NP methylation NN I-NP and CC O specific JJ B-NP DNA NN I-NP binding NN I-NP proteins NNS I-NP may MD B-VP regulate VB I-VP transcription NN B-NP of IN B-PP the DT B-NP IFN-gamma NN I-NP gene NN I-NP in IN B-PP response NN I-PP to TO I-PP extracellular JJ B-NP signals NNS I-NP . . O Inorganic JJ B-NP lead NN I-NP activates VBZ B-VP NF-kappa NN B-NP B NN I-NP in IN B-PP primary JJ B-NP human JJ I-NP CD4+ JJ I-NP T NN I-NP lymphocytes NNS I-NP . . O Inorganic JJ B-NP lead NN I-NP ( ( O Pb NN B-NP ) ) O is VBZ B-VP a DT B-NP ubiquitous JJ I-NP environmental JJ I-NP contaminant NN I-NP that WDT B-NP produces VBZ B-VP a DT B-NP variety NN I-NP of IN B-PP effects NNS B-NP on IN B-PP humoral JJ B-NP and CC I-NP cell NN I-NP mediated JJ I-NP immune JJ I-NP responses NNS I-NP . . O The DT B-NP underlying VBG I-NP molecular JJ I-NP mechanism NN I-NP for IN B-PP Pb NN B-NP 's POS B-NP complex JJ I-NP effects NNS I-NP on IN B-PP the DT B-NP immune JJ I-NP system NN I-NP remain VBP B-VP obscure JJ B-ADJP . . O Many JJ B-NP of IN B-PP Pb NN B-NP 's POS B-NP effects NNS I-NP on IN B-PP the DT B-NP immune JJ I-NP system NN I-NP could MD B-VP be VB I-VP explained VBN I-VP through IN B-PP activation NN B-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP COMMA COMMA O NF-kappa NN B-NP B NN I-NP . . O NF-kappa NN B-NP B NN I-NP is VBZ B-VP critical JJ B-ADJP for IN B-PP T NN B-NP lymphocyte NN I-NP function NN I-NP and CC O is VBZ B-VP a DT B-NP strong JJ I-NP inducer NN I-NP of IN B-PP HIV-LTR NN B-NP activation NN I-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR Pb NN B-NP at IN B-PP physiologically RB B-NP relevant JJ I-NP concentrations NNS I-NP activates VBZ B-VP NF-kappa NN B-NP B NN I-NP in IN B-PP primary JJ B-NP human JJ I-NP CD4+ JJ I-NP T NN I-NP lymphocytes NNS I-NP . . O Pb-induced JJ B-NP activation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP is VBZ B-VP blocked VBN I-VP by IN B-PP antibodies NNS B-NP for IN B-PP p65 NN B-NP and CC O p50 NN B-NP subunits NNS B-NP but CC B-CONJP not RB I-CONJP cRel NN B-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP p65:p50 NN I-NP heterodimer NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O is VBZ B-VP involved VBN I-VP . . O Functional JJ B-NP activation NN I-NP of IN B-PP gene NN B-NP expression NN I-NP by IN B-PP Pb NN B-NP was VBD B-VP confirmed VBN I-VP using VBG B-VP primary JJ B-NP CD4+ JJ I-NP T NN I-NP cells NNS I-NP transfected VBN B-VP with IN B-PP an DT O NF-kappa NN B-NP B NN I-NP dependent JJ B-NP reporter NN I-NP gene NN I-NP construct NN I-NP . . O Pb NN B-NP did VBD B-VP not RB I-VP activate VB I-VP NF-kappa NN B-NP B NN I-NP in IN B-PP 4 CD B-NP different JJ I-NP T NN I-NP cell NN I-NP lines NNS I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR lymphoid JJ B-NP cell NN I-NP lines NNS I-NP may MD B-VP not RB I-VP be VB I-VP reliable JJ B-NP surrogates NNS I-NP for IN B-PP the DT B-NP study NN I-NP of IN B-PP transcriptional JJ B-NP activation NN I-NP in IN B-PP human JJ B-NP T NN I-NP cells NNS I-NP . . O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP may MD B-VP be VB I-VP an DT B-NP important JJ I-NP molecular JJ I-NP mediator NN I-NP of IN B-PP Pb-induced JJ B-NP immunotoxicity NN I-NP . . O Calcium-dependent JJ B-NP immediate-early JJ I-NP gene NN I-NP induction NN I-NP in IN B-PP lymphocytes NNS B-NP is VBZ B-VP negatively RB I-VP regulated VBN I-VP by IN B-PP p21Ha-ras NN B-NP . . O The DT B-NP induction NN I-NP of IN B-PP immediate-early JJ O ( ( O IE JJ B-ADJP ) ) O response NN B-NP genes NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP egr-1 NN B-NP COMMA COMMA O c-fos NN B-NP COMMA COMMA O and CC O c-jun NN B-NP COMMA COMMA O occurs VBZ B-VP rapidly RB B-ADVP after IN B-PP the DT B-NP activation NN I-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP . . O The DT B-NP process NN I-NP of IN B-PP activation NN B-NP involves VBZ B-VP calcium NN B-NP mobilization NN I-NP COMMA COMMA O activation NN B-NP of IN B-PP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O COMMA COMMA O and CC O phosphorylation NN B-NP of IN B-PP tyrosine NN B-NP kinases NNS I-NP . . O p21(ras) NN B-NP COMMA COMMA O a DT B-NP guanine NN I-NP nucleotide NN I-NP binding NN I-NP factor NN I-NP COMMA COMMA O mediates VBZ B-VP T-cell NN B-NP signal NN I-NP transduction NN I-NP through IN B-PP PKC-dependent JJ B-NP and CC I-NP PKC-independent JJ I-NP pathways NNS I-NP . . O The DT B-NP involvement NN I-NP of IN B-PP p21(ras) NN B-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP calcium-dependent JJ B-NP signals NNS I-NP has VBZ B-VP been VBN I-VP suggested VBN I-VP through IN B-PP analysis NN B-NP of IN B-PP its PRP$ B-NP role NN I-NP in IN B-PP the DT B-NP activation NN I-NP of IN B-PP NF-AT NN B-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP inductions NNS I-NP of IN B-PP the DT B-NP IE JJ I-NP genes NNS I-NP in IN B-PP response NN I-PP to TO I-PP calcium NN B-NP signals NNS I-NP in IN B-PP Jurkat NN B-NP cells NNS I-NP ( ( O in IN B-PP the DT I-PP presence NN I-PP of IN I-PP activated VBN B-NP p21(ras) NN I-NP ) ) O and CC O their PRP$ B-NP correlated VBN I-NP consequences NNS I-NP . . O The DT B-NP expression NN I-NP of IN B-PP activated VBN B-NP p21(ras) NN I-NP negatively RB B-ADVP regulated VBD B-VP the DT B-NP induction NN I-NP of IN B-PP IE JJ B-NP genes NNS I-NP by IN B-PP calcium NN B-NP ionophore NN I-NP . . O This DT B-NP inhibition NN I-NP of IN B-PP calcium-activated JJ B-NP IE JJ I-NP gene NN I-NP induction NN I-NP was VBD B-VP reversed VBN I-VP by IN B-PP treatment NN B-NP with IN B-PP cyclosporin NN B-NP A NN I-NP COMMA COMMA O suggesting VBG B-VP the DT B-NP involvement NN I-NP of IN B-PP calcineurin NN B-NP in IN B-PP this DT B-NP regulation NN I-NP . . O A DT B-NP later JJ I-NP result NN I-NP of IN B-PP inhibition NN B-NP of IN B-PP this DT B-NP activation NN I-NP pathway NN I-NP by IN B-PP p21(ras) NN B-NP was VBD B-VP down-regulation NN B-NP of IN B-PP the DT B-NP activity NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP AP-1 NN I-NP and CC O subsequent JJ B-NP coordinate JJ I-NP reductions NNS I-NP in IN B-PP IL-2 NN B-NP gene NN I-NP expression NN I-NP and CC O protein NN B-NP production NN I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR p2l(ras) NN B-NP is VBZ B-VP an DT B-NP essential JJ I-NP mediator NN I-NP in IN B-PP generating VBG B-VP not RB B-CONJP only RB I-CONJP positive JJ O but CC B-CONJP also RB I-CONJP negative JJ B-NP modulatory JJ I-NP mechanisms NNS I-NP controlling VBG B-VP the DT B-NP competence NN I-NP of IN B-PP T NN B-NP cells NNS I-NP in IN B-PP response NN I-PP to TO I-PP inductive JJ B-NP stimulations NNS I-NP . . O CD14-mediated JJ B-NP signal NN I-NP pathway NN I-NP of IN B-PP Porphyromonas NN B-NP gingivalis NN I-NP lipopolysaccharide NN I-NP in IN B-PP human JJ B-NP gingival JJ I-NP fibroblasts NNS I-NP . . O Lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O induces VBZ B-VP expression NN B-NP of IN B-PP inflammatory JJ B-NP cytokines NNS I-NP in IN B-PP monocytes\/macrophages NNS B-NP via IN B-PP CD14 NN B-NP COMMA COMMA O one CD B-NP of IN B-PP the DT B-NP LPS NN I-NP receptors NNS I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP expressed VBN I-VP predominantly RB B-ADVP in IN B-PP these DT B-NP cells NNS I-NP . . O It PRP B-NP has VBZ B-VP been VBN I-VP demonstrated VBN I-VP that IN B-SBAR Porphyromonas NN B-NP gingivalis NN I-NP LPS NN I-NP ( ( O P-LPS NN B-NP ) ) O also RB B-ADVP is VBZ B-VP able JJ B-ADJP to TO B-VP induce VB I-VP inflammatory JJ B-NP cytokines NNS I-NP in IN B-PP human JJ B-NP gingival JJ I-NP fibroblasts NNS I-NP . . O Therefore RB B-ADVP COMMA COMMA O it PRP B-NP is VBZ B-VP important JJ B-ADJP to TO B-VP determine VB I-VP whether IN B-SBAR CD14 NN B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP gingival JJ B-NP fibroblasts NNS I-NP and CC O to TO B-VP define VB I-VP the DT B-NP P-LPS-mediated JJ I-NP signal-transducing JJ I-NP mechanism NN I-NP in IN B-PP the DT B-NP cells NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP observed VBD B-VP unexpectedly RB B-ADVP by IN B-PP immunohistochemical JJ O COMMA COMMA O Western JJ B-NP blotting NN I-NP ( ( O immunoblotting NN B-NP ) ) O COMMA COMMA O and CC O Northern NN B-NP ( ( I-NP RNA NN I-NP ) ) I-NP blotting NN I-NP assays NNS B-NP that IN B-SBAR CD14 NN B-NP is VBZ B-VP expressed VBN I-VP at IN B-PP high JJ B-NP density NN I-NP in IN B-PP human JJ B-NP gingival JJ I-NP fibroblasts NNS I-NP . . O P-LPS-induced JJ B-NP expression NN I-NP of IN B-PP the DT O monocyte NN B-NP chemoattractant NN I-NP protein NN I-NP 1 CD I-NP ( ( O MCP-1 NN B-NP ) ) O gene NN B-NP in IN B-PP the DT B-NP cells NNS I-NP was VBD B-VP inhibited VBN I-VP markedly RB B-ADVP by IN B-PP treatment NN B-NP with IN B-PP anti-human JJ B-NP CD14 NN I-NP antibody NN I-NP and CC O was VBD B-VP completely RB I-VP inhibited VBN I-VP by IN B-PP herbimycin NN B-NP A NN I-NP COMMA COMMA O a DT B-NP potent JJ I-NP inhibitor NN I-NP of IN B-PP tyrosine NN B-NP kinase NN I-NP . . O The DT B-NP inhibitor NN I-NP also RB B-ADVP dramatically RB B-VP inhibited VBD I-VP monocyte NN B-NP chemotactic JJ I-NP activity NN I-NP of IN B-PP and CC O MCP-1 NN B-NP production NN I-NP by IN B-PP the DT B-NP cells NNS I-NP . . O Furthermore RB B-ADVP COMMA COMMA O P-LPS-induced JJ B-NP expression NN I-NP of IN B-PP the DT B-NP MCP-1 JJ I-NP gene NN I-NP in IN B-PP the DT B-NP cells NNS I-NP also RB B-ADVP was VBD B-VP blocked VBN I-VP by IN B-PP inhibitors NNS B-NP of IN B-PP two CD B-NP transcription NN I-NP factors NNS I-NP COMMA COMMA O i.e. FW B-ADVP COMMA COMMA O curcumin NN B-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP AP-1 NN B-NP COMMA COMMA O and CC O pyrolidine NN B-NP dithiocarbamate NN I-NP COMMA COMMA O an DT B-NP inhibitor NN I-NP of IN B-PP NF-kappaB NN B-NP . . O Both DT B-NP inhibitors NNS I-NP inhibited VBD B-VP monocyte NN B-NP chemotactic JJ I-NP activity NN I-NP in IN B-PP the DT B-NP culture NN I-NP supernatant JJ I-NP of IN B-PP P-LPS-treated JJ B-NP cells NNS I-NP . . O Gel NN B-NP shift NN I-NP mobility NN I-NP assay NN I-NP showed VBD B-VP stimulation NN B-NP of IN B-PP the DT O AP-1 NN B-NP and CC O NF-kappaB NN B-NP contents NNS B-NP in IN B-PP P-LPS-treated JJ B-NP cells NNS I-NP . . O This DT B-NP study NN I-NP is VBZ B-VP the DT B-NP first JJ I-NP to TO B-VP demonstrate VB I-VP the DT B-NP expression NN I-NP of IN B-PP CD14 NN B-NP in IN B-PP human JJ B-NP gingival JJ I-NP fibroblasts NNS I-NP and CC O to TO B-VP show VB I-VP that IN B-SBAR the DT B-NP signal-transducing JJ I-NP pathway NN I-NP of IN B-PP P-LPS NN B-NP in IN B-PP the DT B-NP cells NNS I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP CD14 NN B-NP . . O Tyrosines NNS B-NP 113 CD B-NP COMMA COMMA O 128 CD B-NP COMMA COMMA O and CC O 145 CD B-NP of IN B-PP SLP-76 NN B-NP are VBP B-VP required VBN I-VP for IN B-PP optimal JJ B-NP augmentation NN I-NP of IN B-PP NFAT NN B-NP promoter NN I-NP activity NN I-NP . . O SLP-76 NN B-NP ( ( O SH2 NN B-NP domain NN I-NP leukocyte NN I-NP protein NN I-NP of IN B-PP 76 CD B-NP kDa NN I-NP ) ) O is VBZ B-VP a DT B-NP recently RB I-NP identified VBN I-NP substrate NN I-NP of IN B-PP the DT B-NP TCR-stimulated JJ I-NP protein NN I-NP tyrosine NN I-NP kinases NNS I-NP that WDT B-NP functions VBZ B-VP in IN B-PP the DT B-NP signal NN I-NP transduction NN I-NP cascade NN I-NP linking VBG B-VP the DT B-NP TCR NN I-NP with IN B-PP IL-2 NN B-NP gene NN I-NP expression NN I-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP demonstrate VBP B-VP that IN B-SBAR engagement NN B-NP of IN B-PP the DT B-NP TCR NN I-NP results VBZ B-VP in IN B-PP tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP SLP-76 NN B-NP in IN B-PP its PRP$ B-NP amino-terminal JJ I-NP acidic JJ I-NP region NN I-NP . . O Two CD B-NP tyrosines NNS I-NP ( ( O Y113 NN B-NP and CC O Y128 NN B-NP ) ) O fall VBP B-VP within IN B-PP an DT B-NP identical JJ I-NP five CD I-NP amino-acid JJ I-NP motif NN I-NP and CC O are VBP B-VP shown VBN I-VP to TO B-VP be VB I-VP phosphorylated VBN I-VP upon IN B-PP TCR NN B-NP ligation NN I-NP . . O Although IN B-SBAR mutation NN B-NP of IN B-PP either CC O Y113 NN B-NP and CC O Y128 NN B-NP has VBZ B-VP a DT B-NP minimal JJ I-NP effect NN I-NP on IN B-PP SLP-76 NN B-NP function NN I-NP COMMA COMMA O mutation NN B-NP of IN B-PP both DT B-NP residues NNS I-NP decreases VBZ B-VP significantly RB B-ADVP the DT B-NP ability NN I-NP of IN B-PP SLP-76 NN B-NP to TO B-VP promote VB I-VP T NN B-NP cell NN I-NP activation NN I-NP . . O A DT B-NP third JJ I-NP tyrosine NN I-NP within IN B-PP the DT B-NP amino-terminal JJ I-NP region NN I-NP ( ( O Y145 NN B-NP ) ) O appears VBZ B-VP to TO I-VP be VB I-VP the DT B-NP most RBS I-NP important JJ I-NP for IN B-PP optimal JJ B-NP SLP-76 NN I-NP function NN I-NP COMMA COMMA O as IN B-SBAR altering VBG B-VP it PRP B-NP alone RB B-ADVP to TO B-PP phenylalanine NN B-NP has VBZ B-VP a DT B-NP potent JJ I-NP impact NN I-NP on IN B-PP SLP-76 NN B-NP augmentation NN I-NP of IN B-PP NFAT NN B-NP promoter NN I-NP activity NN I-NP . . O The DT B-NP catalytic JJ I-NP domain NN I-NP of IN B-PP pp56(lck) NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP its PRP$ B-NP regulatory JJ I-NP domain NN I-NP COMMA COMMA O is VBZ B-VP sufficient JJ B-ADJP for IN B-PP inducing VBG B-VP IL-2 NN B-NP production NN I-NP . . O The DT B-NP lymphoid JJ I-NP src NN I-NP kinase NN I-NP pp56(lck) NN I-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP be VB I-VP essential JJ B-ADJP for IN B-PP the DT B-NP induction NN I-NP of IN B-PP different JJ B-NP T NN I-NP lymphocyte NN I-NP responses NNS I-NP COMMA COMMA O including VBG B-PP CD4-mediated JJ B-NP enhancement NN I-NP of IN B-PP Ag-induced JJ B-NP T NN I-NP cell NN I-NP activation NN I-NP COMMA COMMA O early JJ B-NP T NN I-NP cell NN I-NP differentiation NN I-NP COMMA COMMA O induction NN B-NP of IN B-PP IL-2 NN B-NP production NN I-NP COMMA COMMA O and CC O cytotoxicity NN B-NP . . O It PRP B-NP is VBZ B-VP assumed VBN I-VP that IN B-SBAR pp56(lck) NN B-NP acts VBZ B-VP on IN B-PP these DT B-NP processes NNS I-NP by IN B-PP phosphorylating VBG B-VP substrates NNS B-NP . . O However RB B-ADVP COMMA COMMA O it PRP B-NP has VBZ B-VP been VBN I-VP recently RB I-VP reported VBN I-VP that IN B-SBAR the DT B-NP NH2 NN I-NP regulatory JJ I-NP domain NN I-NP is VBZ B-VP sufficient JJ B-ADJP to TO B-VP mediate VB I-VP CD4 NN B-NP accessory JJ I-NP function NN I-NP . . O In IN B-PP this DT B-NP report NN I-NP we PRP B-NP address VBP B-VP the DT B-NP contribution NN I-NP of IN B-PP the DT B-NP regulatory JJ I-NP and CC I-NP catalytic JJ I-NP domains NNS I-NP of IN B-PP pp56(lck) NN B-NP to TO B-PP another DT B-NP function NN I-NP of IN B-PP this DT B-NP enzyme NN I-NP independent JJ B-ADJP of IN B-PP CD4 NN B-NP : : O TCR-induced JJ B-NP IL-2 NN I-NP production NN I-NP . . O Two CD B-NP pp56(lck) NN I-NP mutants NNS I-NP lacking VBG B-VP either CC O the DT B-NP entire JJ I-NP catalytic JJ I-NP domain NN I-NP or CC O the DT B-NP entire JJ I-NP NH2 NN I-NP regulatory JJ I-NP domain NN I-NP were VBD B-VP generated VBN I-VP COMMA COMMA O and CC O their PRP$ B-NP abilities NNS I-NP to TO B-VP trigger VB I-VP transactivation NN B-NP of IN B-PP the DT O TCR-regulated JJ O nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP ( ( O NF-AT NN B-NP ) ) O region NN B-NP of IN B-PP the DT B-NP IL-2 NN I-NP promoter NN I-NP were VBD B-VP compared VBN I-VP . . O Only RB B-NP the DT B-NP catalytic JJ I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP the DT B-NP NH2 NN I-NP regulatory JJ I-NP COMMA COMMA O domain NN B-NP of IN B-PP pp56(lck) NN B-NP was VBD B-VP able JJ B-ADJP to TO B-VP induce VB I-VP NF-AT NN B-NP region NN I-NP transactivation NN I-NP on IN B-PP its PRP$ B-NP own JJ I-NP and CC O to TO B-VP cooperate VB I-VP with IN B-PP other JJ B-NP intracellular JJ I-NP signals NNS I-NP to TO B-VP trigger VB I-VP this DT B-NP response NN I-NP . . O Moreover RB B-ADVP COMMA COMMA O the DT B-NP catalytic JJ I-NP domain NN I-NP of IN B-PP pp56(lck) NN B-NP was VBD B-VP able JJ B-ADJP to TO B-VP induce VB I-VP IL-2 NN B-NP cytokine NN I-NP production NN I-NP to TO B-PP an DT B-NP extent NN I-NP similar JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP wild-type JJ B-NP pp56(lck) NN I-NP . . O We PRP B-NP conclude VBP B-VP that IN B-SBAR different JJ B-NP domains NNS I-NP of IN B-PP the DT B-NP pp56(lck) NN I-NP molecule NN I-NP contribute VBP B-VP to TO I-VP regulate VB I-VP distinct JJ B-NP biologic JJ I-NP functions NNS I-NP . . O In IN B-PP fact NN B-NP COMMA COMMA O while IN B-SBAR the DT B-NP NH2 NN I-NP regulatory JJ I-NP domain NN I-NP is VBZ B-VP sufficient JJ B-ADJP to TO B-VP mediate VB I-VP CD4 NN B-NP accessory JJ I-NP function NN I-NP COMMA COMMA O we PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP catalytic JJ I-NP domain NN I-NP of IN B-PP pp56(lck) NN B-NP is VBZ B-VP sufficient JJ B-ADJP for IN B-PP induction NN B-NP of IN B-PP IL-2 NN B-NP production NN I-NP COMMA COMMA O mimicking VBG B-VP TCR NN B-NP ligation NN I-NP . . O Isolation NN B-NP and CC O characterization NN B-NP of IN B-PP murine JJ B-NP fra-1 NN I-NP : : O induction NN B-NP mediated VBN B-VP by IN B-PP CD40 NN B-NP and CC O surface NN B-NP Ig NN I-NP is VBZ B-VP protein NN B-NP kinase NN I-NP C NN I-NP dependent JJ B-ADJP . . O The DT B-NP murine JJ I-NP fra-1 NN I-NP gene NN I-NP COMMA COMMA O encoding VBG B-VP Fos-related JJ B-NP Ag NN I-NP 1 CD I-NP COMMA COMMA O was VBD B-VP isolated VBN I-VP from IN B-PP a DT B-NP splenic JJ I-NP cDNA NN I-NP library NN I-NP and CC O sequenced VBN B-VP . . O Murine JJ B-NP fra-1 NN I-NP was VBD B-VP highly RB B-ADJP homologous JJ I-ADJP to TO B-PP rat NN B-NP and CC O human JJ B-ADJP fra-1 NN B-NP . . O Oligonucleotide NN B-NP primers NNS I-NP based VBN B-PP on IN B-PP the DT B-NP murine JJ I-NP sequence NN I-NP were VBD B-VP used VBN I-VP to TO B-VP construct VB I-VP a DT B-NP quantitative JJ I-NP reverse NN I-NP transcription-PCR NN I-NP assay NN I-NP for IN B-PP gene NN B-NP expression NN I-NP . . O B NN B-NP lymphocyte NN I-NP stimulation NN I-NP via IN B-PP both CC O CD40 NN B-NP and CC O surface NN B-NP Ig NN I-NP ( ( O sIg NN B-NP ) ) O receptors NNS B-NP substantially RB B-ADVP induced VBD B-VP fra-1 NN B-NP expression NN I-NP COMMA COMMA O and CC O for IN B-PP both DT B-NP receptors NNS I-NP COMMA COMMA O induction NN B-NP was VBD B-VP protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O dependent JJ B-ADJP . . O This DT B-NP contrasts VBZ B-VP with IN B-PP induction NN B-NP of IN B-PP c-fos NN B-NP by IN B-PP both CC O CD40 NN B-NP and CC O sIg NN B-NP COMMA COMMA O which WDT B-NP is VBZ B-VP PKC NN B-ADJP independent JJ I-ADJP and CC O indicates VBZ B-VP that IN B-SBAR CD40 NN B-NP is VBZ B-VP capable JJ B-ADJP of IN B-PP signaling VBG B-VP through IN B-PP PKC NN B-NP or CC O a DT B-NP closely RB I-NP related JJ I-NP kinase NN I-NP . . O Induction NN B-NP of IN B-PP fra-1 NN B-NP following VBG B-PP engagement NN B-NP of IN B-PP CD40 NN B-NP did VBD B-VP not RB I-VP require VB I-VP protein NN B-NP synthesis NN I-NP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR the DT B-NP PKC-dependent JJ I-NP linkage NN I-NP between IN B-PP CD40 NN B-NP and CC O fra-1 NN B-NP is VBZ B-VP direct JJ B-ADJP . . O CD40-mediated JJ B-NP fra-1 NN I-NP induction NN I-NP did VBD B-VP require VB I-VP tyrosine NN B-NP kinase NN I-NP activity NN I-NP . . O These DT B-NP results NNS I-NP demonstrate VBP B-VP that IN B-SBAR CD40 NN B-NP COMMA COMMA O like IN B-PP sIg NN B-NP COMMA COMMA O may MD B-VP employ VB I-VP PKC NN B-NP in IN B-PP producing VBG B-VP select JJ B-NP outcomes NNS I-NP COMMA COMMA O that IN B-SBAR individual JJ B-NP B NN I-NP cell NN I-NP receptors NNS I-NP may MD B-VP signal VB I-VP downstream JJ B-NP events NNS I-NP via IN B-PP both CC B-NP PKC-dependent JJ I-NP and CC I-NP PKC-independent JJ I-NP pathways NNS I-NP COMMA COMMA O and CC O that IN B-SBAR multiple JJ B-NP signal NN I-NP transduction NN I-NP pathways NNS I-NP may MD B-VP be VB I-VP used VBN I-VP to TO B-VP activate VB I-VP the DT B-NP expression NN I-NP of IN B-PP closely RB B-NP related JJ I-NP genes NNS I-NP . . O Apoptosis NN B-NP signaling NN I-NP pathways NNS I-NP in IN B-PP normal JJ B-NP T NN I-NP cells NNS I-NP : : O differential JJ B-NP activity NN I-NP of IN B-PP Bcl-2 NN B-NP and CC O IL-1beta-converting JJ B-NP enzyme NN I-NP family NN I-NP protease NN I-NP inhibitors NNS I-NP on IN B-PP glucocorticoid- NN B-NP and CC O Fas-mediated JJ B-ADJP cytotoxicity NN B-NP . . O Fas-mediated JJ B-NP apoptosis NN I-NP plays VBZ B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP regulating VBG B-VP the DT B-NP immune JJ I-NP response NN I-NP in IN B-PP peripheral JJ B-NP T NN I-NP cells NNS I-NP . . O Restimulation NN B-NP of IN B-PP T NN B-NP cell NN I-NP blasts NNS I-NP up-regulates VBZ B-VP Fas NN B-NP and CC O Fas NN B-NP ligand NN I-NP expression NN I-NP COMMA COMMA O with IN B-PP subsequent JJ B-NP interaction NN I-NP leading VBG B-VP to TO B-PP cell NN B-NP death NN I-NP . . O Overexpression NN B-NP of IN B-PP Bcl-2 NN B-NP in IN B-PP tumor NN B-NP cells NNS I-NP blocks VBZ B-VP apoptosis NN B-NP induced VBN B-VP by IN B-PP many JJ B-NP stimuli NNS I-NP COMMA COMMA O but CC O inhibition NN B-NP of IN B-PP Fas-mediated JJ B-NP killing NN I-NP has VBZ B-VP not RB I-VP been VBN I-VP consistently RB I-VP observed VBN I-VP . . O To TO B-VP examine VB I-VP the DT B-NP behavior NN I-NP of IN B-PP Bcl-2 NN B-NP in IN B-PP normal JJ B-NP cells NNS I-NP COMMA COMMA O T NN B-NP cell NN I-NP blasts NNS I-NP were VBD B-VP transiently RB I-VP transfected VBN I-VP with IN B-PP Bcl-2 NN B-NP and CC O related JJ B-NP gene NN I-NP products NNS I-NP to TO B-VP determine VB I-VP the DT B-NP effect NN I-NP on IN B-PP apoptotic JJ B-NP signaling NN I-NP . . O Transient JJ B-NP overexpression NN I-NP of IN B-PP Bcl-2 NN B-NP in IN B-PP mouse NN B-NP and CC O human JJ B-ADJP T NN B-NP cell NN I-NP blasts NNS I-NP did VBD B-VP not RB I-VP block VB I-VP Fas-mediated JJ B-NP apoptosis NN I-NP COMMA COMMA O whereas IN O etoposide- NN B-NP and CC O glucocorticoid-induced JJ B-ADJP cytotoxicity NN B-NP was VBD B-VP potently RB I-VP inhibited VBN I-VP . . O Expression NN B-NP of IN B-PP Bcl-xL NN B-NP and CC O adenovirus NN B-NP E1B NN I-NP 19K NN I-NP did VBD B-VP not RB I-VP interfere VB I-VP with IN B-PP anti-Fas JJ B-NP killing NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O interleukin-1beta-converting JJ B-NP enzyme NN I-NP family NN I-NP protease NN I-NP inhibitors NNS I-NP Ac-DEVD-CHO NN B-NP and CC O CrmA NN B-NP blocked VBD B-VP Fas-mediated JJ B-NP apoptosis NN I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR peripheral JJ B-NP T NN I-NP cells NNS I-NP use VBP B-VP distinct JJ B-NP apoptosis NN I-NP signaling NN I-NP pathways NNS I-NP with IN B-PP differential JJ B-NP sensitivity NN I-NP to TO B-PP Bcl-2 NN B-NP and CC O interleukin-1beta-converting JJ B-NP enzyme NN I-NP family NN I-NP protease NN I-NP inhibitors NNS I-NP . . O Since IN B-SBAR T NN B-NP cells NNS I-NP normally RB B-ADVP express VBP B-VP Bcl-2 NN B-NP and CC O Bcl-xL NN B-NP following VBG B-PP activation NN B-NP COMMA COMMA O their PRP$ B-NP inability NN I-NP to TO B-VP block VB I-VP Fas-mediated JJ B-NP apoptosis NN I-NP may MD B-VP allow VB I-VP for IN B-PP the DT B-NP elimination NN I-NP of IN B-PP self-reactive JJ B-NP cells NNS I-NP and CC O the DT B-NP appropriate JJ I-NP regulation NN I-NP of IN B-PP immune JJ B-NP responses NNS I-NP . . O Comparative JJ B-NP analysis NN I-NP identifies VBZ B-VP conserved VBN B-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP receptor-associated JJ I-NP factor NN I-NP 3 CD I-NP binding NN I-NP sites NNS I-NP in IN B-PP the DT B-NP human JJ I-NP and CC I-NP simian JJ I-NP Epstein-Barr JJ I-NP virus NN I-NP oncogene NN I-NP LMP1 NN I-NP . . O Nonhuman JJ B-NP primates NNS I-NP are VBP B-VP naturally RB I-VP infected VBN I-VP with IN B-PP a DT B-NP B-lymphotropic JJ I-NP herpesvirus NN I-NP closely RB B-ADJP related JJ I-ADJP to TO B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O . . O These DT B-NP simian JJ I-NP EBV NNS I-NP share VBP B-VP considerable JJ B-NP genetic JJ I-NP COMMA COMMA I-NP biologic JJ I-NP COMMA COMMA I-NP and CC I-NP epidemiologic JJ I-NP features NNS I-NP with IN B-PP human JJ B-NP EBV NN I-NP COMMA COMMA O including VBG B-PP virus-induced JJ B-NP tumorigenesis NN I-NP . . O However RB B-ADVP COMMA COMMA O latent JJ B-NP COMMA COMMA I-NP transformation-associated JJ I-NP viral JJ I-NP genes NNS I-NP demonstrate VBP B-VP marked JJ B-NP sequence NN I-NP divergence NN I-NP among IN B-PP species NNS B-NP despite IN B-PP the DT B-NP conserved VBN I-NP functions NNS I-NP . . O We PRP B-NP have VBP B-VP cloned VBN I-VP the DT O latent JJ B-NP membrane NN I-NP protein NN I-NP 1 CD I-NP ( ( O LMP1 NN B-NP ) ) O homologs NNS B-NP from IN B-PP the DT B-NP simian JJ I-NP EBV NN I-NP naturally RB B-VP infecting VBG I-VP baboons NNS B-NP ( ( O cercopithicine NN B-NP herpesvirus NN I-NP 12 CD I-NP COMMA COMMA O herpesvirus NN B-NP papio NN I-NP ) ) O and CC O rhesus NN B-NP monkeys NNS I-NP ( ( O cercopithicine NN B-NP herpesvirus NN I-NP 15 CD I-NP ) ) O for IN B-PP a DT B-NP comparative JJ I-NP study NN I-NP with IN B-PP the DT B-NP human JJ I-NP EBV NN I-NP oncogene NN I-NP . . O The DT B-NP transmembrane NN I-NP domains NNS I-NP are VBP B-VP well RB I-VP conserved VBN I-VP COMMA COMMA O but CC O there EX B-NP is VBZ B-VP striking JJ B-NP sequence NN I-NP divergence NN I-NP of IN B-PP the DT B-NP carboxy-terminal JJ I-NP cytoplasmic JJ I-NP domain NN I-NP essential JJ B-ADJP for IN B-PP B-cell NN B-NP immortalization NN I-NP and CC O interaction NN B-NP with IN B-PP the DT B-NP tumor NN I-NP necrosis NN I-NP factor NN I-NP receptor NN I-NP signaling NN I-NP pathway NN I-NP . . O Nevertheless RB B-ADVP COMMA COMMA O the DT B-NP simian JJ I-NP EBV NN I-NP LMP1s NNS I-NP retain VBP B-VP most JJS B-NP functions NNS I-NP in IN B-PP common NN I-PP with IN I-PP EBV NN B-NP LMP1 NN I-NP COMMA COMMA O including VBG B-PP the DT B-NP ability NN I-NP to TO B-VP induce VB I-VP NF-(kappa)B NN B-NP activity NN I-NP in IN B-PP human JJ B-NP cells NNS I-NP COMMA COMMA O to TO B-VP bind VB I-VP the DT B-NP tumor NN I-NP necrosis NN I-NP factor-associated JJ I-NP factor NN I-NP 3 CD I-NP ( ( O TRAF3 NN B-NP ) ) O in FW B-ADVP vitro FW I-ADVP COMMA COMMA O and CC O to TO B-VP induce VB I-VP expression NN B-NP of IN B-PP tumor NN B-NP necrosis NN I-NP factor-responsive JJ I-NP genes NNS I-NP COMMA COMMA O such JJ B-PP as IN I-PP ICAM1 NN B-NP COMMA COMMA O in IN B-PP human JJ B-NP B NN I-NP lymphocytes NNS I-NP . . O Multiple JJ B-NP TRAF3 NN I-NP binding NN I-NP sites NNS I-NP containing VBG B-VP a DT B-NP PXQXT\/S NN I-NP core NN I-NP sequence NN I-NP can MD B-VP be VB I-VP identified VBN I-VP in IN B-PP the DT B-NP simian JJ I-NP EBV NN I-NP LMP1s NNS I-NP by IN B-PP an DT B-NP in FW I-NP vitro FW I-NP binding NN I-NP assay NN I-NP . . O A DT B-NP PXQXT\/S-containing JJ I-NP sequence NN I-NP is VBZ B-VP also RB B-ADVP present JJ B-ADJP in IN B-PP the DT B-NP cytoplasmic JJ I-NP domain NN I-NP of IN B-PP the DT O Hodgkin NN B-NP 's POS B-NP disease NN I-NP marker NN I-NP COMMA COMMA O CD30 NN B-NP COMMA COMMA O and CC O binds VBZ B-VP TRAF3 NN B-NP in FW B-ADVP vitro FW I-ADVP . . O The DT B-NP last JJ I-NP 13 CD I-NP amino NN I-NP acids NNS I-NP containing VBG B-VP a DT B-NP PXQXT\/S NN I-NP sequence NN I-NP are VBP B-VP highly RB I-VP conserved VBN I-VP in IN B-PP human JJ B-NP and CC I-NP simian JJ I-NP EBV NN I-NP LMP1 NN I-NP but CC O do VBP B-VP not RB I-VP bind VB I-VP TRAF3 NN B-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP distinct JJ I-NP role NN I-NP for IN B-PP this DT B-NP conserved VBN I-NP region NN I-NP of IN B-PP LMP1 NN B-NP . . O The DT B-NP conserved VBN I-NP TRAF3 NN I-NP binding NN I-NP sites NNS I-NP in IN B-PP LMP1 NN B-NP and CC O the DT O CD30 NN O Hodgkin NN B-NP 's POS B-NP disease NN I-NP marker NN I-NP provides VBZ B-VP further JJ B-NP evidence NN I-NP that IN B-SBAR a DT B-NP TRAF3-mediated JJ I-NP signal NN I-NP transduction NN I-NP pathway NN I-NP may MD B-VP be VB I-VP important JJ B-ADJP in IN B-PP malignant JJ B-NP transformation NN I-NP . . O Rapid JJ B-NP shuttling NN I-NP of IN B-PP NF-AT NN B-NP in IN B-PP discrimination NN B-NP of IN B-PP Ca2+ NN B-NP signals NNS I-NP and CC O immunosuppression NN B-NP . . O Cells NNS B-NP need VBP B-VP to TO I-VP distinguish VB I-VP between IN B-PP transient JJ B-NP Ca2+ NN I-NP signals NNS I-NP that WDT B-NP induce VBP B-VP events NNS B-NP such JJ B-PP as IN I-PP muscle NN B-NP contraction NN I-NP COMMA COMMA O secretion NN B-NP COMMA COMMA O adhesion NN B-NP and CC O synaptic JJ B-NP transmission NN I-NP COMMA COMMA O and CC O sustained JJ B-NP Ca2+ NN I-NP signals NNS I-NP that WDT B-NP are VBP B-VP involved VBN I-VP in IN B-PP cell NN B-NP proliferation NN B-NP and CC O differentiation NN B-NP . . O The DT B-NP latter JJ I-NP class NN I-NP of IN B-PP events NNS B-NP is VBZ B-VP blocked VBN I-VP in IN B-PP lymphocytes NNS B-NP by IN B-PP the DT B-NP immunosuppressive JJ I-NP drugs NNS I-NP cyclosporin NN B-NP A NN I-NP and CC O FK506 NN B-NP COMMA COMMA O which WDT B-NP inhibit VBP B-VP calcineurin NN B-NP COMMA COMMA O a DT B-NP Ca2+-activated JJ I-NP serine\/threonine NN I-NP phosphatase NN I-NP necessary JJ B-ADJP for IN B-PP the DT B-NP nuclear JJ I-NP import NN I-NP of IN B-PP NF-AT NN B-NP transcription NN I-NP factors NNS I-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR sustained JJ B-NP high JJ I-NP concentrations NNS I-NP of IN B-PP Ca2+ NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP transient JJ B-NP pulses NNS I-NP COMMA COMMA O are VBP B-VP required VBN I-VP to TO B-VP maintain VB I-VP NF-AT NN B-NP transcription NN I-NP factors NNS I-NP in IN B-PP the DT B-NP nucleus NN I-NP COMMA COMMA O where WRB B-ADVP they PRP B-NP participate VBP B-VP in IN B-PP Ca2+-dependent JJ B-NP induction NN I-NP of IN B-PP genes NNS B-NP required VBN B-VP for IN B-PP lymphocyte NN B-NP activation NN B-NP and CC O proliferation NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O overexpression NN B-NP and CC O constitutive JJ B-NP nuclear JJ I-NP localization NN I-NP of IN B-PP NF-AT NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP Jun NN B-NP COMMA COMMA O Fos NN B-NP COMMA COMMA O NF-kappaB NN B-NP COMMA COMMA O Oct NN B-NP or CC O Ets NN B-NP family NN B-NP members NNS I-NP COMMA COMMA O renders VBZ B-VP the DT B-NP interleukin-2 NN I-NP enhancer NN I-NP in IN B-PP Jurkat NN B-NP T NN I-NP lymphocytes NNS I-NP resistant JJ B-ADJP to TO B-PP FK506 NN B-NP and CC O cyclosporin NN B-NP A NN I-NP . . O Thus RB B-ADVP a DT B-NP primary JJ I-NP effect NN I-NP of IN B-PP these DT B-NP immunosuppressive JJ I-NP reagents NNS I-NP is VBZ B-VP to TO B-VP control VB I-VP the DT B-NP subcellular JJ I-NP localization NN I-NP of IN B-PP the DT B-NP NF-AT NN I-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP . . O Interferons NNS B-NP induce VBP B-VP normal JJ B-NP and CC I-NP aberrant JJ I-NP retinoic-acid NN I-NP receptors NNS I-NP type NN I-NP alpha NN I-NP in IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP cells NNS I-NP : : O potentiation NN B-NP of IN B-PP the DT B-NP induction NN I-NP of IN B-PP retinoid-dependent JJ B-NP differentiation NN I-NP markers NNS I-NP . . O Treatment NN B-NP of IN B-PP the DT O acute JJ O promyelocytic JJ O ( ( O APL NN B-ADJP ) ) O cell NN B-NP line NN I-NP NB4 NN I-NP with IN B-PP interferon NN B-NP alpha NN I-NP ( ( O IFN(alpha) NN B-NP ) ) O COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP IFN(beta) NN B-NP and CC O gamma NN B-NP COMMA COMMA O results VBZ B-VP in IN B-PP an DT B-NP increased VBN I-NP expression NN I-NP of IN B-PP the DT B-NP transcripts NNS I-NP coding VBG B-VP for IN B-PP retinoic-acid JJ B-NP receptor NN I-NP type NN I-NP alpha NN I-NP ( ( O RAR(alpha) NN B-NP ) ) O and CC O the DT B-NP leukemia-specific JJ I-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP PML-RAR NN I-NP . . O Transcriptional JJ B-NP induction NN I-NP of IN B-PP the DT O RAR(alpha) NN B-NP and CC O PML-RAR NN B-NP mRNAs NNS B-NP is VBZ B-VP rapid JJ B-ADJP and CC O it PRP B-NP is VBZ B-VP parallelled VBN I-VP by IN B-PP an DT B-NP increase NN I-NP in IN B-PP the DT B-NP corresponding JJ I-NP proteins NNS I-NP . . O Up-regulation NN B-NP of IN B-PP RAR(alpha) NN B-NP and CC O PML-RAR NN B-NP gene NN B-NP expression NN I-NP by IN B-PP IFN(alpha) NN B-NP is VBZ B-VP accompanied VBN I-VP by IN B-PP a DT B-NP strong JJ I-NP potentiation NN I-NP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP 2 CD B-NP retinoid-dependent JJ I-NP granulocytic JJ I-NP markers NNS I-NP COMMA COMMA B-NP i.e. FW I-NP COMMA COMMA O granulocyte-colony-stimulating JJ B-NP factor NN I-NP receptor NN I-NP mRNA NN I-NP and CC O leukocyte NN B-NP alkaline NN I-NP phosphatase NN I-NP . . O However RB B-ADVP COMMA COMMA O IFN(alpha) NN B-NP does VBZ B-VP not RB I-VP have VB I-VP any DT B-NP effects NNS I-NP on IN B-PP the DT B-NP retinoid-dependent JJ I-NP regulation NN I-NP of IN B-PP the DT B-NP myeloid JJ I-NP surface NN I-NP markers NNS I-NP CD11b NN B-NP and CC O CD33 NN B-NP . . O The DT B-NP IFN-dependent JJ I-NP increase NN I-NP in IN B-PP RAR(alpha) NN B-NP levels NNS I-NP and CC O the DT B-NP enhancing JJ I-NP effect NN I-NP of IN B-PP the DT B-NP cytokine NN I-NP on IN B-PP retinoid-dependent JJ B-NP granulocytic JJ I-NP markers NNS I-NP expression NN I-NP may MD B-VP be VB I-VP a DT B-NP characteristic NN I-NP of IN B-PP PML-RAR NN B-NP positive JJ I-NP cells NNS I-NP COMMA COMMA O since IN B-SBAR the DT B-NP phenomena NNS I-NP are VBP B-VP not RB I-VP observed VBN I-VP in IN B-PP HL-60 NN B-NP promyelocytes NNS I-NP . . O Interferons NNS B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP retinoids NNS B-NP inhibit VBP B-VP the DT B-NP growth NN I-NP of IN B-PP NB4 NN B-NP cells NNS I-NP COMMA COMMA O although IN B-SBAR the DT B-NP 2 CD I-NP classes NNS I-NP of IN B-PP compounds NNS B-NP do VBP B-VP not RB I-VP significantly RB I-VP interact VBP I-VP in IN B-PP terms NNS I-PP of IN I-PP anti-proliferative JJ B-NP activity NN I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP the DT B-NP possible JJ I-NP use NN I-NP of IN B-PP combinations NNS B-NP between IN B-PP IFNs NNS B-NP and CC O retinoic JJ B-NP acid NN I-NP in IN B-PP the DT B-NP cyto-differentiating JJ I-NP treatment NN I-NP of IN B-PP APL NN B-NP patients NNS I-NP . . O Susceptibility NN B-NP to TO B-PP natural JJ B-NP killer NN I-NP cells NNS I-NP and CC O down JJ B-NP regulation NN I-NP of IN B-PP MHC NN B-NP class NN I-NP I CD I-NP expression NN I-NP in IN B-PP adenovirus NN B-NP 12 CD I-NP transformed VBN I-NP cells NNS I-NP are VBP B-VP regulated VBN I-VP by IN B-PP different JJ B-NP E1A NN I-NP domains NNS I-NP . . O All DT B-NP human JJ I-NP adenoviruses NNS I-NP transform VBP B-VP rodent JJ B-NP cells NNS I-NP in FW B-ADVP vitro FW I-ADVP COMMA COMMA O but CC O only RB B-NP cells NNS I-NP transformed VBN B-VP by IN B-PP serotypes NNS B-NP belonging VBG B-VP to TO B-PP subgroups NNS B-NP A NN B-NP ( ( O Ad12 NN B-NP ) ) O and CC O B NN B-NP ( ( O Ad3 NN B-NP ) ) O are VBP B-VP tumorigenic JJ B-ADJP for IN B-PP immunocompetent JJ B-NP animals NNS I-NP . . O In IN B-PP these DT B-NP cells NNS I-NP COMMA COMMA O the DT B-NP expression NN I-NP of IN B-PP MHC-class NN B-NP I CD I-NP antigens NNS I-NP is VBZ B-VP repressed VBN I-VP and CC O might MD B-VP allow VB I-VP them PRP B-NP to TO B-VP escape VB I-VP from IN B-PP recognition NN B-NP by IN B-PP cytotoxic JJ B-NP T NN I-NP lymphocytes NNS I-NP ( ( O CTL NN B-NP ) ) O and CC O to TO B-VP develop VB I-VP in IN B-PP tumor NN B-NP . . O Furthermore RB B-ADVP COMMA COMMA O these DT B-NP cell NN I-NP lines NNS I-NP appear VBP B-VP resistant JJ B-ADJP to TO B-PP lysis NN B-NP by IN B-PP natural JJ B-NP killer NN I-NP ( ( O NK NN B-NP ) ) O cells NNS B-NP . . O To TO B-VP determine VB I-VP the DT B-NP E1A NN I-NP domain NN I-NP ( ( I-NP s NNS I-NP ) ) O responsible JJ B-ADJP for IN B-PP these DT B-NP properties NNS I-NP several JJ B-NP cell NN I-NP lines NNS I-NP were VBD B-VP created VBN I-VP by IN B-PP transforming VBG B-NP baby NN B-NP rat NN I-NP kidney NN I-NP ( ( O BRK NN B-NP ) ) O cells NNS B-NP with IN B-PP a DT B-NP set NN I-NP of IN B-PP plasmids NNS B-NP expressing VBG B-VP different JJ B-NP Ad2\/Ad12 NN I-NP hybrid NN I-NP E1A NN I-NP gene NN I-NP products NNS I-NP . . O The DT B-NP MHC NN I-NP class NN I-NP 1 CD I-NP gene NN I-NP expression NN I-NP was VBD B-VP inhibited VBN I-VP in IN B-PP cells NNS B-NP expressing VBG B-VP the DT B-NP Ad12 NN I-NP 13S NN I-NP mRNA NN I-NP product NN I-NP and CC B-PP in IN B-PP cells NNS B-NP transformed VBN B-VP with IN B-PP Ad2\/Ad12 NN B-NP hybrid NN I-NP E1A NN I-NP gene NN I-NP product NN I-NP harboring VBG B-VP the DT B-NP C-terminal JJ I-NP part NN I-NP of IN B-PP the DT O conserved VBN B-NP region NN I-NP ( ( O CR NN B-NP ) ) O 3 CD B-NP of IN B-PP Ad12 NN B-NP . . O Susceptibility NN B-NP of IN B-PP these DT B-NP transformed VBN I-NP cell NN I-NP lines NNS I-NP to TO B-PP NK NN B-NP cells NNS I-NP was VBD B-VP determined VBN I-VP by IN B-PP cytolytic JJ B-NP assays NNS I-NP . . O The DT B-NP results NNS I-NP obtained VBD B-VP suggest VBP B-VP that IN B-SBAR two CD B-NP Ad12 NN I-NP E1A NN I-NP domains NNS I-NP are VBP B-VP required VBN I-VP to TO B-VP induce VB I-VP resistance NN B-NP of IN B-PP the DT B-NP cell NN I-NP lines NNS I-NP to TO B-PP NK NN B-NP cells NNS I-NP . . O An DT B-NP IL-2 NN I-NP response NN I-NP element NN I-NP in IN B-PP the DT B-NP human JJ I-NP IL-2 NN I-NP receptor NN I-NP alpha NN I-NP chain NN I-NP promoter NN I-NP is VBZ B-VP a DT B-NP composite JJ I-NP element NN I-NP that WDT B-NP binds VBZ B-VP Stat5 NN B-NP COMMA COMMA O Elf-1 NN B-NP COMMA COMMA O HMG-I(Y) NN B-NP and CC O a DT B-NP GATA NN I-NP family NN I-NP protein NN I-NP . . O Expression NN B-NP of IN B-PP the DT O human JJ O interleukin-2 NN B-NP ( ( O IL-2 NN B-NP ) ) O receptor NN B-NP alpha NN I-NP chain NN I-NP gene NN I-NP is VBZ B-VP potently RB I-VP upregulated VBN I-VP by IN B-PP its PRP$ B-NP own JJ I-NP ligand NN I-NP COMMA COMMA O IL-2 NN B-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O we PRP B-NP characterize VBP B-VP an DT B-NP essential JJ I-NP upstream JJ I-NP IL-2 NN I-NP response NN I-NP element NN I-NP that WDT B-NP contains VBZ B-VP both CC O consensus NN B-NP and CC O non-consensus JJ B-ADJP GAS NN B-NP motifs NNS I-NP COMMA COMMA O two CD B-NP putative JJ I-NP Ets NN B-NP binding NN I-NP sites NNS I-NP ( ( O EBS NN B-NP ) ) O COMMA COMMA O one CD B-NP of IN B-PP which WDT B-NP overlaps VBZ B-VP the DT B-NP consensus NN I-NP GAS NN I-NP motif NN I-NP COMMA COMMA O and CC O a DT B-NP GATA NN I-NP motif NN I-NP COMMA COMMA O which WDT B-NP overlaps VBZ B-VP the DT B-NP non-consensus JJ I-NP GAS NN I-NP motif NN I-NP . . O We PRP B-NP demonstrate VBP B-VP that IN B-SBAR although IN B-SBAR the DT B-NP individual JJ I-NP components NNS I-NP of IN B-PP this DT B-NP element NN I-NP do VBP B-VP not RB I-VP respond VB I-VP to TO B-PP IL-2 NN B-NP COMMA COMMA O together RB B-ADVP they PRP B-NP form VBP B-VP a DT B-NP composite JJ I-NP element NN I-NP capable JJ B-ADJP of IN B-PP conferring VBG B-VP IL-2 NN B-NP responsiveness NN I-NP to TO B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP . . O Multiple JJ B-NP factors NNS I-NP including VBG B-PP Stat5 NN B-NP COMMA COMMA O Elf-1 NN B-NP COMMA COMMA O HMG-I(Y) NN B-NP and CC O GATA NN B-NP family NN I-NP proteins NNS I-NP bind VBP B-VP to TO B-PP the DT B-NP IL-2 NN I-NP response NN I-NP element NN I-NP and CC O mutation NN B-NP of IN B-PP any DT B-NP one CD I-NP of IN B-PP these DT B-NP binding VBG I-NP sites NNS I-NP diminishes VBZ B-VP the DT B-NP activity NN I-NP of IN B-PP this DT B-NP element NN I-NP . . O An DT B-NP unidentified JJ I-NP Ets NN I-NP family NN I-NP protein NN I-NP binds VBZ B-VP to TO B-PP the DT B-NP EBS NN I-NP overlapping VBG B-VP the DT B-NP consensus NN I-NP GAS NN I-NP motif NN I-NP and CC O appears VBZ B-VP to TO I-VP negatively RB I-VP regulate VB I-VP the DT B-NP human JJ I-NP IL-2R NN I-NP alpha NN I-NP promoter NN I-NP . . O Thus RB B-ADVP COMMA COMMA O IL-2-induced JJ B-NP IL-2R NN I-NP alpha NN I-NP promoter NN I-NP activity NN I-NP requires VBZ B-VP a DT B-NP complex JJ I-NP upstream JJ I-NP element NN I-NP COMMA COMMA O which WDT B-NP appears VBZ B-VP to TO I-VP contain VB I-VP binding VBG B-NP sites NNS I-NP for IN B-PP both CC B-NP positive JJ I-NP and CC I-NP negative JJ I-NP regulatory JJ I-NP factors NNS I-NP . . O Tyrosine NN B-NP kinase NN I-NP and CC O cAMP-dependent JJ B-NP protein NN I-NP kinase NN I-NP activities NNS B-NP in IN B-PP CD40-activated JJ B-NP human JJ I-NP B NN I-NP lymphocytes NNS I-NP . . O In FW B-ADVP vitro FW I-ADVP COMMA COMMA O human JJ B-NP B NN I-NP lymphocytes NNS I-NP undergo VBP B-VP long-term JJ B-NP proliferation NN I-NP when WRB B-ADVP activated VBN B-VP through IN B-PP CD40 NN B-NP COMMA COMMA O a DT B-NP protein NN I-NP expressed VBN B-VP on IN B-PP their PRP$ B-NP cell NN I-NP surface NN I-NP . . O The DT B-NP nature NN I-NP of IN B-PP CD40-dependent JJ B-NP signals NNS I-NP in IN B-PP proliferating VBG B-NP fresh JJ I-NP human JJ I-NP Epstein-Barr JJ I-NP virus-negative JJ I-NP B NN I-NP lymphocytes NNS I-NP is VBZ B-VP currently RB B-ADVP unknown JJ B-ADJP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O a DT B-NP CD40-dependent JJ I-NP B NN I-NP cell NN I-NP culture NN I-NP system NN I-NP was VBD B-VP used VBN I-VP to TO B-VP examine VB I-VP the DT B-NP role NN I-NP of IN B-PP different JJ B-NP signal NN I-NP transduction NN I-NP elements NNS I-NP . . O Protein NN B-NP kinase NN I-NP C NN I-NP ( ( O PKC NN B-NP ) ) O depletion NN B-NP generated VBN B-VP by IN B-PP a DT B-NP long-term JJ I-NP phorbol NN I-NP 12 CD I-NP myristate NN I-NP 13-acetate NN I-NP treatment NN I-NP had VBD B-VP weak JJ B-NP effects NNS I-NP on IN B-PP proliferation NN B-NP . . O Rather RB B-ADVP COMMA COMMA O tyrosine NN B-NP phosphorylation NN I-NP was VBD B-VP shown VBN I-VP to TO I-VP be VB I-VP directly RB I-VP involved VBN I-VP in IN B-PP mediating VBG B-VP CD40-dependent JJ B-NP signals NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT O cAMP-dependent JJ B-NP protein NN I-NP kinase NN I-NP specific JJ B-NP inhibitor NN I-NP H-89 NN I-NP totally RB B-ADVP inhibited VBD B-VP HIV-1 NN B-NP LTR NN I-NP activity NN I-NP at IN B-PP a DT B-NP concentration NN I-NP as RB B-NP low JJ I-NP as IN I-NP 100 CD I-NP nM NN I-NP without IN B-PP affecting VBG B-VP cellular JJ B-NP proliferation NN I-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assay NN I-NP ( ( O EMSA NN B-NP ) ) O and CC O supershift NN B-NP assay NN I-NP using VBG B-VP an DT B-NP NF-kappa NN I-NP B NN I-NP binding NN I-NP sequence NN I-NP from IN B-PP the DT B-NP kappa NN I-NP light JJ I-NP chain NN I-NP as IN B-PP a DT B-NP probe NN I-NP COMMA COMMA O revealed VBD B-VP that IN B-SBAR both CC O p65 NNS B-NP ( ( O RelA NN B-NP ) ) O and CC O c-Rel NN B-NP were VBD B-VP present JJ B-ADJP in IN B-PP CD40-stimulated JJ B-NP B NN I-NP cells NNS I-NP . . O While IN B-SBAR PKC NN B-NP depletion NN I-NP did VBD B-VP not RB I-VP alter VB I-VP the DT B-NP NF-kappa NN I-NP B NN I-NP level NN I-NP COMMA COMMA O treatment NN B-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP with IN B-PP H-89 NN B-NP or CC O herbimycin NN B-NP A NN I-NP provoked VBD B-VP a DT B-NP decrease NN I-NP in IN B-PP the DT B-NP NF-kappa NN I-NP B NN I-NP level NN I-NP . . O These DT B-NP observations NNS I-NP establish VBP B-VP the DT B-NP importance NN I-NP of IN B-PP different JJ B-NP signal NN I-NP transducing NN I-NP pathways NNS I-NP leading VBG B-VP to TO B-PP CD40 NN B-NP activation NN I-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP . . O Active JJ B-NP suppression NN I-NP of IN B-PP the DT B-NP class NN I-NP II CD I-NP transactivator-encoding JJ I-NP AIR-1 NN I-NP locus NN I-NP is VBZ B-VP responsible JJ B-ADJP for IN B-PP the DT B-NP lack NN I-NP of IN B-PP major JJ B-NP histocompatibility NN I-NP complex NN I-NP class NN I-NP II CD I-NP gene NN I-NP expression NN I-NP observed VBN B-VP during IN B-PP differentiation NN B-NP from IN B-PP B NN B-NP cells NNS I-NP to TO B-PP plasma NN B-NP cells NNS I-NP . . O In IN B-PP this DT B-NP study NN I-NP the DT B-NP genetic JJ I-NP control NN I-NP of IN B-PP major JJ B-NP histocompatibility NN I-NP complex NN I-NP ( ( O MHC NN B-NP ) ) O class NN B-NP II CD I-NP gene NN I-NP expression NN I-NP during IN B-PP the DT B-NP transition NN I-NP from IN B-PP B NN B-NP cell NN I-NP to TO B-PP plasma NN B-NP cell NN I-NP has VBZ B-VP been VBN I-VP analyzed VBN I-VP . . O Class NN B-NP II CD I-NP molecules NNS I-NP are VBP B-VP not RB I-VP expressed VBN I-VP in IN B-PP plasma NN B-NP cells NNS I-NP because IN B-PP of IN I-PP an DT B-NP active JJ I-NP suppression NN I-NP resulting VBG B-VP in IN B-PP the DT B-NP abrogation NN I-NP of IN B-PP class NN B-NP II CD I-NP gene NN I-NP transcription NN I-NP . . O We PRP B-NP show VBP B-VP here RB B-ADVP that IN B-SBAR the DT B-NP plasma NN I-NP cell-specific JJ I-NP repressor NN I-NP function NN I-NP COMMA COMMA O designated VBN B-VP SIR NN B-NP ( ( O suppressor NN B-NP of IN B-PP immune JJ B-NP response NN I-NP genes NNS I-NP ) ) O COMMA COMMA O does VBZ B-VP not RB I-VP act VB I-VP directly RB B-ADVP on IN B-PP the DT B-NP transcription NN I-NP of IN B-PP class NN B-NP II CD I-NP genes NNS I-NP COMMA COMMA B-PP but CC I-PP instead RB I-PP on IN B-PP the DT B-NP transcription NN I-NP of IN B-PP the DT B-NP AIR-1 NN I-NP gene NN I-NP COMMA COMMA O whose WP$ B-NP product NN I-NP COMMA COMMA O the DT B-NP class NN I-NP II CD I-NP transactivator NN I-NP ( ( O CIITA NN B-NP ) ) O COMMA COMMA O is VBZ B-VP fundamental JJ B-ADJP for IN B-PP the DT B-NP regulation NN I-NP of IN B-PP the DT B-NP constitutive JJ I-NP and CC I-NP inducible JJ I-NP expression NN I-NP of IN B-PP MHC NN B-NP class NN I-NP II CD I-NP genes NNS I-NP . . O This DT B-NP was VBD B-VP unambiguously RB I-VP demonstrated VBN I-VP by IN B-PP the DT B-NP fact NN I-NP that IN B-SBAR plasmacytoma NN B-NP x NN B-NP B NN B-NP cell NN I-NP hybrids NNS B-NP carrying VBG B-VP an DT B-NP AIR-1 NN I-NP locus NN I-NP derived VBN B-VP from IN B-PP CIITA-expressing JJ B-NP cells NNS I-NP do VBP B-VP not RB I-VP express VB I-VP CIITA-specific JJ B-NP transcripts NNS I-NP . . O Transfection NN B-NP of IN B-PP a DT B-NP cDNA NN I-NP containing VBG B-VP the DT B-NP human JJ I-NP CIITA NN I-NP coding NN I-NP sequence NN I-NP under IN B-PP the DT B-NP control NN I-NP of IN B-PP an DT B-NP heterologous JJ I-NP promoter NN I-NP restores VBZ B-VP expression NN B-NP of IN B-PP human JJ B-NP MHC NN I-NP class NN I-NP II CD I-NP genes NNS I-NP in IN B-PP the DT B-NP hybrids NNS I-NP and CC O is VBZ B-VP responsible JJ B-ADJP for IN B-PP de FW B-NP novo FW I-NP expression NN I-NP of IN B-PP mouse NN B-NP MHC NN I-NP class NN I-NP II CD I-NP genes NNS I-NP in IN B-PP both CC O the DT B-NP mouse NN I-NP plasmacytoma NN I-NP cell NN I-NP line NN I-NP and CC O the DT B-NP hybrids NNS I-NP . . O These DT B-NP results NNS I-NP confirm VBP B-VP and CC O extend VBP B-VP the DT B-NP notion NN I-NP of IN B-PP the DT B-NP functional JJ I-NP conservation NN I-NP of IN B-PP the DT B-NP AIR-1 JJ I-NP gene NN I-NP product NN I-NP across IN B-PP species NNS B-NP barriers NNS I-NP . . O Interestingly RB B-ADVP COMMA COMMA O in IN B-PP CIITA-transfected JJ B-NP cell NN I-NP hybrids NNS I-NP COMMA COMMA O cell NN B-NP surface NN I-NP expression NN I-NP of IN B-PP the DT B-NP human JJ I-NP HLA-DQ NN I-NP heterodimer NN I-NP was VBD B-VP not RB I-VP observed VBN I-VP . . O This DT B-NP result NN I-NP was VBD B-VP not RB O attributable JJ B-ADJP to TO B-PP lack NN B-NP of IN B-PP HLA-DQ NN B-NP alpha NN I-NP or CC O -DQ NN B-NP beta NN B-NP transcription NN B-NP COMMA COMMA O because IN B-SBAR both DT B-NP transcripts NNS I-NP were VBD B-VP present JJ B-ADJP in IN B-PP the DT B-NP CIITA-transfected JJ I-NP hybrids NNS I-NP COMMA COMMA O although IN B-SBAR at IN B-PP reduced VBN B-NP levels NNS I-NP . . O These DT B-NP findings NNS I-NP further RB B-ADVP support VBP B-VP our PRP$ B-NP previous JJ I-NP observations NNS I-NP on IN B-PP the DT B-NP distinct JJ I-NP regulation NN I-NP of IN B-PP expression NN B-NP of IN B-PP the DT B-NP human JJ I-NP HLA-DQ NN I-NP class NN I-NP II CD I-NP subset NN I-NP COMMA COMMA O which WDT B-NP may MD B-VP be VB I-VP thus RB I-VP controlled VBN I-VP at IN B-PP the DT B-NP posttranscriptional JJ I-NP level NN I-NP by IN B-PP a DT B-NP CIITA-independent JJ I-NP mechanism NN I-NP . . O Chromosome NN B-NP 1 CD I-NP aneusomy NN I-NP with IN B-PP 1p36 NN B-NP under-representation NN I-NP is VBZ B-VP related JJ B-ADJP to TO B-PP histologic JJ B-NP grade NN I-NP COMMA COMMA O DNA NN B-NP aneuploidy NN I-NP COMMA COMMA O high JJ B-NP c-erb NN I-NP B-2 NN I-NP and CC O loss NN B-NP of IN B-PP bcl-2 NN B-NP expression NN I-NP in IN B-PP ductal JJ B-NP breast NN I-NP carcinoma NN I-NP . . O Chromosome NN B-NP 1 CD I-NP abnormalities NNS I-NP with IN B-PP loss NN B-NP of IN B-PP 1p36 NN B-NP have VBP B-VP been VBN I-VP investigated VBN I-VP in IN B-PP 95 CD B-NP breast-cancer NN I-NP samples NNS I-NP by IN B-PP means NNS I-PP of IN I-PP a DT O dual-target JJ O fluorescence NN B-NP in-situ FW I-NP hybridization NN I-NP ( ( O FISH NN B-NP ) ) O technique NN B-NP using VBG B-VP the DT O pUC NN B-NP 1.77 CD I-NP and CC O p1-79 NN B-NP probes NNS B-NP COMMA COMMA O specific JJ O for IN B-PP the DT O 1q12 NN B-NP and CC O 1p36 NN B-NP regions NNS B-NP COMMA COMMA B-ADJP respectively RB I-ADJP . . O Abnormalities NNS B-NP for IN B-PP one CD B-NP or CC O both DT B-NP probes NNS I-NP were VBD B-VP detected VBN I-VP in IN B-PP 83\/95 CD B-NP samples NNS I-NP . . O Relative JJ B-NP 1p36 NN I-NP under-representation NN I-NP was VBD B-VP found VBN I-VP in IN B-PP 79\/95 CD B-NP . . O The DT B-NP clinical JJ I-NP relevance NN I-NP of IN B-PP these DT B-NP alterations NNS I-NP was VBD B-VP studied VBN I-VP by IN B-PP comparing VBG B-VP the DT B-NP FISH NN I-NP results NNS I-NP with IN B-PP several JJ B-NP parameters NNS I-NP currently RB B-VP used VBN I-VP in IN B-PP breast-cancer JJ B-NP pathology NN I-NP . . O Distinct JJ B-NP patterns NNS I-NP of IN B-PP chromosome NN B-NP 1 CD I-NP abnormalities NNS I-NP were VBD B-VP found VBN I-VP among IN B-PP the DT B-NP histologic JJ I-NP types NNS I-NP of IN B-PP breast NN B-NP carcinoma NN I-NP . . O Lobular JJ B-NP or CC I-NP mucinous JJ I-NP samples NNS I-NP showed VBD B-VP few JJ B-NP or CC I-NP no DT I-NP alterations NNS I-NP COMMA COMMA O whereas IN O most JJS B-NP ductal JJ I-NP samples NNS I-NP had VBD B-VP high JJ B-NP chromosome NN I-NP 1 CD I-NP polysomy NN I-NP with IN B-PP under-representation NN B-NP of IN B-PP 1p36 NN B-NP . . O In IN B-PP ductal JJ B-NP carcinomas NNS I-NP COMMA COMMA O chromosome NN B-NP 1 CD I-NP alterations NNS I-NP increased VBD B-VP with IN B-PP histologic JJ B-NP grade NN I-NP COMMA COMMA O DNA NN B-NP aneuploidy NN I-NP COMMA COMMA O loss NN B-NP of IN B-PP bcl-2 NN B-NP and CC O high JJ B-NP c-erb NN I-NP B-2 NN I-NP expression NN I-NP . . O These DT B-NP associations NNS I-NP were VBD B-VP found VBN I-VP to TO I-VP be VB I-VP statistically RB B-ADVP significant JJ B-ADJP . . O No DT B-NP correlation NN I-NP between IN B-PP chromosome NN B-NP 1 CD I-NP alterations NNS I-NP and CC O nuclear JJ B-NP grade NN B-NP COMMA COMMA O age NN B-NP COMMA COMMA O size NN B-NP COMMA COMMA O lymph-node JJ B-NP involvement NN I-NP COMMA COMMA O hormonal JJ B-NP receptor NN I-NP presence NN I-NP COMMA COMMA O proliferation NN B-NP activity NN I-NP or CC O p53 NN B-NP protein NN I-NP expression NN I-NP was VBD B-VP detected VBN I-VP . . O These DT B-NP results NNS I-NP indicate VBP B-VP the DT B-NP utility NN I-NP of IN B-PP this DT B-NP FISH NN I-NP technique NN I-NP for IN B-PP a DT B-NP better JJR I-NP definition NN I-NP of IN B-PP the DT B-NP biological JJ I-NP characteristics NNS I-NP of IN B-PP ductal JJ B-NP carcinomas NNS I-NP . . O Silencing NN B-NP of IN B-PP human JJ B-NP fetal JJ I-NP globin NN I-NP expression NN I-NP is VBZ B-VP impaired JJ I-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP the DT B-NP adult JJ I-NP beta-globin IN I-NP gene NN I-NP activator NN I-NP protein NN I-NP EKLF NN I-NP . . O Globin NN B-NP genes NNS I-NP are VBP B-VP subject JJ B-ADJP to TO B-PP tissue-specific JJ B-NP and CC I-NP developmental JJ I-NP stage-specific JJ I-NP regulation NN I-NP . . O A DT B-NP switch NN I-NP from IN B-PP human JJ B-NP fetal JJ I-NP ( ( O gamma NN B-NP ) ) O -to TO B-PP adult JJ B-NP ( ( O beta NN B-NP ) ) O -globin NN B-NP expression NN I-NP occurs VBZ B-VP within IN B-PP erythroid JJ B-NP precursor JJ I-NP cells NNS I-NP of IN B-PP the DT B-NP adult JJ I-NP lineage NN I-NP . . O Previously RB B-ADVP we PRP B-NP and CC O others NNS B-NP showed VBD B-VP by IN B-PP targeted VBN B-NP gene NN I-NP disruption NN I-NP that IN B-SBAR the DT B-NP zinc NN I-NP finger NN I-NP gene NN I-NP COMMA COMMA O erythroid JJ B-NP Kruppel-like JJ I-NP factor NN I-NP ( ( O EKLF NN B-NP ) ) O COMMA COMMA O is VBZ B-VP required VBN I-VP for IN B-PP expression NN B-NP of IN B-PP the DT B-NP beta-globin NN I-NP gene NN I-NP in IN B-PP mice NNS B-NP COMMA COMMA O presumably RB B-PP through IN I-PP interaction NN B-NP with IN B-PP a DT B-NP high-affinity JJ I-NP binding VBG I-NP site NN I-NP in IN B-PP the DT B-NP proximal JJ I-NP promoter NN I-NP . . O To TO B-VP examine VB I-VP the DT B-NP role NN I-NP of IN B-PP EKLF NN B-NP in IN B-PP the DT B-NP developmental JJ I-NP regulation NN I-NP of IN B-PP the DT B-NP human JJ I-NP gamma-globin NN I-NP gene NN I-NP we PRP B-NP interbred VBD B-VP EKLF NN B-NP heterozygotes NNS I-NP ( ( O +\/- CC O ) ) O with IN B-PP mice NNS B-NP harboring VBG B-VP a DT B-NP human JJ I-NP beta-globin NN I-NP yeast NN I-NP artificial JJ I-NP chromosome NN I-NP transgene NN I-NP . . O We PRP B-NP find VBP B-VP that IN B-SBAR in IN B-PP the DT I-PP absence NN I-PP of IN I-PP EKLF NN B-NP COMMA COMMA O while IN B-SBAR human JJ B-NP beta-globin NN I-NP expression NN I-NP is VBZ B-VP dramatically RB I-VP reduced VBN I-VP COMMA COMMA O gamma-globin NN B-NP transcripts NNS I-NP are VBP B-VP elevated JJ I-VP approximately RB B-ADVP 5-fold RB I-ADVP . . O Impaired JJ B-NP silencing NN I-NP of IN B-PP gamma-globin NN B-NP expression NN I-NP identifies VBZ B-VP EKLF NN B-NP as IN B-PP the DT B-NP first JJ I-NP transcription NN I-NP factor NN I-NP participating VBG B-VP quantitatively RB B-ADVP in IN B-PP the DT O gamma-globin NN B-NP to TO O beta-globin NN B-NP switch NN B-NP . . O Our PRP$ B-NP findings NNS I-NP are VBP B-VP compatible JJ B-ADJP with IN B-PP a DT B-NP competitive JJ I-NP model NN I-NP of IN B-PP switching NN B-NP in IN B-PP which WDT B-NP EKLF NN B-NP mediates VBZ B-VP an DT B-NP adult JJ I-NP stage-specific JJ I-NP interaction NN I-NP between IN B-PP the DT B-NP beta-globin NN I-NP gene NN I-NP promoter NN I-NP and CC O the DT B-NP locus NN I-NP control NN I-NP region NN I-NP that WDT B-NP excludes VBZ B-VP the DT B-NP gamma-globin NN I-NP gene NN I-NP . . O Modulatory JJ B-NP effects NNS I-NP of IN B-PP glucocorticoids NNS B-NP and CC O catecholamines NNS B-NP on IN B-PP human JJ O interleukin-12 NN B-NP and CC O interleukin-10 NN B-NP production NN B-NP : : O clinical JJ B-NP implications NNS I-NP . . O Interleukin-12 NN B-NP ( ( O IL-12 NN B-NP ) ) O is VBZ B-VP a DT B-NP key JJ I-NP inducer NN I-NP of IN B-PP differentiation NN B-NP of IN B-PP uncommitted JJ O T NN B-NP helper NN I-NP ( ( O TH NN B-NP ) ) O cells NNS B-NP toward IN B-PP the DT B-NP TH1 NN I-NP phenotype NN I-NP COMMA COMMA O which WDT B-NP regulates VBZ B-VP cellular JJ B-NP immunity NN I-NP COMMA COMMA O whereas IN O IL-10 NN B-NP inhibits VBZ B-VP TH1 NN B-NP functions NNS I-NP and CC O potentiates VBZ B-VP TH2-regulated JJ B-NP responses NNS I-NP ( ( O i.e. FW B-NP COMMA COMMA I-NP humoral JJ I-NP immunity NN I-NP ) ) O . . O To TO B-VP examine VB I-VP the DT B-NP potential JJ I-NP effects NNS I-NP of IN B-PP stress NN B-NP on IN B-PP TH1\/TH2 NN B-NP balance NN I-NP COMMA COMMA O we PRP B-NP studied VBD B-VP the DT B-NP ability NN I-NP of IN B-PP three CD B-NP prototype NN I-NP stress NN I-NP hormones NNS I-NP - : O dexamethasone NN B-NP ( ( O a DT B-NP synthetic JJ I-NP glucocorticoid NN I-NP ) ) O and CC O the DT B-NP catecholamines NNS I-NP norepinephrine NN B-NP and CC O epinephrine NN B-NP - : O to TO B-VP alter VB I-VP the DT B-NP production NN I-NP of IN B-PP IL-12 NN B-NP ( ( O p70 NN B-NP ) ) O and CC O IL-10 NN B-NP induced VBN B-VP by IN B-PP bacterial JJ B-NP lipopolysaccharide NN B-NP ( ( O LPS NN B-NP ) ) O in IN B-PP human JJ B-NP whole JJ I-NP blood NN I-NP . . O Dexamethasone NN B-NP inhibited VBD B-VP LPS-induced JJ B-NP bioactive JJ I-NP IL-12 NN I-NP production NN I-NP in IN B-PP a DT B-NP dose-dependent JJ I-NP fashion NN I-NP and CC B-PP at IN B-PP physiologically RB B-NP relevant JJ I-NP concentrations NNS I-NP ; : O Nasal JJ O NK- NN B-NP and CC O T-cell NN B-NP lymphomas NNS B-NP share VBP B-VP the DT B-NP same JJ I-NP type NN I-NP of IN B-PP Epstein-Barr JJ B-NP virus NN I-NP latency NN I-NP as IN B-PP nasopharyngeal JJ B-NP carcinoma NN I-NP and CC O Hodgkin NN B-NP 's POS B-NP disease NN I-NP . . O Nasal JJ B-NP T\/NK-cell JJ I-NP lymphomas NNS I-NP can MD B-VP be VB I-VP further RBR I-VP separated VBN I-VP into IN B-PP those DT B-NP of IN B-PP natural JJ B-NP killer NN I-NP ( ( O NK NN B-NP ) ) O cell NN B-NP lineage NN I-NP or CC B-PP of IN B-PP T-cell NN B-NP lineage NN I-NP COMMA COMMA O with IN B-PP differences NNS B-NP in IN B-PP cellular JJ B-NP phenotype NN I-NP COMMA COMMA O T-cell NN B-NP receptor NN I-NP ( ( O TcR NN B-NP ) ) O gene NN B-NP rearrangement NN I-NP and CC O TcR NN B-NP transcript NN I-NP expression NN I-NP . . O Both CC O NK- NN B-NP and CC O T-cell NN B-NP subtypes NNS B-NP are VBP B-VP closely RB I-VP associated VBN I-VP with IN B-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O EBV NN B-NP gene NN I-NP expression NN I-NP was VBD B-VP determined VBN I-VP in IN B-PP 23 CD B-NP cases NNS I-NP of IN B-PP nasal JJ B-NP lymphoma NN I-NP ( ( O NL NN B-NP ) ) O by IN B-PP in FW B-NP situ FW I-NP hybridisation NN I-NP ( ( O ISH NN B-NP ) ) O COMMA COMMA O reverse JJ B-NP transcriptase-polymerase NN I-NP chain NN I-NP reaction NN I-NP ( ( O RT-PCR NN B-NP ) ) O and CC O immunohistochemistry NN B-NP ( ( O IH NN B-NP ) ) O . . O Of IN B-PP the DT B-NP 23 CD I-NP cases NNS I-NP COMMA COMMA O 19 CD B-NP were VBD B-VP classified VBN I-VP as IN B-PP NK-cell NN O and CC O 4 CD B-NP as IN B-PP T-cell NN B-NP tumours NNS I-NP . . O ISH NN B-NP for IN B-PP EBV-encoded JJ B-NP small JJ I-NP non-polyadenylated JJ I-NP RNAs NNS I-NP showed VBD B-VP that IN B-SBAR all DT B-NP cases NNS I-NP COMMA COMMA O whether IN B-SBAR NK NN B-NP or CC O T NN B-NP COMMA COMMA O harboured VBD B-VP EBV NN B-NP in IN B-PP virtually RB B-NP all DT I-NP tumour NN I-NP cells NNS I-NP . . O RT-PCR NN B-NP demonstrated VBD B-VP that IN B-SBAR NL NN B-NP of IN B-PP both DT B-NP subtypes NNS I-NP expressed VBD B-VP EBNAI NN B-NP of IN B-PP the DT B-NP QUK NN I-NP splice NN I-NP pattern NN I-NP COMMA COMMA O the DT B-NP latent JJ I-NP membrane NN I-NP proteins NNS I-NP COMMA COMMA O LMP1 NN B-NP and CC O 2 CD B-NP and CC O the DT B-NP BamHI NN I-NP A NN I-NP rightward JJ I-NP transcripts NNS I-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP EBNA2 NN B-NP mRNAs NNS I-NP COMMA COMMA O compatible JJ B-ADJP with IN B-PP the DT B-NP latency NN I-NP type NN I-NP II CD I-NP pattern NN I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O analysis NN B-NP of IN B-PP EBV NN B-NP protein NN I-NP expression NN I-NP by IN B-PP IH NN B-NP revealed VBD B-VP a DT B-NP heterogeneous JJ I-NP pattern NN I-NP of IN B-PP EBV NN B-NP gene NN I-NP expression NN I-NP at IN B-PP the DT B-NP single-cell NN I-NP level NN I-NP consisting VBG B-VP of IN B-PP both CC B-NP LMP1+ JJ I-NP and CC I-NP LMP1- JJ I-NP tumour NN I-NP cells NNS I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP mixture NN I-NP of IN B-PP latency NN B-NP I CD B-NP and CC O II CD B-NP . . O Although IN B-SBAR 2 CD B-NP early JJ I-NP lytic JJ I-NP transcripts NNS I-NP COMMA COMMA O BZLF1 NN B-NP and CC O BHRF1 NN B-NP COMMA COMMA O were VBD B-VP also RB I-VP detected VBN I-VP in IN B-PP 13 CD B-NP and CC I-NP 10 CD I-NP cases NNS I-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O the DT B-NP lack NN I-NP of IN B-PP ZEBRA NN B-NP staining NN I-NP in IN B-PP any DT B-NP case NN I-NP indicates VBZ B-VP that IN B-SBAR these DT B-NP lytic JJ I-NP transcripts NNS I-NP are VBP B-VP most RBS I-VP likely RB I-VP expressed VBN I-VP by IN B-PP rare JJ B-NP cells NNS I-NP in IN B-PP the DT B-NP biopsies NNS I-NP entering VBG B-VP lytic JJ B-NP cycle NN I-NP . . O The DT B-NP viral JJ I-NP transcriptional JJ I-NP pattern NN I-NP similar JJ B-ADJP to TO B-PP that DT B-NP of IN B-PP nasopharyngeal JJ B-NP carcinoma NN I-NP and CC O Hodgkin NN B-NP 's POS B-NP disease NN I-NP suggests VBZ B-VP that IN B-SBAR EBV NN B-NP can MD B-VP exploit VB I-VP common JJ B-NP regulatory JJ I-NP mechanisms NNS I-NP for IN B-PP gene NN B-NP transcription NN I-NP in IN B-PP diverse JJ B-NP host NN I-NP cell NN I-NP types NNS I-NP . . O Down-regulation NN B-NP of IN B-PP immunogenic JJ B-NP proteins NNS I-NP ( ( O EBNA2-EBNA6 NN B-NP ) ) O in IN B-PP nasal JJ B-NP lymphoma NN I-NP may MD B-VP enable VB I-VP tumour NN B-NP cells NNS I-NP to TO B-VP evade VB I-VP host NN B-NP cytotoxic JJ I-NP T-cell NN I-NP surveillance NN I-NP . . O Lack NN B-NP of IN B-PP IL-12 NN B-NP signaling NN I-NP in IN B-PP human JJ B-NP allergen-specific JJ I-NP Th2 NN I-NP cells NNS I-NP . . O IL-12 NN B-NP is VBZ B-VP a DT B-NP powerful JJ I-NP skewer NN I-NP of IN B-PP CD4+ JJ B-NP T NN I-NP cell NN I-NP responses NNS I-NP toward IN B-PP the DT B-NP Th1 NN I-NP phenotype NN I-NP by IN B-PP inducing VBG B-VP IFN-gamma NN B-NP production NN I-NP in IN B-PP naive JJ B-NP Th NN I-NP cells NNS I-NP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP we PRP B-NP addressed VBD B-VP the DT B-NP question NN I-NP of IN B-PP whether IN B-SBAR IL-12 NN B-NP can MD B-VP reverse VB I-VP established JJ B-NP Th2 NN I-NP responses NNS I-NP into IN B-PP Th1\/Th0 NN B-NP responses NNS I-NP by IN B-PP inducing VBG B-VP IFN-gamma NN B-NP production NN I-NP in IN B-PP memory NN B-NP Th2 NN I-NP cells NNS I-NP . . O To TO B-PP this DT B-NP aim NN I-NP COMMA COMMA O allergen-specific JJ B-NP CD4+ JJ I-NP T NN B-NP cell NN I-NP clones NNS I-NP ( ( O TCC NN B-NP ) ) O were VBD B-VP generated VBN I-VP from IN B-PP the DT B-NP peripheral JJ I-NP blood NN I-NP of IN B-PP three CD B-NP atopic JJ I-NP patients NNS I-NP COMMA COMMA O and CC O their PRP$ B-NP cytokine NN I-NP profiles NNS I-NP were VBD B-VP analyzed VBN I-VP . . O The DT B-NP majority NN I-NP of IN B-PP these DT B-NP TCC NN I-NP exhibited VBD B-VP a DT B-NP strongly RB I-NP polarized VBN I-NP Th2 NN I-NP cytokine NN I-NP profile NN I-NP COMMA COMMA O and CC O the DT B-NP production NN I-NP of IN B-PP IFN-gamma NN B-NP could MD B-VP not RB I-VP be VB I-VP induced VBN I-VP by IN B-PP exogenous JJ B-NP IL-12 NN I-NP . . O Only RB B-NP those DT I-NP TCC NN I-NP with IN B-PP low JJ B-NP IFN-gamma NN I-NP levels NNS I-NP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP IL-12 NN B-NP responded VBD B-VP to TO B-PP IL-12 NN B-NP by IN B-PP additional JJ B-NP enhancement NN I-NP of IN B-PP IFN-gamma NN B-NP production NN I-NP . . O The DT B-NP IL-12 NN I-NP nonresponsiveness NN I-NP of IN B-PP the DT B-NP Th2 NN I-NP clones NNS I-NP was VBD B-VP further RBR B-ADJP evident JJ I-ADJP by IN B-PP the DT B-NP total JJ I-NP lack NN I-NP of IN B-PP IL-12-induced JJ B-NP phosphorylation NN I-NP of IN B-PP STAT4 NN B-NP ( ( O signal NN B-NP transducer NN I-NP and CC O activator NN B-NP of IN B-PP transcription-4 NN B-NP ) ) O COMMA COMMA O a DT B-NP transcription NN I-NP factor NN I-NP that WDT B-NP is VBZ B-VP typically RB I-VP involved VBN I-VP in IN B-PP IL-12 NN B-NP signaling NN I-NP . . O Consequently RB B-ADVP COMMA COMMA O IL-12 NN B-NP also RB B-ADVP failed VBD B-VP to TO I-VP induce VB I-VP the DT B-NP DNA-binding JJ I-NP activity NN I-NP of IN B-PP STAT4-containing JJ B-NP complexes NNS I-NP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP these DT B-NP Th2 NN I-NP clones NNS I-NP . . O All DT B-NP TCC NN I-NP expressed VBD B-VP equal JJ B-NP levels NNS I-NP of IN B-PP the DT B-NP low-affinity JJ I-NP IL-12R NN I-NP beta1 NN I-NP subunit NN I-NP . . O Our PRP$ B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR human JJ B-NP allergen-specific JJ I-NP Th NN I-NP cells NNS I-NP with IN B-PP strongly RB B-NP polarized VBN I-NP Th2 NN I-NP cytokine NN I-NP profiles NNS I-NP do VBP B-VP not RB I-VP respond VB I-VP to TO B-PP IL-12 NN B-NP and CC O COMMA COMMA O therefore RB O COMMA COMMA O can MD B-VP not RB I-VP be VB I-VP induced VBN I-VP to TO I-VP produce VB I-VP IFN-gamma NN B-NP . . O The DT B-NP apparent JJ I-NP high JJ I-NP frequency NN I-NP of IN B-PP IL-12-nonresponsive JJ B-NP Th NN I-NP cells NNS I-NP within IN B-PP the DT B-NP allergen-specific JJ I-NP populations NNS I-NP in IN B-PP atopic JJ B-NP patients NNS I-NP predicts VBZ B-VP a DT B-NP limited JJ I-NP skewing JJ I-NP potential NN I-NP of IN B-PP IL-12 NN B-NP in IN B-PP the DT B-NP case NN I-NP of IN B-PP established JJ B-NP Th2 NN I-NP responses NNS I-NP COMMA COMMA O but CC O only RB B-VP affecting VBG I-VP newly RB B-NP recruited VBN I-NP naive JJ I-NP Th NN I-NP cells NNS I-NP . . O Characterization NN B-NP of IN B-PP a DT B-NP CD43\/leukosialin-mediated JJ I-NP pathway NN I-NP for IN B-PP inducing VBG B-VP apoptosis NN B-NP in IN B-PP human JJ B-NP T-lymphoblastoid JJ I-NP cells NNS I-NP . . O The DT O monoclonal JJ B-NP antibody NN I-NP ( ( O mAb NN B-NP ) ) O J393 NN B-NP induces VBZ B-VP apoptosis NN B-NP in IN B-PP Jurkat NN B-NP T-cells NNS I-NP . . O NH2-terminal JJ B-NP amino NN I-NP acid NN I-NP sequence NN I-NP analysis NN I-NP identified VBD B-VP the DT B-NP 140-kDa JJ I-NP surface NN I-NP antigen NN I-NP for IN B-PP mAb NN B-NP J393 NN I-NP as IN B-PP CD43\/leukosialin NN B-NP COMMA COMMA O the DT B-NP major JJ I-NP sialoglycoprotein NN I-NP of IN B-PP leukocytes NNS B-NP . . O While IN B-SBAR Jurkat NN B-NP cells NNS I-NP co-expressed VBD B-VP two CD B-NP discrete JJ I-NP cell-surface JJ I-NP isoforms NNS I-NP of IN B-PP CD43 NN B-NP COMMA COMMA O recognized VBN B-VP by IN B-PP mAb NN B-NP J393 NN I-NP and CC O mAb NN B-NP G10-2 NN I-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O only RB B-NP J393\/CD43 NN I-NP signaled VBD B-VP apoptosis NN B-NP . . O J393\/CD43 NN B-NP was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP hyposialylated VBN I-VP COMMA COMMA O bearing VBG B-VP predominantly RB B-NP O-linked JJ I-NP monosaccharide NN I-NP glycans NNS I-NP COMMA COMMA O whereas IN O G10-2\/CD43 NN B-NP bore VBD B-VP complex JJ O sialylated VBN O tetra- JJ B-NP and CC O hexasaccharide NN B-NP chains NNS B-NP . . O Treatment NN B-NP with IN B-PP soluble JJ B-NP COMMA COMMA I-NP bivalent JJ I-NP mAb NN I-NP J393 NN I-NP killed VBD B-VP 25-50 CD B-NP % NN I-NP of IN B-PP the DT B-NP cell NN I-NP population NN I-NP COMMA COMMA O while IN B-SBAR concomitant JJ B-NP engagement NN I-NP of IN B-PP either CC O the DT B-NP CD3.TcR NN I-NP complex NN I-NP or CC O the DT B-NP integrins NNS I-NP CD18 NN B-NP and CC O CD29 NN B-NP significantly RB B-ADVP potentiated VBD B-VP this DT B-NP effect NN I-NP . . O Treatment NN B-NP of IN B-PP Jurkat NN B-NP cells NNS I-NP with IN B-PP mAb NN B-NP J393 NN I-NP induced VBD B-VP tyrosine NN B-NP phosphorylation NN I-NP of IN B-PP specific JJ B-NP protein NN I-NP substrates NNS I-NP that WDT B-NP underwent VBD B-VP hyperphosphorylation NN B-NP upon IN B-PP antigen NN B-NP receptor NN I-NP costimulation NN I-NP . . O Tyrosine NN B-NP kinase NN I-NP inhibition NN I-NP by IN B-PP herbimycin NN B-NP A NN I-NP diminished VBD B-VP J393\/CD43-mediated JJ B-NP apoptosis NN I-NP COMMA COMMA O whereas IN O inhibition NN B-NP of IN B-PP phosphotyrosine NN B-NP phosphatase NN I-NP activity NN I-NP by IN B-PP bis(maltolato)oxovanadium-IV NN B-NP enhanced VBD B-VP cell NN B-NP death NN I-NP . . O Signal NN B-NP transduction NN I-NP through IN B-PP tyrosine NN B-NP kinase NN I-NP activation NN I-NP may MD B-VP lead VB I-VP to TO B-PP altered JJ B-NP gene NN I-NP expression NN I-NP COMMA COMMA O as IN B-SBAR J393\/CD43 NN B-NP ligation NN I-NP prompted VBD B-VP decreases NNS B-NP in IN B-PP the DT B-NP nuclear JJ I-NP localization NN I-NP of IN B-PP the DT B-NP transcriptional JJ I-NP regulatory JJ I-NP protein NN I-NP NF-kappaB NN I-NP and CC O proteins NNS B-NP binding VBG B-VP the DT B-NP interferon-inducible JJ I-NP regulatory JJ I-NP element NN I-NP . . O Since IN B-SBAR peripheral JJ B-NP blood NN I-NP T-lymphocytes NNS I-NP express VBP B-VP cryptic JJ B-NP epitopes NNS I-NP for IN B-PP mAb NN B-NP J393 NN I-NP COMMA COMMA O these DT B-NP findings NNS I-NP demonstrate VBP B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP tightly RB I-NP regulated VBN I-NP CD43-mediated JJ I-NP pathway NN I-NP for IN B-PP inducing VBG B-VP apoptosis NN B-NP in IN B-PP human JJ B-NP T-cell NN I-NP lineages NNS I-NP . . O Stat3 NN B-NP recruitment NN I-NP by IN B-PP two CD B-NP distinct JJ I-NP ligand-induced JJ I-NP COMMA COMMA I-NP tyrosine-phosphorylated JJ I-NP docking NN I-NP sites NNS I-NP in IN B-PP the DT B-NP interleukin-10 NN I-NP receptor NN I-NP intracellular JJ I-NP domain NN I-NP . . O Recent JJ B-NP work NN I-NP has VBZ B-VP shown VBN I-VP that IN B-SBAR IL-10 NN B-NP induces VBZ B-VP activation NN B-NP of IN B-PP the DT B-NP JAK-STAT NN I-NP signaling NN I-NP pathway NN I-NP . . O To TO B-VP define VB I-VP the DT B-NP mechanism NN I-NP underlying VBG B-VP signal NN B-NP transducer NN I-NP and CC O activator NN B-NP of IN B-PP transcription NN B-NP ( ( O STAT NN B-NP ) ) O protein NN B-NP recruitment NN I-NP to TO B-PP the DT O interleukin NN B-NP 10 CD I-NP ( ( O IL-10 NN B-NP ) ) O receptor NN B-NP COMMA COMMA O the DT B-NP STAT NN I-NP proteins NNS I-NP activated VBN B-VP by IN B-PP IL-10 NN B-NP in IN B-PP different JJ B-NP cell NN I-NP populations NNS I-NP were VBD B-VP first RB I-VP defined VBN I-VP using VBG B-VP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP . . O In IN B-PP all DT B-NP cells NNS I-NP tested VBN B-VP COMMA COMMA O IL-10 NN B-NP activated VBD B-VP Stat1 NN B-NP and CC O Stat3 NN B-NP and CC O induced VBD B-VP the DT B-NP formation NN I-NP of IN B-PP three CD B-NP distinct JJ I-NP DNA NN I-NP binding NN I-NP complexes NNS I-NP that WDT B-NP contained VBD B-VP different JJ B-NP combinations NNS I-NP of IN B-PP these DT B-NP two CD I-NP transcription NN I-NP factors NNS I-NP . . O IL-10 NN B-NP also RB B-ADVP activated VBD B-VP Stat5 NN B-NP in IN B-PP Ba\/F3 NN B-NP cells NNS I-NP that IN B-NP stably RB B-ADVP expressed VBD B-VP the DT B-NP murine JJ I-NP IL-10 NN I-NP receptor NN I-NP . . O Using VBG B-VP a DT B-NP structure-function JJ I-NP mutagenesis NN I-NP approach NN I-NP COMMA COMMA O two CD B-NP tyrosine NN I-NP residues NNS I-NP ( ( O Tyr427 NN B-NP and CC O Tyr477 NN B-NP ) ) O in IN B-PP the DT B-NP intracellular JJ I-NP domain NN I-NP of IN B-PP the DT B-NP murine JJ I-NP IL-10 NN I-NP receptor NN I-NP were VBD B-VP found VBN I-VP to TO I-VP be VB I-VP redundantly RB I-VP required VBN I-VP for IN B-PP receptor NN B-NP function NN I-NP and CC B-PP for IN B-PP activation NN B-NP of IN B-PP Stat3 NN B-NP but CC B-PP not RB B-PP for IN I-PP Stat1 NN B-NP or CC O Stat5 NN B-NP . . O Twelve CD B-NP amino NN I-NP acid NN I-NP peptides NNS I-NP encompassing VBG B-VP either DT B-NP of IN B-PP these DT B-NP two CD I-NP tyrosine NN I-NP residues NNS I-NP in IN B-PP phosphorylated JJ B-NP form NN I-NP coprecipitated VBD B-VP Stat3 NN B-NP but CC B-CONJP not RB I-CONJP Stat1 NN B-NP and CC O blocked VBD B-VP IL-10-induced JJ B-NP Stat3 NN I-NP phosphorylation NN I-NP in IN B-PP a DT B-NP cell-free JJ I-NP system NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O tyrosine-phosphorylated JJ B-NP peptides NNS I-NP containing VBG B-VP Tyr374 NN B-NP or CC O Tyr396 NN B-NP did VBD B-VP not RB I-VP interact VB I-VP with IN B-PP Stat3 NN B-NP or CC O block VB B-VP Stat3 NN B-NP activation NN I-NP . . O These DT B-NP data NNS I-NP demonstrate VBP B-VP that IN B-SBAR Stat3 NN B-NP but CC B-NP not RB I-NP Stat1 NN B-NP or CC O Stat5 NN B-NP is VBZ B-VP directly RB I-VP recruited VBN I-VP to TO B-PP the DT B-NP ligand-activated JJ I-NP IL-10 NN I-NP receptor NN I-NP by IN B-PP binding VBG B-VP to TO B-PP specific JJ B-NP but CC I-NP redundant JJ I-NP receptor NN I-NP intracellular JJ I-NP domain NN I-NP sequences NNS I-NP containing VBG B-VP phosphotyrosine NN B-NP . . O This DT B-NP study NN I-NP thus RB B-ADVP supports VBZ B-VP the DT B-NP concept NN I-NP that IN B-SBAR utilization NN B-NP of IN B-PP distinct JJ B-NP STAT NN I-NP proteins NNS I-NP by IN B-PP different JJ B-NP cytokine NN I-NP receptors NNS I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP the DT B-NP expression NN I-NP of IN B-PP particular JJ B-NP ligand-activatable JJ I-NP COMMA COMMA I-NP tyrosine-containing JJ I-NP STAT NN I-NP docking NN I-NP sites NNS I-NP in IN B-PP receptor NN B-NP intracellular JJ I-NP domains NNS I-NP . . O Identification NN B-NP and CC O characterization NN B-NP of IN B-PP a DT B-NP leukocyte-specific JJ I-NP component NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP body NN I-NP . . O The DT B-NP nuclear JJ I-NP body NN I-NP ( ( O NB NN B-NP ) ) O is VBZ B-VP a DT B-NP cellular JJ I-NP organelle NN I-NP that WDT B-NP is VBZ B-VP involved VBN I-VP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP and CC O viral JJ B-NP infection NN I-NP . . O The DT B-NP NB NN I-NP is VBZ B-VP also RB B-ADVP a DT B-NP target NN I-NP of IN B-PP antibodies NNS B-NP in IN B-PP the DT B-NP serum NN I-NP of IN B-PP patients NNS B-NP with IN B-PP the DT B-NP autoimmune JJ I-NP disease NN I-NP primary JJ I-NP biliary JJ I-NP cirrhosis NN I-NP . . O In IN B-PP this DT B-NP study NN I-NP COMMA COMMA O serum NN B-NP from IN B-PP a DT B-NP patient NN I-NP with IN B-PP primary JJ B-NP biliary JJ I-NP cirrhosis NN I-NP was VBD B-VP used VBN I-VP to TO B-VP identify VB I-VP a DT B-NP cDNA NN I-NP encoding VBG B-VP a DT B-NP novel JJ I-NP component NN I-NP of IN B-PP the DT B-NP NB NN I-NP COMMA COMMA O a DT B-NP 140-kDa JJ I-NP protein NN I-NP designated VBN B-VP Sp140 NN B-NP . . O The DT B-NP predicted VBN I-NP amino NN I-NP acid NN I-NP sequence NN I-NP of IN B-PP the DT B-NP amino-terminal JJ I-NP portion NN I-NP of IN B-PP Sp140 NN B-NP was VBD B-VP similar JJ B-ADJP to TO B-PP Sp100 NN B-NP COMMA COMMA O a DT B-NP previously RB I-NP identified VBN I-NP NB NN I-NP protein NN I-NP . . O The DT B-NP carboxyl JJ I-NP portion NN I-NP of IN B-PP Sp140 NN B-NP contained VBD B-VP a DT B-NP zinc-finger JJ I-NP domain NN I-NP and CC O a DT B-NP bromodomain NN I-NP COMMA COMMA O motifs NNS B-NP that WDT B-NP are VBP B-VP present JJ B-ADJP in IN B-PP proteins NNS B-NP regulating VBG B-VP gene NN B-NP transcription NN I-NP . . O High JJ B-NP levels NNS I-NP of IN B-PP Sp140 NN B-NP mRNA NN I-NP were VBD B-VP detected VBN I-VP in IN B-PP human JJ O spleen NN B-NP and CC O peripheral JJ B-NP blood NN I-NP leukocytes NNS B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP other JJ B-NP human JJ I-NP tissues NNS I-NP . . O The DT B-NP level NN I-NP of IN B-PP SP140 NN B-NP mRNA NN I-NP in IN B-PP myeloid JJ B-NP precursor NN I-NP cell NN I-NP lines NNS I-NP HL60 NN B-NP and CC O NB4 NN B-NP markedly RB B-ADVP increased VBD B-VP in IN B-PP response NN I-PP to TO I-PP chemically RB B-NP induced VBN I-NP cellular JJ I-NP differentiation NN I-NP . . O Immunohistochemical JJ B-NP techniques NNS I-NP were VBD B-VP used VBN I-VP to TO B-VP demonstrate VB I-VP that IN B-SBAR SP140 NN B-NP localized VBD B-VP to TO B-PP the DT B-NP NB NN I-NP in IN B-PP differentiated VBN O HL60 NN B-NP and CC O NB4 NN B-NP cells NNS B-NP . . O The DT B-NP location NN I-NP of IN B-PP Sp140 NN B-NP in IN B-PP the DT B-NP NB NN I-NP COMMA COMMA O and CC O expression NN B-NP of IN B-PP this DT B-NP gene NN I-NP in IN B-PP cells NNS B-NP involved VBN B-VP in IN B-PP host NN B-NP defense NN I-NP COMMA COMMA O suggest VBP B-VP that IN B-SBAR Sp140 NN B-NP may MD B-VP be VB I-VP involved VBN I-VP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP and CC O viral JJ B-NP infection NN I-NP . . O T-cell-directed JJ B-NP TAL-1 NN I-NP expression NN I-NP induces VBZ B-VP T-cell NN B-NP malignancies NNS I-NP in IN B-PP transgenic JJ B-NP mice NNS I-NP . . O The DT B-NP TAL-1 NN I-NP gene NN I-NP specifies VBZ B-VP for IN B-PP a DT B-NP basic JJ I-NP domain-helix-loop-helix JJ I-NP protein NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP involved VBN I-VP in IN B-PP the DT B-NP control NN I-NP of IN B-PP normal JJ B-NP hematopoiesis NN I-NP . . O In IN B-PP human JJ B-NP pathology NN I-NP COMMA COMMA O the DT B-NP TAL-1 NN I-NP gene NN I-NP product NN I-NP is VBZ B-VP expressed VBN I-VP in IN B-PP a DT B-NP high JJ I-NP percentage NN I-NP of IN B-PP T-cell NN B-NP acute JJ I-NP lymphoblastic JJ I-NP leukemias NNS I-NP in IN B-PP the DT B-NP pediatric JJ I-NP age NN I-NP range NN I-NP ; : O however RB B-ADVP COMMA COMMA O it PRP B-NP has VBZ B-VP not RB I-VP been VBN I-VP established VBN I-VP whether IN B-SBAR the DT B-NP expression NN I-NP has VBZ B-VP a DT B-NP causal JJ I-NP role NN I-NP in IN B-PP oncogenesis NN B-NP . . O In IN B-PP this DT B-NP report NN I-NP COMMA COMMA O we PRP B-NP describe VBP B-VP the DT B-NP phenotype NN I-NP of IN B-PP mouse NN B-NP transgenic JJ I-NP lines NNS I-NP obtained VBN B-VP by IN B-PP inducing VBG B-VP tal-1 NN B-NP protein NN I-NP expression NN I-NP in IN B-PP lymphoid JJ B-NP tissues NNS I-NP using VBG B-VP the DT B-NP LCK NN I-NP promoter NN I-NP . . O The DT B-NP survival NN I-NP rate NN I-NP of IN B-PP tal-1 NN B-NP transgenic JJ I-NP animals NNS I-NP was VBD B-VP much RB B-ADJP lower JJR I-ADJP as IN B-SBAR compared VBN B-VP with IN B-PP control NN B-NP mice NNS I-NP . . O Histopathological JJ B-NP analysis NN I-NP revealed VBD B-VP lymphomas NNS B-NP of IN B-PP T-cell NN B-NP type NN I-NP COMMA COMMA O often RB B-VP comprising VBG I-VP a DT B-NP minor JJ I-NP B-cell NN I-NP component NN I-NP . . O Some DT B-NP mice NNS I-NP showed VBD B-VP marked JJ B-NP splenic JJ I-NP lymphocyte NN I-NP depletion NN I-NP . . O Primary JJ B-NP lymphocyte NN I-NP cultures NNS I-NP showed VBD B-VP partial JJ B-NP independence NN I-NP from IN B-PP exogenous JJ B-NP growth NN I-NP stimuli NNS I-NP and CC O increased VBD B-VP resistance NN B-NP to TO B-PP low-serum JJ B-NP apoptosis NN I-NP . . O To TO B-VP further RB I-VP unravel VB I-VP the DT B-NP tal-1 NN I-NP oncogenic JJ I-NP potential NN I-NP COMMA COMMA O a DT B-NP strain NN I-NP of IN B-PP tal-1 NN B-NP transgenic JJ I-NP mice NNS I-NP was VBD B-VP crossbred VBN I-VP with IN B-PP p53-\/- JJ B-NP mice NNS I-NP ; : O the DT B-NP survival NN I-NP rate NN I-NP in IN B-PP these DT B-NP animals NNS I-NP was VBD B-VP reduced VBN I-VP by IN B-PP more JJR B-NP than IN I-NP one-half NN I-NP when WRB B-ADVP compared VBN B-VP with IN B-PP that DT B-NP of IN B-PP tal-1 NN B-NP mice NNS I-NP COMMA COMMA O and CC O histopathological JJ B-NP analysis NN I-NP revealed VBD B-VP exclusively RB B-ADVP T-cell NN B-NP lymphomas NNS I-NP . . O These DT B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR TAL-1 NN B-NP COMMA COMMA O expressed VBN B-VP in IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O is VBZ B-VP per FW B-ADVP se FW I-ADVP a DT B-NP potent JJ I-NP oncogene NN I-NP COMMA COMMA O which WDT B-NP may MD B-VP exert VB I-VP a DT B-NP key JJ I-NP leukemogenetic JJ I-NP role NN I-NP in IN B-PP the DT B-NP majority NN I-NP of IN B-PP T-cell NN B-NP acute JJ I-NP lymphoblastic JJ I-NP leukemias NNS I-NP . . O Naive JJ B-NP ( ( I-NP CD45RA+ JJ I-NP ) ) I-NP T NN I-NP lymphocytes NNS I-NP are VBP B-VP more RBR B-ADJP sensitive JJ I-ADJP to TO B-PP oxidative JJ B-NP stress-induced JJ I-NP signals NNS I-NP than IN B-PP memory NN B-NP ( ( I-NP CD45RO+ JJ I-NP ) ) I-NP cells NNS I-NP . . O Formation NN B-NP of IN B-PP reactive JJ B-NP oxygen NN I-NP intermediates NNS I-NP ( ( O ROI NN B-NP ) ) O after IN B-PP oxidative JJ B-NP stress NN I-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO B-VP be VB I-VP an DT B-NP activation NN I-NP signal NN I-NP for IN B-PP T NN B-NP lymphocytes NNS I-NP COMMA COMMA O e.g. FW B-ADVP COMMA COMMA O expression NN B-NP of IN B-PP IL-2 NN B-NP and CC O its PRP$ B-NP receptor NN I-NP are VBP B-VP induced VBN I-VP . . O These DT B-NP ROI-induced JJ I-NP effects NNS I-NP can MD B-VP COMMA COMMA O to TO B-PP a DT B-NP large JJ I-NP extent NN I-NP COMMA COMMA O be VB B-VP attributed VBN I-VP to TO B-PP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factor NN I-NP NF-kappaB NN I-NP . . O Now RB B-ADVP we PRP B-NP have VBP B-VP examined VBN I-VP whether IN B-SBAR naive JJ O and CC O memory NN B-NP T NN B-NP lymphocytes NNS I-NP differ VBP B-VP in IN B-PP their PRP$ B-NP sensitivity NN I-NP to TO B-PP ROI-mediated JJ B-NP signals NNS I-NP . . O When WRB B-ADVP CD45RA+ JJ O ( ( O naive JJ B-ADJP ) ) O and CC O CD45RO+ JJ O ( ( O memory NN B-NP ) ) O T NN B-NP lymphocytes NNS I-NP were VBD B-VP directly RB I-VP stimulated VBN I-VP with IN B-PP H2O2 NN B-NP COMMA COMMA O NF-kappaB NN B-NP nuclear JJ I-NP translocation NN I-NP was VBD B-VP stronger JJR B-ADJP in IN B-PP naive JJ B-NP cells NNS I-NP than IN B-PP in IN B-PP memory NN B-NP cells NNS I-NP and CC O it PRP B-NP could MD B-VP be VB I-VP induced VBN I-VP with IN B-PP lower JJR B-NP doses NNS I-NP . . O The DT B-NP composition NN I-NP of IN B-PP the DT B-NP induced VBN I-NP nuclear JJ I-NP NF-kappaB NN I-NP ( ( O levels NNS B-NP of IN B-PP p50 NN B-NP and CC O RelA NN B-NP proteins NNS B-NP ) ) O was VBD B-VP similar JJ B-ADJP in IN B-PP these DT B-NP cell NN I-NP types NNS I-NP . . O The DT B-NP magnitude NN B-NP and CC O kinetics NNS B-NP of IN B-PP intracellular JJ B-NP ROI NN I-NP were VBD B-VP similar JJ B-ADJP COMMA COMMA O suggesting VBG B-VP that IN B-SBAR there EX B-NP were VBD B-VP no DT B-NP differences NNS I-NP in IN B-PP ROI-forming JJ B-NP mechanisms NNS I-NP or CC O antioxidative JJ B-NP capacities NNS I-NP . . O The DT B-NP probable JJ I-NP regulatory JJ I-NP point NN I-NP was VBD B-VP the DT B-NP cytoplasmic JJ I-NP IkappaB NN I-NP inhibitor NN I-NP : : O in IN B-PP CD45RA+ JJ B-NP cells NNS I-NP COMMA COMMA O H2O2 NN B-NP caused VBD B-VP a DT B-NP more RBR I-NP profound JJ I-NP depression NN I-NP in IN B-PP the DT B-NP levels NNS I-NP of IN B-PP IkappaB NN B-NP alpha NN I-NP . . O These DT B-NP findings NNS I-NP indicate VBP B-VP that IN B-SBAR T NN B-NP cells NNS I-NP representing VBG B-VP different JJ O activation NN B-NP and\/or CC O differentiation NN B-NP stages NNS B-NP can MD B-VP be VB I-VP differentially RB B-ADJP responsive JJ I-ADJP to TO B-PP ROI-mediated JJ B-NP signals NNS I-NP . . O Potent JJ B-NP gene NN I-NP regulatory JJ I-NP and CC I-NP antiproliferative JJ I-NP activities NNS I-NP of IN B-PP 20-methyl JJ B-NP analogues NNS I-NP of IN B-PP 1COMMA25 CD B-NP dihydroxyvitamin NN I-NP D3 NN I-NP . . O The DT B-NP biological JJ I-NP active JJ I-NP form NN I-NP of IN B-PP vitamin NN B-NP D3 NN I-NP COMMA COMMA O 1COMMA25-dihydroxyvitamin NN B-NP D3 NN I-NP ( ( O VD NN B-NP ) ) O COMMA COMMA O regulates VBZ B-VP cellular JJ B-NP growth NN B-NP and CC O differentiation NN B-NP . . O This DT B-NP provides VBZ B-VP the DT B-NP hormone NN I-NP with IN B-PP an DT B-NP interesting JJ I-NP therapeutic JJ I-NP potential NN I-NP . . O However RB B-ADVP COMMA COMMA O hypercalcemia NN B-NP is VBZ B-VP a DT B-NP side JJ I-NP effect NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP caused VBN I-VP by IN B-PP VD NN B-NP 's POS B-NP classical JJ I-NP action NN I-NP COMMA COMMA O the DT B-NP regulation NN I-NP of IN B-PP calcium NN B-NP homeostasis NN I-NP . . O This DT B-NP made VBD B-VP the DT B-NP need NN I-NP for IN B-PP VD NN B-NP analogues NNS I-NP with IN B-PP selectively RB B-NP increased VBN I-NP cell NN I-NP regulatory JJ I-NP properties NNS I-NP . . O Studies NNS B-NP with IN B-PP 20-epi JJ B-NP analogues NNS I-NP pointed VBD B-VP out RP B-PRT the DT B-NP importance NN I-NP of IN B-PP the DT B-NP carbon-20 NN I-NP position NN I-NP and CC O led VBD B-VP to TO B-PP the DT B-NP development NN I-NP of IN B-PP 20-methyl NN B-NP derivatives NNS I-NP of IN B-PP VD NN B-NP . . O In IN B-PP this DT B-NP report NN I-NP the DT B-NP biological JJ I-NP properties NNS I-NP of IN B-PP the DT B-NP compounds NNS I-NP ZK161422 NN B-NP and CC O ZK157202 NN B-NP COMMA COMMA O which WDT B-NP are VBP B-VP 20-methyl- NN B-NP and CC O 20-methyl-23-eneanalogues NN B-NP COMMA COMMA O respectively RB B-ADVP COMMA COMMA O have VBP B-VP been VBN I-VP analyzed VBN I-VP in IN B-PP comparison NN I-PP with IN I-PP VD NN B-NP . . O Both DT B-NP compounds NNS I-NP show VBP B-VP about IN B-ADVP 2-fold RB I-ADVP lower JJR B-NP affinity NN I-NP to TO B-PP the DT B-NP VD NN I-NP receptor NN I-NP ( ( O VDR NN B-NP ) ) O than IN B-PP VD NN B-NP . . O However RB B-ADVP COMMA COMMA O compared VBN B-VP to TO B-PP VD NN B-NP COMMA COMMA O their PRP$ B-NP antiproliferative JJ I-NP effect NN I-NP is VBZ B-VP up RB B-ADJP to TO I-ADJP 30-fold RB I-ADJP higher JJR I-ADJP on IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP and CC O even RB B-ADJP up RB I-ADJP to TO I-ADJP 300-fold RB I-ADJP higher JJR I-ADJP on IN B-PP human JJ B-NP breast NN I-NP cancer NN I-NP MCF-7 NN I-NP cells NNS I-NP . . O Whereas IN B-SBAR the DT B-NP hypercalcemic JJ I-NP effect NN I-NP for IN B-PP ZK157202 NN B-NP is VBZ B-VP also RB I-VP increased VBN I-VP 10-fold RB B-ADVP COMMA COMMA O ZK161422 NN B-NP has VBZ B-VP the DT B-NP same JJ I-NP calcium-mobilizing JJ I-NP potency NN I-NP as IN B-PP VD NN B-NP . . O Moreover RB B-ADVP COMMA COMMA O ZK161422 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP ZK157202 NN B-NP COMMA COMMA O showed VBD B-VP preference NN B-NP for IN B-PP gene NN B-NP activation NN I-NP from IN B-PP a DT B-NP promoter NN I-NP carrying VBG B-VP a DT B-NP VD NN I-NP response NN I-NP element NN I-NP with IN B-PP a DT B-NP palindromic JJ I-NP arrangement NN I-NP of IN B-PP two CD B-NP hexameric JJ I-NP receptor NN I-NP binding NN I-NP sites NNS I-NP spaced VBN B-VP by IN B-PP 9 CD B-NP nucleotides NNS I-NP ( ( O IP9 NN B-NP ) ) O rather RB B-CONJP than IN I-CONJP for IN B-PP activation NN B-NP from IN B-PP a DT B-NP response NN I-NP element NN I-NP formed VBN B-VP by IN B-PP a DT B-NP direct JJ I-NP repeat NN I-NP spaced VBN B-VP by IN B-PP 3 CD B-NP nucleotides NNS I-NP ( ( O DR3 NN B-NP ) ) O . . O This DT B-NP observation NN I-NP supports VBZ B-VP a DT B-NP model NN I-NP COMMA COMMA O in IN B-PP which WDT B-NP promoter NN B-NP selectivity NN I-NP reflects VBZ B-VP the DT B-NP selectively RB I-NP increased VBN I-NP antiproliferative JJ I-NP effect NN I-NP of IN B-PP VD NN B-NP analogues NNS I-NP . . O Interferon NN B-NP augments VBZ B-VP PML NN B-NP and CC O PML\/RAR NN B-NP alpha NN I-NP expression NN B-NP in IN B-PP normal JJ B-NP myeloid JJ I-NP and CC I-NP acute JJ I-NP promyelocytic JJ I-NP cells NNS I-NP and CC O cooperates VBZ B-VP with IN B-PP all-trans JJ B-NP retinoic JJ I-NP acid NN I-NP to TO B-VP induce VB I-VP maturation NN B-NP of IN B-PP a DT B-NP retinoid-resistant JJ I-NP promyelocytic JJ I-NP cell NN I-NP line NN I-NP . . O The DT B-NP PML NN I-NP gene NN I-NP is VBZ B-VP fused VBN I-VP to TO B-PP the DT B-NP retinoic JJ I-NP acid NN I-NP receptor NN I-NP alpha NN I-NP gene NN I-NP ( ( O RAR NN B-NP alpha NN I-NP ) ) O in IN B-PP the DT O acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP ( ( O APL NN B-NP ) ) O 15 CD B-NP ; : I-NP 17 CD I-NP translocation NN I-NP . . O PML NN B-NP is VBZ B-VP expressed VBN I-VP in IN B-PP diverse JJ B-NP tissues NNS B-NP and CC O cell NN B-NP lines NNS I-NP and CC O localized JJ B-VP in IN B-PP the DT B-NP nucleus NN I-NP with IN B-PP a DT B-NP typical JJ I-NP speckled JJ I-NP pattern NN I-NP . . O In IN B-PP the DT B-NP bone NN I-NP marrow NN I-NP COMMA COMMA O it PRP B-NP is VBZ B-VP preferentially RB I-VP expressed VBN I-VP in IN B-PP myeloid JJ B-NP cells NNS I-NP . . O PML NN B-NP appears VBZ B-VP to TO I-VP be VB I-VP transcriptionally RB I-VP regulated VBN I-VP by IN B-PP class NN O I CD B-NP and CC O II CD B-NP interferons NNS B-NP COMMA COMMA O which WDT B-NP raises VBZ B-VP the DT B-NP possibility NN I-NP that IN B-SBAR interferons NNS B-NP modulate VBP B-VP the DT O function NN B-NP and CC O growth NN B-NP and CC O differentiation NN B-NP potential NN B-NP of IN B-PP normal JJ B-NP myeloid JJ I-NP cells NNS B-NP and CC O precursors NNS B-NP by IN B-PP activating VBG B-VP PML-dependent JJ B-NP pathways NNS I-NP . . O Generation NN B-NP of IN B-PP CD1+RelB+ JJ B-NP dendritic JJ I-NP cells NNS I-NP and CC O tartrate-resistant JJ B-NP acid NN I-NP phosphatase-positive JJ I-NP osteoclast-like JJ I-NP multinucleated JJ I-NP giant JJ I-NP cells NNS I-NP from IN B-PP human JJ B-NP monocytes NNS I-NP . . O We PRP B-NP previously RB B-ADVP showed VBD B-VP that IN B-SBAR granulocyte-macrophage JJ B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O GM-CSF NN B-NP ) ) O and CC O macrophage NN B-NP colony-stimulating JJ I-NP factor NN I-NP ( ( O M-CSF NN B-NP ) ) O stimulate VBP B-VP the DT B-NP differentiation NN I-NP of IN B-PP human JJ B-NP monocytes NNS I-NP into IN B-PP two CD B-NP phenotypically RB I-NP distinct JJ I-NP types NNS I-NP of IN B-PP macrophages NNS B-NP . . O However RB B-ADVP COMMA COMMA O in FW B-ADVP vivo FW I-ADVP COMMA COMMA O not RB B-CONJP only RB I-CONJP CSF NN B-NP but CC B-CONJP also RB I-CONJP many JJ B-NP other JJ I-NP cytokines NNS I-NP are VBP B-VP produced VBN I-VP under IN B-PP various JJ B-NP conditions NNS I-NP . . O Those DT B-NP cytokines NNS I-NP may MD B-VP modulate VB I-VP the DT B-NP differentiation NN I-NP of IN B-PP monocytes NNS B-NP by IN B-PP CSFs NNS B-NP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP COMMA COMMA O we PRP B-NP showed VBD B-VP that IN B-SBAR CD14+ JJ B-NP adherent JJ I-NP human JJ I-NP monocytes NNS I-NP can MD B-VP differentiate VB I-VP into IN B-PP CD1+relB+ JJ B-NP dendritic JJ B-NP cells NNS I-NP ( ( O DC NN B-NP ) ) O by IN B-PP the DT B-NP combination NN I-NP of IN B-PP GM-CSF NN B-NP plus CC O interleukin-4 NN B-NP ( ( O IL-4 NN B-NP ) ) O and CC O that IN B-SBAR they PRP B-NP differentiate VBP B-VP into IN B-PP tartrate-resistant JJ B-NP acid NN I-NP phosphatase NN I-NP ( ( I-NP TRAP NN I-NP ) ) I-NP -positive JJ I-NP osteoclast-like JJ I-NP multinucleated JJ B-NP giant JJ I-NP cells NNS I-NP ( ( O MGC NN B-NP ) ) O by IN B-PP the DT B-NP combination NN I-NP of IN B-PP M-CSF NN B-NP plus CC O IL-4 NN B-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP monocyte-derived JJ I-NP DC NN I-NP were VBD B-VP not RB O terminally RB B-NP differentiated VBN I-NP cells NNS I-NP ; : O they PRP B-NP could MD B-VP still RB I-VP convert VB I-VP to TO B-PP macrophages NNS B-NP in IN B-PP response NN I-PP to TO I-PP M-CSF NN B-NP . . O Tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O stimulated VBD B-VP the DT B-NP terminal JJ I-NP differentiation NN I-NP of IN B-PP the DT B-NP DC NN I-NP by IN B-PP downregulating VBG B-VP the DT B-NP expression NN I-NP of IN B-PP the DT B-NP M-CSF NN I-NP receptor NN I-NP COMMA COMMA O cfms NN B-NP mRNA NN I-NP COMMA COMMA O and CC O aborting VBG B-VP the DT B-NP potential NN I-NP to TO B-VP convert VB I-VP to TO B-PP macrophages NNS B-NP . . O In IN B-PP contrast NN I-PP to TO I-PP IL-4 NN B-NP COMMA COMMA O interferon-gamma NN B-NP ( ( O IFN-gamma NN B-NP ) ) O had VBD B-VP no DT B-NP demonstrable JJ I-NP effect NN I-NP on IN B-PP the DT B-NP differentiation NN I-NP of IN B-PP monocytes NNS B-NP . . O Rather RB B-ADVP COMMA COMMA O IFN-gamma NN B-NP antagonized VBD B-VP the DT B-NP effect NN I-NP of IN B-PP IL-4 NN B-NP and CC O suppressed VBD B-VP the DT O DC NN B-NP and CC O MGC NN B-NP formation NN B-NP induced VBN B-VP by IN B-PP GM-CSF NN B-NP + CC O IL-4 NN B-NP and CC O M-CSF NN B-NP + CC O IL-4 NN B-NP COMMA COMMA O respectively RB B-ADVP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O these DT B-NP results NNS I-NP provide VBP B-VP a DT B-NP new JJ I-NP aspect NN I-NP to TO B-PP our PRP$ B-NP knowledge NN I-NP of IN B-PP monocyte NN B-NP differentiation NN I-NP and CC O provide VBP B-VP evidence NN B-NP that IN B-SBAR human JJ B-NP monocytes NNS I-NP are VBP B-VP flexible JJ B-ADJP in IN B-PP their PRP$ B-NP differentiation NN I-NP potential NN I-NP and CC O are VBP B-VP precursors NNS B-NP not RB B-CONJP only RB I-CONJP of IN B-PP macrophages NNS B-NP but CC B-CONJP also RB I-CONJP of IN B-PP CD1+relB+DC NN B-NP and CC O TRAP-positive JJ B-NP MGC NN I-NP . . O Such PDT B-NP a DT I-NP diverse JJ I-NP pathway NN I-NP of IN B-PP monocyte NN B-NP differentiation NN I-NP may MD B-VP constitute VB I-VP one CD B-NP of IN B-PP the DT B-NP basic JJ I-NP mechanisms NNS I-NP of IN B-PP immune JJ B-NP regulation NN I-NP . . O T NN B-NP cell NN I-NP response NN I-NP to TO B-PP Epstein-Barr JJ B-NP virus NN I-NP transactivators NNS I-NP in IN B-PP chronic JJ B-NP rheumatoid JJ I-NP arthritis NN I-NP . . O Rheumatoid JJ B-NP arthritis NN I-NP is VBZ B-VP a DT B-NP multistep JJ I-NP disorder NN I-NP associated VBN B-VP with IN B-PP autoimmune JJ B-NP features NNS I-NP of IN B-PP yet RB B-NP unknown JJ I-NP etiology NN I-NP . . O Implication NN B-NP of IN B-PP viruses NNS B-NP such JJ B-PP as IN I-PP Epstein-Barr JJ B-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O in IN B-PP rheumatoid JJ B-NP arthritis NN I-NP pathogenesis NN I-NP has VBZ B-VP been VBN I-VP suspected VBN I-VP on IN B-PP the DT I-PP basis NN I-PP of IN I-PP several JJ B-NP indirect JJ I-NP observations NNS I-NP COMMA COMMA O but CC O thus RB B-ADVP far RB I-ADVP COMMA COMMA O a DT B-NP direct JJ I-NP link NN I-NP between IN B-PP EBV NN B-NP and CC O rheumatoid JJ B-NP arthritis NN I-NP has VBZ B-VP not RB I-VP been VBN I-VP provided VBN I-VP . . O Here RB B-ADVP we PRP B-NP show VBP B-VP that IN B-SBAR a DT B-NP large JJ I-NP fraction NN I-NP of IN B-PP T NN B-NP cells NNS I-NP infiltrating VBG B-VP affected VBN B-NP joints NNS I-NP from IN B-PP a DT B-NP patient NN I-NP with IN B-PP chronic JJ B-NP rheumatoid JJ I-NP arthritis NN I-NP recognizes VBZ B-VP two CD B-NP EBV NN I-NP transactivators NNS I-NP ( ( O BZLF1 NN B-NP and CC O BMLF1 NN B-NP ) ) O in IN B-PP a DT B-NP major JJ I-NP histocompatibility NN I-NP complex-restricted JJ I-NP fashion NN I-NP . . O Responses NNS B-NP to TO B-PP these DT B-NP EBV NN I-NP antigens NNS I-NP by IN B-PP synovial JJ B-NP lymphocytes NNS I-NP from IN B-PP several JJ B-NP other JJ I-NP chronic JJ I-NP rheumatoid JJ I-NP arthritis NN I-NP patients NNS I-NP were VBD B-VP readily RB B-ADJP detectable JJ I-ADJP . . O Thus RB B-ADVP these DT B-NP results NNS I-NP suggest VBP B-VP a DT B-NP direct JJ I-NP contribution NN I-NP of IN B-PP EBV NN B-NP to TO B-PP chronic JJ B-NP rheumatoid JJ I-NP arthritis NN I-NP pathogenesis NN I-NP . . O They PRP B-NP also RB B-ADVP demonstrate VBP B-VP for IN B-PP the DT B-NP first JJ I-NP time NN I-NP the DT B-NP occurrence NN I-NP of IN B-PP T NN B-NP cell NN I-NP responses NNS I-NP against IN B-PP EBV NN B-NP transactivating VBG I-NP factors NNS I-NP COMMA COMMA O which WDT B-NP might MD B-VP be VB I-VP central JJ B-ADJP in IN B-PP the DT B-NP control NN I-NP of IN B-PP virus NN B-NP reactivation NN I-NP . . O Differential JJ B-NP nuclear JJ I-NP localization NN I-NP of IN B-PP p50 NN B-NP COMMA COMMA O p52 NN B-NP COMMA COMMA O and CC O RelB NN B-NP proteins NNS B-NP in IN B-PP human JJ B-NP accessory JJ I-NP cells NNS I-NP of IN B-PP the DT B-NP immune JJ I-NP response NN I-NP in FW B-ADVP situ FW I-ADVP . . O The DT B-NP Rel\/NF-kappa NN I-NP B NN I-NP proteins NNS I-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O p52 NN B-NP COMMA COMMA O p65 NN B-NP COMMA COMMA O c-Rel NN B-NP COMMA COMMA O and CC O RelB NN B-NP COMMA COMMA O constitute VBP B-VP a DT B-NP family NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP involved VBN B-VP in IN B-PP the DT B-NP positive JJ I-NP regulation NN I-NP of IN B-PP a DT B-NP variety NN I-NP of IN B-PP genes NNS B-NP during IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O Recently RB B-ADVP COMMA COMMA O it PRP B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP that IN B-SBAR RelB NN B-NP knockout JJ I-NP mice NNS I-NP have VBP B-VP no DT B-NP dendritic JJ B-NP cells NNS I-NP ( ( O DC NN B-NP ) ) O . . O An DT B-NP overexpression NN I-NP of IN B-PP p50 NN B-NP has VBZ B-VP been VBN I-VP described VBN I-VP in IN B-PP follicular JJ B-NP dendritic JJ I-NP cells NNS I-NP ( ( O FDC NN B-NP ) ) O . . O A DT B-NP constitutive JJ I-NP NF-kappa NN I-NP B NN I-NP activity NN I-NP has VBZ B-VP been VBN I-VP reported VBN I-VP in IN B-PP mature JJ B-NP macrophages NNS I-NP . . O This DT B-NP led VBD B-VP to TO B-PP the DT B-NP hypothesis NN I-NP that IN B-SBAR some DT B-NP of IN B-PP the DT B-NP Rel\/NF-kappa NN I-NP B NN I-NP proteins NNS I-NP were VBD B-VP key JJ B-NP nuclear JJ I-NP factors NNS I-NP in IN B-PP functions NNS B-NP of IN B-PP accessory JJ B-NP cells NNS I-NP of IN B-PP the DT B-NP immune JJ I-NP response NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP investigated VBD B-VP in FW B-ADVP situ FW I-ADVP the DT B-NP nuclear JJ I-NP localization NN I-NP of IN B-PP Rel\/NF-kappa NN B-NP B NN I-NP proteins NNS I-NP in IN B-PP accessory JJ B-NP cells NNS I-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP by IN B-PP immunohistochemistry NN B-NP and CC O double JJ B-NP labeling NN I-NP by IN B-PP immunofluorescence NN B-NP from IN B-PP five CD B-NP normal JJ I-NP human JJ I-NP tonsils NNS I-NP and CC O five CD B-NP lymph NN I-NP nodes NNS I-NP with IN B-PP follicular JJ B-NP hyperplasia NN I-NP . . O Nuclear JJ O p65 NN B-NP and CC O c-Rel NN B-NP proteins NNS B-NP were VBD B-VP found VBN I-VP in IN B-PP all DT B-NP cell NN I-NP types NNS I-NP including VBG B-PP lymphocytes NNS B-NP . . O In IN B-PP germinal JJ B-NP centers NNS I-NP GC NN I-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O p52 NN B-NP COMMA COMMA O and CC O RelB NN B-NP were VBD B-VP found VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP FDC NN B-NP only RB B-ADVP and CC O were VBD B-VP not RB I-VP detected VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP CD68+ JJ B-NP cells NNS I-NP . . O In IN B-PP T NN B-NP cell NN I-NP areas NNS I-NP COMMA COMMA O p50 NN B-NP COMMA COMMA O p52 NN B-NP COMMA COMMA O and CC O RelB NN B-NP were VBD B-VP found VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP of IN B-PP HLA-DR+ JJ B-NP cells NNS I-NP with IN B-PP an DT O antigen-presenting JJ B-NP cell NN I-NP ( ( O APC NN B-NP ) ) O morphology NN B-NP . . O p52 NN B-NP and CC O RelB NN B-NP were VBD B-VP detected VBN I-VP in IN B-PP the DT B-NP nuclei NNS I-NP in IN B-PP both CC B-NP CD1a+ JJ I-NP and CC I-NP CD68+ JJ I-NP cells NNS I-NP from IN B-PP the DT B-NP T NN I-NP cell NN I-NP area NN I-NP COMMA COMMA O whereas IN O p50 NN B-NP was VBD B-VP found VBN I-VP only RB B-PP in IN I-PP CD68- JJ B-NP and CC I-NP CD1a- JJ I-NP cells NNS I-NP . . O Cells NNS B-NP with IN B-PP nuclear JJ B-NP p50 NN I-NP were VBD B-VP negative JJ B-ADJP for IN B-PP the DT O CD38 NN B-NP COMMA COMMA O CD20 NN B-NP and CC O CD2 NN B-NP markers NNS B-NP . . O These DT B-NP results NNS I-NP show VBP B-VP that IN B-SBAR COMMA COMMA O physiologically RB B-ADVP COMMA COMMA O high JJ B-NP levels NNS I-NP of IN B-PP nuclear JJ B-NP of IN B-PP p50 NN B-NP COMMA COMMA O p52 NN B-NP and CC O RelB NN B-NP are VBP B-VP restricted JJ I-VP to TO B-PP accessory JJ B-NP cells NNS I-NP of IN B-PP the DT B-NP immune JJ I-NP system NN I-NP COMMA COMMA O which WDT B-NP include VBP B-VP FDC NN B-NP in IN B-PP GC NN B-NP COMMA COMMA O and CC O DC NN B-NP and CC O macrophages NNS B-NP in IN B-PP the DT B-NP T NN I-NP cell NN I-NP zone NN I-NP COMMA COMMA O that IN B-SBAR specialized VBN B-NP scavenger NN I-NP macrophages NNS I-NP from IN B-PP GC NN B-NP do VBP B-VP not RB I-VP have VB I-VP detectable JJ B-NP levels NNS I-NP of IN B-PP p52 NN B-NP and CC O RelB NN B-NP COMMA COMMA O whereas IN O macrophages NNS B-NP from IN B-PP the DT B-NP T NN I-NP cell NN I-NP area NN I-NP COMMA COMMA O known VBN B-VP to TO I-VP present VB I-VP the DT B-NP antigen NN I-NP to TO B-PP T NN B-NP cells NNS I-NP COMMA COMMA O do VBP B-VP have VB I-VP both CC B-NP nuclear JJ I-NP p52 NN B-NP and CC O RelB NN B-NP COMMA COMMA O and CC O that IN B-SBAR in IN B-PP the DT B-NP T NN I-NP cell NN I-NP zone NN I-NP COMMA COMMA O p52 NN B-NP and CC O RelB NN B-NP are VBP B-VP located JJ B-ADJP in IN B-PP nuclei NNS B-NP of IN B-PP both DT B-NP CD1a+ JJ I-NP COMMA COMMA I-NP CD68+ JJ I-NP or CC I-NP both DT I-NP COMMA COMMA I-NP cells NNS I-NP APC NN I-NP COMMA COMMA O whereas IN O p50 NN B-NP is VBZ B-VP restricted JJ I-VP to TO B-PP CD1a- NN B-NP and CC I-NP CD68- JJ I-NP APC NN I-NP . . O The DT B-NP different JJ I-NP patterns NNS I-NP of IN B-PP p50 NN B-NP COMMA COMMA O p52 NN B-NP and CC O RelB NN B-NP protein NN B-NP nuclear JJ I-NP localization NN I-NP may MD B-VP provide VB I-VP insight NN B-NP into IN B-PP their PRP$ B-NP different JJ I-NP roles NNS I-NP during IN B-PP the DT B-NP immune JJ I-NP response NN I-NP in FW B-ADVP vivo FW I-ADVP . . O Signal NN B-NP transduction NN I-NP by IN B-PP DR3 NN B-NP COMMA COMMA O a DT B-NP death NN I-NP domain-containing JJ I-NP receptor NN I-NP related JJ B-ADJP to TO B-PP TNFR-1 NN B-NP and CC O CD95 NN B-NP . . O Tumor NN B-NP necrosis NN I-NP factor NN I-NP receptor-1 NN I-NP ( ( O TNFR-1 NN B-NP ) ) O and CC O CD95 NN B-NP ( ( O also RB B-VP called VBN I-VP Fas NN B-NP or CC O APO-1 NN B-NP ) ) O are VBP B-VP cytokine NN B-NP receptors NNS I-NP that WDT B-NP engage VBP B-VP the DT B-NP apoptosis NN I-NP pathway NN I-NP through IN B-PP a DT B-NP region NN I-NP of IN B-PP intracellular JJ B-NP homology NN I-NP COMMA COMMA O designated VBD B-VP the DT B-NP " `` I-NP death NN I-NP domain NN I-NP . . O " '' O Another DT B-NP death NN I-NP domain-containing NN I-NP member NN I-NP of IN B-PP the DT B-NP TNFR NN I-NP family NN I-NP COMMA COMMA O death NN B-NP receptor NN I-NP 3 CD I-NP ( ( O DR3 NN B-NP ) ) O COMMA COMMA O was VBD B-VP identified VBN I-VP and CC O was VBD B-VP shown VBN I-VP to TO I-VP induce VB I-VP both CC O apoptosis NNS B-NP and CC O activation NN B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappaB NN I-NP . . O Expression NN B-NP of IN B-PP DR3 NN B-NP appears VBZ B-VP to TO I-VP be VB I-VP restricted JJ I-VP to TO B-PP tissues NNS B-NP enriched VBN B-VP in IN B-PP lymphocytes NNS B-NP . . O DR3 NN B-NP signal NN I-NP transduction NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP a DT B-NP complex NN I-NP of IN B-PP intracellular JJ B-NP signaling VBG I-NP molecules NNS I-NP including VBG B-PP TRADD NN B-NP COMMA COMMA O TRAF2 NN B-NP COMMA COMMA O FADD NN B-NP COMMA COMMA O and CC O FLICE NN B-NP . . O Thus RB B-ADVP COMMA COMMA O DR3 NN B-NP likely RB B-ADVP plays VBZ B-VP a DT B-NP role NN I-NP in IN B-PP regulating VBG B-VP lymphocyte NN B-NP homeostasis NN I-NP . . O Cloning NN B-NP and CC O expression NN B-NP of IN B-PP the DT B-NP Epstein-Barr JJ I-NP virus-encoded JJ I-NP dUTPase NN I-NP : : O patients NNS B-NP with IN B-PP acute JJ B-NP COMMA COMMA I-NP reactivated VBN I-NP or CC I-NP chronic JJ I-NP virus NN I-NP infection NN I-NP develop VBP B-VP antibodies NNS B-NP against IN B-PP the DT B-NP enzyme NN I-NP . . O The DT B-NP gene NN I-NP encoding VBG B-VP the DT O Epstein-Barr JJ B-NP virus NN I-NP ( ( B-NP EBV NN I-NP ) ) I-NP -specific JJ I-NP dUTPase NN I-NP was VBD B-VP amplified VBN I-VP from IN B-PP virus NN B-NP DNA NN I-NP by IN B-PP PCR NN B-NP . . O The DT B-NP active JJ I-NP enzyme NN I-NP was VBD B-VP expressed VBN I-VP in IN B-PP Escherichia FW B-NP coli FW I-NP and CC B-PP in IN B-PP insect NN B-NP cells NNS I-NP as IN B-PP a DT B-NP non-fusion JJ I-NP protein NN I-NP . . O The DT B-NP protein NN I-NP from IN B-PP E. FW B-NP coli FW I-NP specifically RB B-ADVP converted VBD B-VP dUTP NN B-NP to TO B-PP dUMP NN B-NP and CC O did VBD B-VP not RB I-VP react VB I-VP with IN B-PP other JJ B-NP dNTPs NNS B-NP or CC O NTPs NNS B-NP . . O Preliminary JJ B-NP experiments NNS I-NP yielded VBD B-VP a DT B-NP Km NN I-NP value NN I-NP of IN B-PP about RB B-NP 0.8 CD I-NP microM NN I-NP for IN B-PP dUTP NN B-NP . . O MAbs NNS B-NP against IN B-PP the DT B-NP dUTPase NN I-NP reacted VBD B-VP with IN B-PP a DT B-NP protein NN I-NP of IN B-PP approximately RB B-NP 31 CD I-NP kDa NN I-NP in IN B-PP 12-O-tetradecanoyl-phorbol-13-acetate NN B-NP ( ( B-NP TPA NN I-NP ) ) I-NP -stimulated JJ I-NP B NN I-NP cells NNS I-NP harbouring VBG B-VP either CC O type NN B-NP 1 CD I-NP or CC O type NN B-NP 2 CD I-NP EBV NN B-NP . . O The DT B-NP protein NN I-NP was VBD B-VP found VBN I-VP in IN B-PP untreated JJ B-NP cells NNS I-NP at IN B-PP low JJ B-NP levels NNS I-NP COMMA COMMA O whereas IN O induction NN B-NP of IN B-PP the DT B-NP lytic JJ I-NP replication NN I-NP cycle NN I-NP by IN B-PP TPA NN B-NP treatment NN I-NP or CC B-PP by IN B-PP providing VBG B-VP the DT B-NP immediate JJ I-NP early JJ I-NP transactivator NN I-NP BZLF1 NN I-NP in IN B-PP trans NN B-NP resulted VBD B-VP in IN B-PP increased VBN B-NP expression NN I-NP . . O We PRP B-NP demonstrated VBD B-VP that IN B-SBAR the DT B-NP virus NN I-NP dUTPase NN I-NP isolated VBN B-VP from IN B-PP EBV-infected JJ B-NP cells NNS I-NP is VBZ B-VP a DT B-NP phosphoprotein NN I-NP . . O The DT B-NP protein NN I-NP expressed VBN B-VP in IN B-PP insect NN B-NP cells NNS I-NP was VBD B-VP used VBN I-VP to TO B-VP test VB I-VP for IN B-PP the DT B-NP presence NN I-NP of IN B-PP specific JJ B-NP antibodies NNS I-NP in IN B-PP sera NN B-NP from IN B-PP normal JJ B-NP COMMA COMMA I-NP healthy JJ I-NP carriers NNS I-NP and CC B-PP from IN B-PP patients NNS B-NP with IN B-PP various JJ B-NP diseases NNS I-NP . . O While IN B-SBAR the DT B-NP sera NN I-NP of IN B-PP EBV-negative JJ B-NP individuals NNS I-NP ( ( O 0\/3 CD B-NP ) ) O or CC O healthy JJ B-NP carriers NNS I-NP ( ( O 0\/33 CD B-NP ) ) O did VBD B-VP not RB I-VP contain VB I-VP detectable JJ B-NP levels NNS I-NP of IN B-PP antibodies NNS B-NP COMMA COMMA O patients NNS B-NP with IN B-PP mononucleosis NN B-NP ( ( O 5\/18 CD B-NP ) ) O COMMA COMMA O chronic JJ B-NP EBV NN I-NP infection NN I-NP ( ( O 2\/7 CD B-NP ) ) O COMMA COMMA O EBV NN B-NP reactivation NN I-NP ( ( O 7\/20 CD B-NP ) ) O and CC O human JJ B-NP immunodeficiency NN I-NP virus NN I-NP infection NN I-NP ( ( O 5\/24 CD B-NP ) ) O showed VBD B-VP elevated JJ B-NP antibody NN I-NP titres NNS I-NP against IN B-PP the DT B-NP enzyme NN I-NP . . O This DT B-NP indicated VBD B-VP that IN B-SBAR the DT B-NP dUTPase NN I-NP is VBZ B-VP expressed VBN I-VP during IN B-PP EBV NN B-NP replication NN B-NP and CC O reactivation NN B-NP . . O The DT B-NP enzyme NN I-NP might MD B-VP therefore RB I-VP be VB I-VP a DT B-NP potential JJ I-NP target NN I-NP for IN B-PP drug NN B-NP therapy NN I-NP under IN B-PP conditions NNS B-NP of IN B-PP active JJ B-NP DNA NN I-NP replication NN I-NP . . O Prostaglandin NN B-NP E2 NN I-NP induction NN I-NP of IN B-PP binding NN B-NP activity NN I-NP to TO B-PP CRE NN B-NP and CC O AP-2 NN B-NP elements NNS B-NP in IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP . . O Prostaglandins NNP B-NP of IN B-PP the DT B-NP E NN I-NP series NNS I-NP are VBP B-VP immunomodulatory JJ B-NP agents NNS I-NP which WDT B-NP exert VBP B-VP inhibitory JJ O as RB B-CONJP well RB I-CONJP as IN I-CONJP stimulatory JJ B-NP effects NNS I-NP on IN B-PP a DT B-NP variety NN I-NP of IN B-PP immune JJ B-NP responses NNS I-NP . . O Since IN B-SBAR it PRP B-NP is VBZ B-VP known VBN I-VP that IN B-SBAR PGE2 NN B-NP is VBZ B-VP able JJ B-ADJP to TO B-VP increase VB I-VP cAMP NN B-NP levels NNS I-NP COMMA COMMA O we PRP B-NP investigated VBD B-VP whether IN B-SBAR it PRP B-NP can MD B-VP affect VB I-VP gene NN B-NP expression NN I-NP through IN B-PP the DT B-NP activation NN I-NP of IN B-PP the DT B-NP transcription NN I-NP factors NNS I-NP which WDT B-NP bind VBP B-VP enhancer NN B-NP elements NNS I-NP in IN B-PP the DT B-NP promoter NN I-NP regions NNS I-NP of IN B-PP cAMP-regulated JJ B-NP genes NNS I-NP . . O Using VBG B-VP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assay NN I-NP COMMA COMMA O we PRP B-NP demonstrated VBD B-VP that IN B-SBAR a DT B-NP short JJ I-NP treatment NN I-NP of IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP with IN B-PP PGE2 NN B-NP induces VBZ B-VP specific JJ B-NP binding NN I-NP activity NN I-NP to TO B-PP CRE NN B-NP and CC O AP-2 NN B-NP COMMA COMMA O but CC B-NP not RB I-NP AP-1 NN B-NP COMMA COMMA O DNA NN B-NP elements NNS I-NP . . O Since IN B-SBAR the DT B-NP okadaic JJ I-NP acid NN I-NP COMMA COMMA O a DT B-NP potent JJ I-NP protein NN I-NP phosphatase NN I-NP inhibitor NN I-NP COMMA COMMA O prolongs VBZ B-VP the DT B-NP induction NN I-NP of IN B-PP the DT B-NP binding NN I-NP activity NN I-NP COMMA COMMA O phosphorylation NN B-NP events NNS I-NP are VBP B-VP likely JJ B-ADJP to TO B-VP occur VB I-VP . . O This DT B-NP activity NN I-NP seems VBZ B-VP to TO I-VP be VB I-VP due JJ B-PP to TO I-PP increased VBN B-NP cAMP NN I-NP levels NNS I-NP because IN B-SBAR forskolin NN B-NP and CC O IBMX NN B-NP mimic VBP B-VP the DT B-NP effects NNS I-NP of IN B-PP PGE2 NN B-NP . . O More RBR B-ADVP interestingly RB I-ADVP COMMA COMMA O transfection NN B-NP experiments NNS I-NP with IN B-PP CRE-CAT NN B-NP plasmide NN I-NP show VBP B-VP that IN B-SBAR PGE2 NN B-NP activates VBZ B-VP the DT B-NP transcription NN I-NP of IN B-PP a DT B-NP CRE-containing NN I-NP promoter NN I-NP . . O These DT B-NP data NNS I-NP support VBP B-VP the DT B-NP positive JJ I-NP role NN I-NP for IN B-PP PGE2 NN B-NP on IN B-PP some DT B-NP immune JJ I-NP functions NNS I-NP . . O Regulation NN B-NP of IN B-PP cytokine NN B-NP and CC O cytokine NN B-NP receptor NN I-NP expression NN B-NP by IN B-PP glucocorticoids NNS B-NP . . O Glucocorticoids NNS B-NP ( ( O GCS NNS B-NP ) ) O profoundly RB B-ADVP inhibit VBP B-VP several JJ B-NP aspects NNS I-NP of IN B-PP T NN B-NP cell NN I-NP immunity NN I-NP largely RB B-PP through IN I-PP inhibition NN B-NP of IN B-PP cytokine NN B-NP expression NN I-NP at IN B-PP the DT B-NP transcriptional JJ I-NP and CC I-NP posttranscriptional JJ I-NP levels NNS I-NP . . O GCS NNS B-NP were VBD B-VP also RB I-VP reported VBN I-VP to TO I-VP act VB I-VP indirectly RB B-ADVP by IN B-PP inducing VBG B-VP transforming VBG B-NP growth NN I-NP factor-beta NN I-NP expression NN I-NP COMMA COMMA O which WDT B-NP in IN B-PP turn NN B-NP blocks VBZ B-VP T NN B-NP cell NN I-NP immunity NN I-NP . . O In IN B-PP exerting VBG B-VP their PRP$ B-NP antiproliferative JJ I-NP effects NNS I-NP COMMA COMMA O GCS NNS B-NP diffuse VBP B-VP into IN B-PP target NN B-NP cells NNS I-NP where WRB B-ADVP they PRP B-NP bind VBP B-VP their PRP$ B-NP cytoplasmic JJ I-NP receptor NN I-NP COMMA COMMA O which WDT B-NP in IN B-PP turn NN B-NP translocates VBZ B-VP to TO B-PP the DT B-NP nucleus NN I-NP where WRB B-ADVP it PRP B-NP inhibits VBZ B-VP transcription NN B-NP of IN B-PP cytokine NN B-NP genes NNS I-NP through IN B-PP direct JJ B-NP binding NN I-NP to TO B-PP the DT B-NP glucocorticoid NN I-NP response NN I-NP elements NNS I-NP ( ( O GRE NN B-NP ) ) O COMMA COMMA O which WDT B-NP are VBP B-VP located JJ B-ADJP in IN B-PP the DT B-NP promoter NN I-NP region NN I-NP of IN B-PP cytokine NN B-NP genes NNS I-NP or CC B-PP COMMA COMMA O alternatively RB B-ADVP COMMA COMMA B-PP through IN I-PP antagonism NN B-NP of IN B-PP the DT B-NP action NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP required VBN B-VP for IN B-PP optimal JJ B-NP transcriptional JJ I-NP activation NN I-NP . . O In IN B-PP contrast NN I-PP to TO I-PP their PRP$ B-NP inhibitory JJ I-NP effects NNS I-NP on IN B-PP cytokine NN B-NP expression NN I-NP COMMA COMMA O GCS NNS B-NP up-regulate VBP B-VP cytokine NN B-NP receptor NN I-NP expression NN I-NP that WDT B-NP correlates VBZ B-VP with IN B-PP enhanced VBN B-NP cytokine NN I-NP effects NNS I-NP on IN B-PP target NN B-NP cells NNS I-NP . . O In IN B-PP this DT B-NP review NN I-NP COMMA COMMA O we PRP B-NP summarize VBP B-VP the DT B-NP current JJ I-NP state NN I-NP of IN B-PP knowledge NN B-NP of IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP action NN B-NP of IN B-PP GCS NNS B-NP COMMA COMMA O including VBG B-PP the DT B-NP phenomenon NN I-NP of IN B-PP steroid-induced JJ B-NP rebound NN I-NP COMMA COMMA O which WDT B-NP ensues VBZ B-VP upon IN B-PP GCS NNS B-NP withdrawal NN I-NP . . O The DT B-NP Oct-2 NN I-NP transcription NN I-NP factor NN I-NP . . O The DT B-NP Oct-2 NN I-NP transcription NN I-NP factor NN I-NP is VBZ B-VP a DT B-NP member NN I-NP of IN B-PP the DT O POU NN B-NP ( ( O Pit-Oct-Unc NN B-NP ) ) O family NN B-NP of IN B-PP transcription NN B-NP factors NNS I-NP and CC O is VBZ B-VP expressed VBN I-VP only RB B-ADVP in IN B-PP B NN B-NP lymphocytes NNS I-NP and CC B-PP in IN B-PP neuronal JJ B-NP cells NNS I-NP but CC B-PP not RB B-PP in IN I-PP other JJ B-NP cell NN I-NP types NNS I-NP . . O The DT B-NP primary JJ I-NP RNA NN I-NP transcript NN I-NP of IN B-PP the DT B-NP gene NN I-NP is VBZ B-VP subject JJ B-ADJP to TO B-PP alternative JJ B-NP splicing NN I-NP to TO B-VP yield VB I-VP different JJ B-NP variants NNS I-NP which WDT B-NP can MD B-VP either CC O activate VBP B-VP or CC O repress VBP B-VP gene NN B-NP expression NN I-NP . . O The DT B-NP forms NNS I-NP produced VBN B-VP in IN B-PP B NN B-NP lymphocytes NNS I-NP have VBP B-VP a DT B-NP predominantly RB I-NP activating JJ I-NP effect NN I-NP on IN B-PP gene NN B-NP expression NN I-NP whereas IN O those DT B-NP produced VBN B-VP in IN B-PP neuronal JJ B-NP cells NNS I-NP have VBP B-VP a DT B-NP predominantly RB I-NP inhibitory JJ I-NP effect NN I-NP and CC O can MD B-VP repress VB I-VP the DT B-NP expression NN I-NP of IN B-PP both CC O the DT B-NP herpes NN I-NP simplex NN I-NP virus NN I-NP immediate-early JJ I-NP genes NNS I-NP and CC O the DT B-NP cellular JJ I-NP tyrosine NN I-NP hydroxylase NN I-NP gene NN I-NP . . O Thus RB B-ADVP Oct-2 NN B-NP plays VBZ B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP cellular JJ B-NP gene NN I-NP expression NN I-NP in IN B-PP both CC O B NN B-NP cells NNS I-NP and CC O neuronal JJ B-NP cells NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP in IN B-PP the DT B-NP control NN I-NP of IN B-PP viral JJ B-NP latency NN I-NP . . O Tissue NN B-NP and CC O cell-type JJ B-NP specific JJ B-NP expression NN I-NP of IN B-PP the DT B-NP tuberous JJ I-NP sclerosis NN I-NP gene NN I-NP COMMA COMMA O TSC2 NN B-NP COMMA COMMA O in IN B-PP human JJ B-NP tissues NNS I-NP . . O TSC2 NN B-NP is VBZ B-VP a DT B-NP gene NN I-NP on IN B-PP chromosome NN B-NP 16p13.3 NN I-NP associated VBN B-VP with IN B-PP the DT B-NP autosomal JJ I-NP dominant JJ I-NP neurocutaneous JJ I-NP disorder NN I-NP COMMA COMMA O tuberous JJ B-NP sclerosis NN I-NP complex NN I-NP ( ( O TSC NN B-NP ) ) O . . O By IN B-PP using VBG B-VP a DT B-NP partial JJ I-NP nucleotide JJ I-NP sequence NN I-NP from IN B-PP the DT B-NP cloned VBN I-NP TSC2 NN I-NP and CC O polymerase NN B-NP chain NN I-NP reaction NN I-NP methodology NN I-NP COMMA COMMA O we PRP B-NP constructed VBD B-VP a DT B-NP digoxigenin-labeled JJ I-NP complementary JJ I-NP DNA NN I-NP probe NN I-NP to TO B-VP examine VB I-VP TSC2 NN B-NP gene NN I-NP expression NN I-NP in IN B-PP autopsy- NN B-NP or CC O biopsy-derived JJ B-ADJP human JJ B-NP tissues NNS I-NP by IN B-PP in FW B-NP situ FW I-NP hybridization NN I-NP . . O TSC2 NN B-NP messenger NN I-NP RNA NN I-NP was VBD B-VP widely RB I-VP expressed VBN I-VP in IN B-PP various JJ B-NP cell NN I-NP types NNS I-NP throughout IN B-PP the DT B-NP body NN I-NP COMMA COMMA O including VBG B-PP epithelia NN B-NP COMMA COMMA O lymphocytes NNS B-NP COMMA COMMA O and CC O cells NNS B-NP with IN B-PP endocrine JJ B-NP functions NNS I-NP COMMA COMMA O e.g. FW B-ADVP COMMA COMMA O adrenal JJ B-NP cortex NN I-NP and CC O anterior JJ B-NP pituitary NN I-NP . . O It PRP B-NP was VBD O prominently RB B-ADVP and CC O selectively RB B-ADVP ( ( O within IN B-PP the DT B-NP central JJ I-NP nervous JJ I-NP system NN I-NP ) ) B-VP expressed VBN I-VP in IN B-PP pyramidal JJ B-NP cells NNS I-NP of IN B-PP the DT B-NP cerebral JJ I-NP cortex NN I-NP and CC O other JJ B-NP motor NN I-NP neurons NNS I-NP COMMA COMMA O e.g. FW B-ADVP COMMA COMMA B-PP in IN I-PP spinal JJ B-NP cord NN I-NP and CC O brainstem NN B-NP nuclei NNS I-NP . . O Visceral JJ B-NP TSC2 NN I-NP expression NN I-NP was VBD B-VP comparable JJ B-ADJP in IN B-PP autopsy NN B-NP tissues NNS I-NP from IN B-PP patients NNS B-NP with IN B-PP and CC B-PP without IN B-PP TSC NN B-NP ; : O TSC2 NN B-NP messenger NN I-NP RNA NN I-NP expression NN I-NP was VBD B-VP most RBS B-ADJP prominent JJ I-ADJP in IN B-PP cells NNS B-NP with IN B-PP a DT B-NP rapid JJ I-NP mitotic JJ I-NP rate NN B-NP and CC O turnover NN B-NP COMMA COMMA O e.g. FW B-ADVP COMMA COMMA O epithelia NN B-NP and CC O lymphocytes NNS B-NP COMMA COMMA O with IN B-PP central JJ B-NP nervous JJ I-NP system NN I-NP pyramidal JJ B-NP cells NNS I-NP and CC O other JJ B-NP neurons NNS I-NP being VBG B-VP an DT B-NP obvious JJ I-NP exception NN I-NP COMMA COMMA B-PP and\/or CC I-PP in IN B-PP cells NNS B-NP with IN B-PP important JJ B-NP secretory\/transport NN I-NP functions NNS I-NP . . O This DT B-NP widespread JJ I-NP expression NN I-NP of IN B-PP the DT B-NP TSC2 NN I-NP gene NN I-NP supports VBZ B-VP the DT B-NP view NN I-NP that IN B-SBAR it PRP B-NP encodes VBZ B-VP a DT B-NP protein NN I-NP vital JJ B-ADJP to TO B-PP cell NN B-NP growth NN B-NP and CC O metabolism NN B-NP or CC O one CD B-NP that WDT B-NP functions VBZ B-VP as IN B-PP a DT B-NP tumor\/growth NN I-NP suppressor NN I-NP . . O Cell NN B-NP specific JJ I-NP expression NN I-NP of IN B-PP human JJ B-NP Bruton NN B-NP 's POS B-NP agammaglobulinemia NN I-NP tyrosine NN I-NP kinase NN I-NP gene NN I-NP ( ( O Btk NN B-NP ) ) O is VBZ B-VP regulated VBN I-VP by IN B-PP Sp1- NN B-NP and CC O Spi-1\/PU.1-family NN B-NP members NNS I-NP . . O Bruton NN B-NP 's POS B-NP agammaglobulinemia NN I-NP tyrosine NN I-NP kinase NN I-NP ( ( O Btk NN B-NP ) ) O is VBZ B-VP a DT B-NP cytoplasmic JJ I-NP tyrosine NN I-NP kinase NN I-NP involved VBN B-VP in IN B-PP the DT B-NP human JJ I-NP disease NN I-NP X-linked JJ B-NP agammaglobulinemia NN I-NP ( ( O XLA NN B-NP ) ) O . . O The DT B-NP gene NN I-NP is VBZ B-VP expressed VBN I-VP in IN B-PP all DT B-NP hematopoietic JJ I-NP cells NNS I-NP with IN B-PP the DT B-NP exception NN I-NP of IN B-PP T-cells NNS B-NP and CC O plasma NN B-NP cells NNS I-NP . . O For IN B-PP this DT B-NP expression NN I-NP pattern NN I-NP the DT B-NP first JJ I-NP 280 CD I-NP bp NN I-NP upstream JJ B-ADJP of IN B-PP the DT B-NP major JJ I-NP transcriptional JJ I-NP start NN I-NP site NN I-NP seems VBZ B-VP to TO I-VP be VB I-VP sufficient JJ B-ADJP . . O In FW B-NP vitro FW I-NP footprinting NN I-NP analysis NN I-NP within IN B-PP this DT B-NP part NN I-NP of IN B-PP the DT B-NP promoter NN I-NP revealed VBD B-VP two CD B-NP Sp1 NN I-NP binding NN I-NP sites NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP a DT B-NP PU-box NN I-NP . . O The DT B-NP transcription NN I-NP factor NN I-NP Spi-1\/PU.1 NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP the DT B-NP closely RB I-NP related JJ I-NP factor NN I-NP Spi-B NN I-NP bound VBD B-VP to TO B-PP the DT B-NP PU-box NN I-NP in IN B-PP B-cells NNS B-NP . . O In IN B-PP the DT B-NP erythroleukemia NN I-NP cell NN I-NP line NN I-NP K562 NN I-NP COMMA COMMA O due IN B-PP to TO I-PP the DT B-NP absence NN I-NP of IN B-PP Spi-B NN B-NP COMMA COMMA O only RB B-NP PU.1 NN I-NP bound VBD B-VP to TO B-PP the DT B-NP Btk NN I-NP promoter NN I-NP . . O Mutation NN B-NP of IN B-PP either DT B-NP site NN I-NP reduced VBD B-VP the DT B-NP expression NN I-NP in IN B-PP transient JJ B-NP transfection NN I-NP experiments NNS I-NP . . O However RB B-ADVP COMMA COMMA O mutation NN B-NP of IN B-PP the DT B-NP PU NN I-NP box NN I-NP had VBD B-VP no DT B-NP effect NN I-NP in IN B-PP the DT B-NP T-cell NN I-NP line NN I-NP Jurkat NN I-NP COMMA COMMA O where WRB B-ADVP none NN B-NP of IN B-PP the DT B-NP Spi-1 NN I-NP family NN I-NP members NNS I-NP is VBZ B-VP expressed VBN I-VP . . O In IN B-PP addition NN B-NP Spi-B NN B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP PU.1 NN B-NP were VBD B-VP able JJ B-ADJP to TO B-VP transactivate VB I-VP Btk NN B-NP expression NN I-NP . . O In IN B-PP fetal JJ B-NP liver NN I-NP of IN B-PP PU.1-\/- JJ B-NP mice NNS I-NP COMMA COMMA O which WDT B-NP lack VBP B-VP lymphoid JJ B-NP and CC I-NP myeloid JJ I-NP cells NNS I-NP COMMA COMMA O expression NN B-NP of IN B-PP Btk NN B-NP was VBD B-VP reduced VBN I-VP two- CD B-ADVP to TO B-ADVP threefold RB B-ADVP but CC O not RB B-VP abolished VBN I-VP . . O Collectively RB B-ADVP this DT B-NP study NN I-NP shows VBZ B-VP that IN B-SBAR expression NN B-NP of IN B-PP the DT B-NP Btk NN I-NP gene NN I-NP is VBZ B-VP regulated VBN I-VP by IN B-PP the DT B-NP combined JJ I-NP action NN I-NP of IN B-PP Sp1- NN B-NP and CC O PU.1-family NN B-NP members NNS I-NP . . O Elf-1 NN B-NP and CC O Stat5 NN B-NP bind VBP B-VP to TO B-PP a DT B-NP critical JJ I-NP element NN I-NP in IN B-PP a DT B-NP new JJ I-NP enhancer NN I-NP of IN B-PP the DT B-NP human JJ I-NP interleukin-2 NN I-NP receptor NN I-NP alpha NN I-NP gene NN I-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP Mol NNP B-NP Cell NNP I-NP Biol NNP I-NP 1997 CD B-NP Apr NNP I-NP ; : O 17 CD B-NP ( ( I-NP 4 CD I-NP ) ) O : : O 2351 CD B-NP } ) O The DT O interleukin NN B-NP 2 CD I-NP receptor NN I-NP alpha-chain NN I-NP ( ( O IL-2R NN B-NP alpha NN I-NP ) ) O gene NN B-NP is VBZ B-VP a DT B-NP key JJ I-NP regulator NN I-NP of IN B-PP lymphocyte NN B-NP proliferation NN I-NP . . O IL-2R NN B-NP alpha NN I-NP is VBZ O rapidly RB B-ADVP and CC O potently RB B-ADVP induced VBN B-VP in IN B-PP T NN B-NP cells NNS I-NP in IN B-PP response NN I-PP to TO I-PP mitogenic JJ B-NP stimuli NNS I-NP . . O Interleukin NN B-NP 2 CD I-NP ( ( O IL-2 NN B-NP ) ) O stimulates VBZ B-VP IL-2R NN B-NP alpha. NN I-NP transcription NN I-NP COMMA COMMA O thereby RB B-ADVP amplifying VBG B-VP expression NN B-NP of IN B-PP its PRP$ B-NP own JJ I-NP high-affinity NN I-NP receptor NN I-NP . . O IL-2R NN B-NP alpha NN I-NP transcription NN I-NP is VBZ B-VP at IN B-ADVP least JJS I-ADVP in IN B-PP part NN B-NP controlled VBN B-VP by IN B-PP two CD B-NP positive JJ I-NP regulatory JJ I-NP regions NNS I-NP COMMA COMMA O PRRI NN B-NP and CC O PRRII NN B-NP . . O PRRI NN B-NP is VBZ B-VP an DT B-NP inducible JJ I-NP proximal JJ I-NP enhancer NN I-NP COMMA COMMA O located JJ B-ADJP between IN B-PP nucleotides NNS B-NP -276 CD B-NP and CC O -244 CD B-NP COMMA COMMA O which WDT B-NP contains VBZ B-VP NF-kappaB NN B-NP and CC O SRE\/CArG NN B-NP motifs NNS B-NP . . O PRRII NN B-NP is VBZ B-VP a DT B-NP T-cell-specific JJ I-NP enhancer NN I-NP COMMA COMMA O located JJ B-ADJP between IN B-PP nucleotides NNS B-NP -137 CD B-NP and CC O -64 CD B-NP COMMA COMMA O which WDT B-NP binds VBZ B-VP the DT B-NP T-cell-specific JJ I-NP Ets NN I-NP protein NN I-NP Elf-1 NN I-NP and CC O HMG-I(Y) NN B-NP proteins NNS I-NP . . O However RB B-ADVP COMMA COMMA O none NN B-NP of IN B-PP these DT B-NP proximal JJ I-NP regions NNS I-NP account VBP B-VP for IN B-PP the DT B-NP induction NN I-NP of IN B-PP IL-2R NN B-NP alpha NN I-NP transcription NN I-NP by IN B-PP IL-2 NN B-NP . . O To TO B-VP find VB I-VP new JJ B-NP regulatory JJ I-NP regions NNS I-NP of IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP gene NN I-NP COMMA COMMA O 8.5 CD B-NP kb NN I-NP of IN B-PP the DT B-NP 5' JJ I-NP end NN I-NP noncoding JJ I-NP sequence NN I-NP of IN B-PP the DT B-NP IL-2R NN I-NP alpha NN I-NP gene NN I-NP have VBP B-VP been VBN I-VP sequenced VBN I-VP . . O We PRP B-NP identified VBD B-VP an DT B-NP 86-nucleotide JJ I-NP fragment NN I-NP that WDT B-NP is VBZ B-VP 90 CD B-NP % NN I-NP identical JJ B-ADJP to TO B-PP the DT B-NP recently RB I-NP characterized VBN I-NP murine JJ B-NP IL-2-responsive JJ I-NP element NN I-NP ( ( O mIL-2rE NN B-NP ) ) O . . O This DT B-NP putative JJ I-NP human JJ I-NP IL-2rE NN I-NP COMMA COMMA O designated VBN B-VP PRRIII NN B-NP COMMA COMMA O confers VBZ B-VP IL-2 NN B-NP responsiveness NN I-NP on IN B-PP a DT B-NP heterologous JJ I-NP promoter NN I-NP . . O PRRIII NN B-NP contains VBZ B-VP a DT B-NP Stat NN I-NP protein NN I-NP binding NN I-NP site NN I-NP that WDT B-NP overlaps VBZ B-VP with IN B-PP an DT B-NP EBS NN I-NP motif NN I-NP ( ( O GASd\/EBSd NN B-NP ) ) O . . O These DT B-NP are VBP B-VP essential JJ B-ADJP for IN B-PP IL-2 NN B-NP inducibility NN I-NP of IN B-PP PRRIII\/CAT NN B-NP reporter NN I-NP constructs NNS I-NP . . O IL-2 NN B-NP induced VBD B-VP the DT B-NP binding NN I-NP of IN B-PP Stat5a NN B-NP and CC O b NN B-NP proteins NNS B-NP to TO B-PP the DT B-NP human JJ I-NP GASd NN I-NP element NN I-NP . . O To TO B-VP confirm VB I-VP the DT B-NP physiological JJ I-NP relevance NN I-NP of IN B-PP these DT B-NP findings NNS I-NP COMMA COMMA O we PRP B-NP carried VBD B-VP out RP B-PRT in FW B-NP vivo FW I-NP footprinting NN I-NP experiments NNS I-NP which WDT B-NP showed VBD B-VP that IN B-SBAR stimulation NN B-NP of IN B-PP IL-2R NN B-NP alpha NN I-NP expression NN I-NP correlated VBD B-VP with IN B-PP occupancy NN B-NP of IN B-PP the DT B-NP GASd NN I-NP element NN I-NP . . O Our PRP$ B-NP data NNS I-NP demonstrate VBP B-VP a DT B-NP major JJ I-NP role NN I-NP of IN B-PP the DT B-NP GASd\/EBSd NN I-NP element NN I-NP in IN B-PP IL-2R NN B-NP alpha NN I-NP regulation NN I-NP and CC O suggest VBP B-VP that IN B-SBAR the DT B-NP T-cell-specific JJ I-NP Elf-1 NN I-NP factor NN I-NP can MD B-VP serve VB I-VP as IN B-PP a DT B-NP transcriptional JJ I-NP repressor NN I-NP . . O Association NN B-NP of IN B-PP TRAF1 NN B-NP COMMA COMMA O TRAF2 NN B-NP COMMA COMMA O and CC O TRAF3 NN B-NP with IN B-PP an DT B-NP Epstein-Barr JJ I-NP virus NN I-NP LMP1 NN I-NP domain NN I-NP important JJ B-ADJP for IN B-PP B-lymphocyte NN B-NP transformation NN I-NP : : O role NN B-NP in IN B-PP NF-kappaB NN B-NP activation NN I-NP . . O The DT B-NP Epstein-Barr JJ I-NP virus NN I-NP ( ( O EBV NN B-NP ) ) O transforming VBG B-NP protein NN I-NP LMP1 NN I-NP appears VBZ B-VP to TO I-VP be VB I-VP a DT B-NP constitutively RB I-NP activated VBN I-NP tumor NN B-NP necrosis NN I-NP factor NN I-NP receptor NN I-NP ( ( O TNFR NN B-NP ) ) O on IN B-PP the DT I-PP basis NN I-PP of IN I-PP an DT B-NP intrinsic JJ I-NP ability NN I-NP to TO B-VP aggregate VB I-VP in IN B-PP the DT B-NP plasma NN I-NP membrane NN I-NP and CC O an DT B-NP association NN I-NP of IN B-PP its PRP$ B-NP cytoplasmic JJ I-NP carboxyl NN B-NP terminus NN I-NP ( ( O CT NN B-NP ) ) O with IN B-PP TNFR-associated JJ B-NP factors NNS I-NP ( ( O TRAFs NNS B-NP ) ) O . . O We PRP B-NP now RB B-ADVP show VBP B-VP that IN B-SBAR in IN B-PP EBV-transformed JJ B-NP B NN I-NP lymphocytes NNS I-NP most JJS B-NP of IN B-PP TRAF1 NN B-NP or CC O TRAF3 NN B-NP and CC O 5 CD B-NP % NN I-NP of IN B-PP TRAF2 NN B-NP are VBP B-VP associated VBN I-VP with IN B-PP LMP1 NN B-NP and CC O that IN B-SBAR most JJS B-NP of IN B-PP LMP1 NN B-NP is VBZ B-VP associated VBN I-VP with IN B-PP TRAF1 NN B-NP or CC O TRAF3 NN B-NP . . O TRAF1 NN B-NP COMMA COMMA O TRAF2 NN B-NP COMMA COMMA O and CC O TRAF3 NN B-NP bind VBP B-VP to TO B-PP a DT B-NP single JJ I-NP site NN I-NP in IN B-PP the DT B-NP LMP1 NN I-NP CT NN I-NP corresponding VBG B-VP to TO B-PP amino NN B-NP acids NNS I-NP ( ( O aa NNS B-NP ) ) O 199 CD B-NP to TO O 214 CD B-NP COMMA COMMA O within IN B-PP a DT B-NP domain NN I-NP which WDT B-NP is VBZ B-VP important JJ B-ADJP for IN B-PP B-lymphocyte NN B-NP growth NN I-NP transformation NN I-NP ( ( O aa NNS B-NP 187 CD B-NP to TO O 231 CD B-NP ) ) O . . O Further JJ O deletional JJ O and CC O alanine NN B-NP mutagenesis NN I-NP analyses NNS B-NP and CC O comparison NN B-NP with IN B-PP TRAF NN B-NP binding NN I-NP sequences NNS I-NP in IN B-PP CD40 NN B-NP COMMA COMMA O in IN B-PP CD30 NN B-NP COMMA COMMA B-PP and CC I-PP in IN B-PP the DT B-NP LMP1 NN I-NP of IN B-PP other JJ B-NP lymphycryptoviruses NNS I-NP provide VBP B-VP the DT B-NP first JJ I-NP evidence NN I-NP that IN B-SBAR PXQXT\/S NN B-NP is VBZ B-VP a DT B-NP core NN I-NP TRAF NN I-NP binding NN I-NP motif NN I-NP . . O The DT B-NP negative JJ I-NP effects NNS I-NP of IN B-PP point NN B-NP mutations NNS I-NP in IN B-PP the DT B-NP LMP1(1-231) NN I-NP core NN I-NP TRAF NN I-NP binding NN I-NP motif NN I-NP on IN B-PP TRAF NN B-NP binding NN I-NP and CC O NF-kappaB NN B-NP activation NN I-NP genetically RB B-ADVP link VBP B-VP the DT B-NP TRAFs NNS I-NP to TO B-PP LMP1(1-231)-mediated JJ B-NP NF-kappaB NN I-NP activation NN I-NP . . O NF-kappaB NN B-NP activation NN I-NP by IN B-PP LMP1(1-231) NN B-NP is VBZ B-VP likely JJ B-ADJP to TO B-VP be VB I-VP mediated VBN I-VP by IN B-PP TRAF1\/TRAF2 NN B-NP heteroaggregates NNS I-NP since IN B-SBAR TRAF1 NN B-NP is VBZ B-VP unique JJ B-ADJP among IN B-PP the DT B-NP TRAFs NNS I-NP in IN B-PP coactivating VBG B-VP NF-kappaB NN B-NP with IN B-PP LMP1(1-231) NN B-NP COMMA COMMA O a DT B-NP TRAF2 NN I-NP dominant-negative JJ I-NP mutant NN I-NP can MD B-VP block VB I-VP LMP1(1-231)-mediated JJ B-NP NF-kappaB NN I-NP activation NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP TRAF1 NN B-NP coactivation NN I-NP COMMA COMMA O and CC O 30 CD B-NP % NN I-NP of IN B-PP TRAF2 NN B-NP is VBZ B-VP associated VBN I-VP with IN B-PP TRAF1 NN B-NP in IN B-PP EBV-transformed JJ B-NP B NN I-NP cells NNS I-NP . . O TRAF3 NN B-NP is VBZ B-VP a DT B-NP negative JJ I-NP modulator NN I-NP of IN B-PP LMP1(1-231)-mediated JJ B-NP NF-kappaB NN I-NP activation NN I-NP . . O Surprisingly RB B-ADVP COMMA COMMA O TRAF1 NN B-NP COMMA COMMA O -2 CD B-NP COMMA COMMA O or CC O -3 CD B-NP does VBZ B-VP not RB I-VP interact VB I-VP with IN B-PP the DT B-NP terminal JJ I-NP LMP1 NN I-NP CT NN I-NP aa NNS I-NP 333 CD B-NP to TO O 386 CD B-NP which WDT B-NP can MD B-VP independently RB I-VP mediate VBP I-VP NF-kappaB NN B-NP activation NN I-NP . . O The DT B-NP constitutive JJ I-NP association NN I-NP of IN B-PP TRAFs NNS B-NP with IN B-PP LMP1 NN B-NP through IN B-PP the DT O aa NNS O 187 CD B-NP to TO O 231 CD B-NP domain NN B-NP which WDT B-NP is VBZ B-VP important JJ B-ADJP in IN B-PP NF-kappaB NN B-NP activation NN I-NP and CC O primary JJ B-NP B-lymphocyte NN I-NP growth NN I-NP transformation NN I-NP implicates VBZ B-VP TRAF NN B-NP aggregation NN I-NP in IN B-PP LMP1 NN B-NP signaling NN I-NP . . O CD40 NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP lipopolysaccharide NN B-NP and CC O anti-IgM JJ B-ADJP stimulation NN B-NP of IN B-PP primary JJ B-NP B NN I-NP lymphocytes NNS I-NP COMMA COMMA O leads VBZ B-VP to TO B-PP a DT B-NP persistent JJ I-NP nuclear JJ I-NP accumulation NN I-NP of IN B-PP RelB NN B-NP . . O In IN B-PP this DT B-NP study NN I-NP we PRP B-NP analyzed VBD B-VP the DT B-NP effect NN I-NP of IN B-PP CD40 NN B-NP stimulation NN I-NP on IN B-PP the DT B-NP activity NN B-NP and CC O nuclear JJ B-NP appearance NN I-NP of IN B-PP Rel\/nuclear NN B-NP factor NN I-NP kappaB NN I-NP ( ( O NF-kappaB NN B-NP ) ) O factors NNS B-NP in IN B-PP primary JJ B-NP murine JJ I-NP B NN I-NP lymphocytes NNS I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR triggering NN B-NP of IN B-PP CD40 NN B-NP signaling NN I-NP pathway NN I-NP ( ( I-NP s NNS I-NP ) ) O by IN B-PP CD40 NN B-NP ligands NNS I-NP expressed VBN B-VP on IN B-PP L NN B-NP cells NNS I-NP led VBD B-VP to TO B-PP strong JJ B-NP activation NN I-NP of IN B-PP an DT B-NP NF-kappaB-controlled JJ I-NP beta-globin NN I-NP reporter NN I-NP gene NN I-NP in IN B-PP primary JJ B-NP B NN I-NP lymphocytes NNS I-NP from IN B-PP transgenic JJ B-NP mice NNS I-NP . . O Analyses NNS B-NP of IN B-PP nuclear JJ B-NP translocation NN I-NP of IN B-PP individual JJ B-NP members NNS I-NP of IN B-PP Rel NN B-NP proteins NNS I-NP after IN B-PP CD40 NN B-NP induction NN I-NP of IN B-PP primary JJ B-NP B NN I-NP cells NNS I-NP showed VBD B-VP a DT B-NP strong JJ I-NP and CC I-NP long-lasting JJ I-NP accumulation NN I-NP of IN B-PP RelB NN B-NP and CC O COMMA COMMA B-NP less RBR I-NP pronounced JJ I-NP COMMA COMMA O of IN B-PP c-Rel NN B-NP . . O LPS NN B-NP stimulation NN I-NP did VBD B-VP not RB I-VP give VB I-VP rise NN B-NP to TO B-PP a DT B-NP persistent JJ I-NP nuclear JJ I-NP accumulation NN I-NP of IN B-PP RelB NN B-NP and CC O c-Rel NN B-NP COMMA COMMA O whereas IN O nuclear JJ B-NP c-Rel NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP RelB NN B-NP COMMA COMMA O accumulated VBD B-VP after IN B-PP B NN B-NP cell NN I-NP receptor NN I-NP stimulation NN I-NP . . O CD40 NN B-NP induced VBD B-VP not RB B-CONJP only RB I-CONJP nuclear JJ B-NP translocation NN I-NP but CC B-CONJP also RB I-CONJP de FW B-NP novo FW I-NP synthesis NN I-NP of IN B-PP RelB NN B-NP RNA NN B-NP and CC O protein NN B-NP . . O S107 NN B-NP plasmacytoma NN I-NP cells NNS I-NP COMMA COMMA O which WDT B-NP express VBP B-VP CD40 NN B-NP but CC O are VBP B-VP defective JJ B-ADJP for IN B-PP the DT B-NP nuclear JJ I-NP appearance NN I-NP of IN B-PP p50\/p65-NF-kappaB NN B-NP COMMA COMMA O do VBP B-VP not RB I-VP express VB I-VP RelB NN B-NP after IN B-PP CD40 NN B-NP stimulation NN I-NP . . O In IN B-PP S107 NN B-NP cells NNS I-NP stably RB B-VP transfected VBN I-VP with IN B-PP relB NN B-NP genes NNS I-NP COMMA COMMA O stimulation NN B-NP of IN B-PP nuclear JJ B-NP RelB NN I-NP translocation NN I-NP by IN B-PP CD40 NN B-NP was VBD B-VP observed VBN I-VP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR stimulation NN B-NP of IN B-PP CD40 NN B-NP signaling NN I-NP pathways NNS I-NP exerts VBZ B-VP a DT B-NP long-lasting JJ I-NP stimulatory JJ I-NP effect NN I-NP on IN B-PP both CC B-NP the DT I-NP transcription NN B-NP and CC O nuclear JJ B-NP translocation NN I-NP of IN B-PP RelB NN B-NP . . O Since IN B-SBAR LPS NN B-NP and CC O anti-IgM NN B-NP were VBD B-VP unable JJ B-ADJP to TO B-VP activate VB I-VP RelB NN B-NP COMMA COMMA O CD40 NN B-NP appears VBZ B-VP to TO I-VP trigger VB I-VP a DT B-NP special JJ I-NP program NN I-NP of IN B-PP gene NN B-NP expression NN I-NP involved VBN B-VP in IN B-PP the DT B-NP proliferation NN B-NP and\/or CC O differentiation NN B-NP of IN B-PP B NN B-NP lymphocytes NNS I-NP . . O Sterol NN B-NP dependent JJ I-NP LDL-receptor NN I-NP gene NN I-NP transcription NN I-NP in IN B-PP lymphocytes NNS B-NP from IN B-PP normal JJ O and CC O CML NN B-NP patients NNS B-NP . . O Sterol NN B-NP regulatory JJ I-NP element NN I-NP ( ( O SRE NN B-NP ) ) O has VBZ B-VP been VBN I-VP recognized VBN I-VP to TO I-VP regulate VB I-VP various JJ B-NP key JJ I-NP genes NNS I-NP coding VBG B-VP for IN B-PP especially RB B-NP low JJ I-NP density NN I-NP lipoprotein NN I-NP ( ( I-NP LDL NN I-NP ) ) I-NP -receptor NN I-NP COMMA COMMA O 3-hydroxy-3-methylglutaryl NN B-NP coenzyme NN I-NP A NN I-NP ( ( O HMG-CoA NN B-NP ) ) O reductase NN B-NP and CC O HMG-CoA NN B-NP synthase NN I-NP known VBN B-VP to TO I-VP play VB I-VP a DT B-NP crucial JJ I-NP role NN I-NP in IN B-PP the DT B-NP cholesterol NN I-NP feedback NN I-NP mechanism NN I-NP . . O The DT B-NP deranged JJ I-NP cholesterol NN I-NP feedback NN I-NP mechanism NN I-NP has VBZ B-VP been VBN I-VP widely RB I-VP recognised VBN I-VP in IN B-PP initiation NN B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP progression NN B-NP of IN B-PP various JJ B-NP types NNS I-NP of IN B-PP cancers NNS B-NP including VBG B-PP chronic JJ B-NP myeloid JJ I-NP leukaemia NN I-NP ( ( O CML NN B-NP ) ) O . . O Consequently RB B-ADVP COMMA COMMA O the DT B-NP present JJ I-NP study NN I-NP was VBD B-VP addressed VBN I-VP to TO B-VP understand VB I-VP this DT B-NP phenomenon NN I-NP and CC O revealed VBD B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP unique JJ I-NP 47 CD I-NP kDa NN I-NP protein NN I-NP factor NN I-NP having VBG B-VP affinity NN B-NP for IN B-PP this DT B-NP SRE NN I-NP sequence NN I-NP in IN B-PP lymphocytes NNS B-NP from IN B-PP normal JJ B-NP subjects NNS I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP its PRP$ B-NP absence NN I-NP in IN B-PP lymphocytes NNS B-NP from IN B-PP untreated JJ B-NP CML NN I-NP patients NNS I-NP . . O However RB B-ADVP COMMA COMMA O this DT B-NP factor NN I-NP appeared VBD B-VP when WRB B-ADVP the DT B-NP CML NN I-NP patients NNS I-NP achieved VBD B-VP complete JJ B-NP haematological JJ I-NP remission NN I-NP ( ( O CHR NN B-NP ) ) O through IN B-PP alpha-interferon NN B-NP therapy NN I-NP . . O Further RB B-ADVP COMMA COMMA O an DT B-NP inverse NN I-NP relationship NN I-NP was VBD B-VP also RB I-VP observed VBN I-VP between IN B-PP sterol NN B-NP modulated JJ I-NP LDL-receptor NN I-NP gene NN I-NP transcription NN I-NP and CC O the DT B-NP binding NN I-NP affinity NN I-NP of IN B-PP this DT B-NP 47 CD I-NP kDa NN I-NP factor NN I-NP to TO B-PP the DT B-NP SRE NN I-NP sequence NN I-NP . . O Based VBN B-PP upon IN B-PP these DT B-NP results NNS I-NP we PRP B-NP propose VBP B-VP that IN B-SBAR alpha-interferon NN B-NP through IN B-PP its PRP$ B-NP receptor NN I-NP initiates VBZ B-VP phosphatidic JJ B-NP acid NN I-NP dependent JJ B-NP signalling NN I-NP which WDT B-NP in IN B-PP turn NN B-NP regulates VBZ B-VP the DT B-NP affinity NN I-NP of IN B-PP 47 CD B-NP kDa NN I-NP sterol NN I-NP regulatory JJ I-NP element NN I-NP binding NN I-NP factor NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP LDL-receptor NN B-NP gene NN I-NP transcription NN I-NP in IN B-PP lymphocytes NNS B-NP from IN B-PP CML NN B-NP patients NNS I-NP . . O Effects NNS B-NP of IN B-PP Ara-C NN B-NP on IN B-PP neutral JJ B-NP sphingomyelinase NN I-NP and CC O mitogen- NN B-NP and CC I-NP stress-activated JJ I-NP protein NN I-NP kinases NNS I-NP in IN B-PP T-lymphocyte NN B-NP cell NN I-NP lines NNS I-NP . . O Neutral JJ B-NP sphingomyelinase NN B-NP ( ( O SMase NN B-NP ) ) O can MD B-VP be VB I-VP activated VBN I-VP by IN B-PP extracellular JJ B-NP signals NNS I-NP to TO B-VP produce VB I-VP ceramide NN B-NP COMMA COMMA O which WDT B-NP may MD B-VP affect VB I-VP mitogen-activated JJ B-NP protein NN I-NP kinase NN I-NP ( ( O MAPK NN B-NP ) ) O activities NNS B-NP . . O Neutral JJ B-NP SMase NN I-NP activity NN I-NP was VBD B-VP assessed VBN I-VP in IN B-PP membranes NNS B-NP from IN B-PP Jurkat NN B-NP COMMA COMMA O a DT B-NP human JJ I-NP T-cell NN I-NP line NN I-NP COMMA COMMA O and CC O EL4 NN B-NP COMMA COMMA O a DT B-NP murine JJ I-NP T-cell NN I-NP line NN I-NP . . O Ara-C NN B-NP activated VBD B-VP SMase NN B-NP with IN B-PP 10 CD B-NP minutes NNS I-NP in IN B-PP both CC O Jurkat NN B-NP and CC O EL4 NN B-NP cells NNS B-NP COMMA COMMA O while IN B-SBAR phorbol NN B-NP ester NN I-NP ( ( O PMA NN B-NP ) ) O had VBD B-VP no DT B-NP effect NN I-NP . . O PMA NN B-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP Ara-C NN B-NP or CC O ceramides NNS B-NP COMMA COMMA O activated VBD B-VP ERK NN B-NP MAPKS NNS I-NP COMMA COMMA O in IN B-PP Jurkat NN B-NP and CC O EL4 NN B-NP . . O PMA NN B-NP acted VBD B-VP synergistically RB B-ADVP with IN B-PP ionomycin NN B-NP to TO B-VP activate VB I-VP JNK NN B-NP MAPKs NNS I-NP in IN B-PP Jurkat NN B-NP and CC O EL4 NN B-NP within IN B-PP 10 CD B-NP minutes NNS I-NP . . O Ara-C NN B-NP activated VBD B-VP JNKs NNS B-NP only RB B-PP after IN I-PP prolonged JJ B-NP incubation NN I-NP ( ( O 90-120 CD B-NP minutes NNS I-NP ) ) O . . O Thus RB B-ADVP COMMA COMMA O ceramide NN B-NP is VBZ B-VP not RB O a DT B-NP positive JJ I-NP signal NN I-NP for IN B-PP ERK NN B-NP activation NN I-NP in IN B-PP T-cell NN B-NP lines NNS I-NP . . O The DT B-NP effects NNS I-NP of IN B-PP Ara-C NN B-NP on IN B-PP JNK NN B-NP activity NN I-NP may MD B-VP be VB I-VP mediated VBN I-VP through IN B-PP secondary JJ B-NP response NN I-NP pathways NNS I-NP . . O { ( B-NP Cortisone-resistant JJ I-NP bronchial JJ I-NP asthma NN I-NP } ) O There EX B-NP is VBZ B-VP general JJ B-NP agreement NN I-NP on IN B-PP the DT B-NP inflammatory JJ I-NP pathogenesis NN I-NP of IN B-PP bronchial JJ B-NP asthma NN I-NP : : O an DT B-NP accumulation NN I-NP of IN B-PP activated VBN B-NP eosinophils NNS I-NP COMMA COMMA O degranulated VBN B-NP mast NN I-NP cells NNS I-NP COMMA COMMA O T NN B-NP lymphocytes NNS I-NP and CC O in IN B-PP very RB B-NP severe JJ I-NP forms NNS I-NP COMMA COMMA O granulocytes NNS B-NP has VBZ B-VP constantly RB I-VP been VBN I-VP found VBN I-VP in IN B-PP the DT B-NP bronchial JJ I-NP mucosa NN I-NP . . O In IN B-PP allergic JJ B-NP bronchial JJ I-NP asthma NN I-NP COMMA COMMA O inflammation NN B-NP seems VBZ B-VP to TO I-VP be VB I-VP orchestrated VBN I-VP predominantly RB B-ADVP by IN B-PP a DT B-NP subset NN I-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP COMMA COMMA O with IN B-PP a DT B-NP phenotype NN I-NP similar JJ B-ADJP to TO B-PP the DT B-NP Th2 NN I-NP subset NN I-NP able JJ B-ADJP to TO B-VP produce VB I-VP IL-4 NN B-NP and CC O IL-5 NN B-NP . . O Although IN B-SBAR corticosteroids NNS B-NP are VBP B-VP the DT B-NP most RBS I-NP potent JJ I-NP therapeutic JJ I-NP agents NNS I-NP used VBN B-VP for IN B-PP this DT B-NP disease NN I-NP COMMA COMMA O their PRP$ B-NP anti-inflammatory JJ I-NP effect NN I-NP differs VBZ B-VP from IN B-PP patient NN B-NP to TO B-PP patient NN B-NP . . O Some DT B-NP criteria NNS I-NP which WDT B-NP can MD B-VP be VB I-VP used VBN I-VP to TO B-VP define VB I-VP steroid-resistant JJ B-NP bronchial JJ I-NP asthma NN I-NP are VBP B-VP listed VBN I-VP here RB B-ADVP . . O This DT B-NP review NN I-NP analyzes VBZ B-VP various JJ B-NP molecular JJ I-NP alterations NNS I-NP responsible JJ B-ADJP for IN B-PP the DT B-NP deficient JJ I-NP response NN I-NP to TO B-PP corticosteroid NN B-NP treatment NN I-NP observed VBN B-VP in IN B-PP steroid-resistant JJ B-NP bronchial JJ I-NP asthmatic JJ I-NP subjects NNS I-NP . . O New JJ B-NP knowledge NN I-NP on IN B-PP the DT B-NP mechanism NN I-NP of IN B-PP steroid NN B-NP resistance NN I-NP may MD B-VP have VB I-VP important JJ B-NP implications NNS I-NP for IN B-PP the DT B-NP treatment NN I-NP of IN B-PP chronic JJ B-NP asthma NN I-NP and CC O other JJ B-NP diseases NNS I-NP . . O Expression NN B-NP of IN B-PP Egr-1 NN B-NP correlates VBZ B-VP with IN B-PP the DT B-NP transformed VBN I-NP phenotype NN I-NP and CC O the DT B-NP type NN I-NP of IN B-PP viral JJ B-NP latency NN I-NP in IN B-PP EBV NN B-NP genome NN I-NP positive JJ B-NP lymphoid JJ I-NP cell NN I-NP lines NNS I-NP . . O In IN B-PP this DT B-NP paper NN I-NP we PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP role NN I-NP of IN B-PP Egr-1 NN B-NP in IN B-PP B NN B-NP cell NN I-NP growth NN I-NP regulation NN I-NP by IN B-PP examining VBG B-VP the DT B-NP gene NN I-NP expression NN I-NP in IN B-PP a DT B-NP panel NN I-NP of IN B-PP B NN B-NP cell NN I-NP lines NNS I-NP COMMA COMMA O including VBG B-PP both CC O EBV NN B-NP genome NN I-NP negative JJ O and CC O EBV NN B-ADJP carrying VBG I-ADJP cell NN B-NP lines NNS I-NP . . O Egr-1 NN B-NP expression NN I-NP correlates VBZ B-VP with IN B-PP the DT B-NP cellular JJ I-NP phenotype NN I-NP and CC O the DT B-NP specific JJ I-NP pattern NN I-NP of IN B-PP viral JJ B-NP latency NN I-NP established VBN B-VP within IN B-PP the DT B-NP individual JJ I-NP cell NN I-NP lines NNS I-NP . . O Thus RB B-ADVP COMMA COMMA O constitutive JJ B-NP activation NN I-NP of IN B-PP Egr-1 NN B-NP gene NN I-NP is VBZ B-VP invariably RB I-VP associated VBN I-VP with IN B-PP unrestricted JJ B-NP expression NN I-NP of IN B-PP viral JJ B-NP latent JJ I-NP genes NNS I-NP in IN B-PP all DT O group NN O III CD O EBV NN B-NP genome NN I-NP carrying VBG B-NP cell NN I-NP lines NNS I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O Egr-1 NN B-NP expression NN I-NP is VBZ B-VP abrogated VBN I-VP in IN B-PP group NN B-NP I NN I-NP Burkitt NN I-NP tumor NN I-NP cells NNS I-NP COMMA COMMA O irrespective JJ B-ADVP of IN B-PP the DT B-NP EBV NN I-NP genome NN I-NP carrying NN I-NP status NN I-NP . . O Activated VBN B-NP viral JJ I-NP gene NN I-NP expression NN I-NP associated VBN B-VP with IN B-PP phenotypic JJ B-NP conversion NN I-NP of IN B-PP group NN B-NP I NN I-NP cell NN I-NP lines NNS I-NP in IN B-PP to TO I-PP group NN B-NP II CD B-NP or CC O III CD B-NP restores VBZ B-VP the DT B-NP Egr-1 NN I-NP gene NN I-NP expression NN I-NP . . O Several JJ B-NP forms NNS I-NP of IN B-PP EGR-1 JJ B-NP protein NN I-NP are VBP B-VP found VBN I-VP within IN B-PP the DT B-NP different JJ I-NP groups NNS I-NP of IN B-PP cell NN B-NP lines NNS I-NP COMMA COMMA O and CC O the DT B-NP binding NN I-NP activity NN I-NP to TO B-PP DNA NN B-NP consensus NN I-NP sequences NNS I-NP was VBD B-VP investigated VBN I-VP . . O Finally RB B-ADVP COMMA COMMA O time NN B-NP course NN I-NP analysis NN I-NP of IN B-PP Egr-1 NN B-NP expression NN I-NP during IN B-PP the DT B-NP early JJ I-NP steps NNS I-NP of IN B-PP EBV NN B-NP infection NN I-NP in FW B-ADVP vitro FW I-ADVP demonstrated VBD B-VP that IN B-SBAR Egr-1 NN B-NP is VBZ B-VP upregulated VBN I-VP within IN B-PP minutes NNS B-NP from IN B-PP the DT B-NP initial JJ I-NP interaction NN I-NP with IN B-PP the DT B-NP B NN I-NP lymphocyte NN I-NP . . O The DT B-NP proximal JJ I-NP regulatory JJ I-NP element NN I-NP of IN B-PP the DT B-NP interferon-gamma NN I-NP promoter NN I-NP mediates VBZ B-VP selective JJ B-NP expression NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O Interferon-gamma NN B-NP ( ( O IFN-gamma NN B-NP ) ) O is VBZ B-VP produced VBN I-VP by IN B-PP natural JJ B-NP killer NN I-NP cells NNS I-NP and CC O certain JJ B-NP subsets NNS I-NP of IN B-PP T NN B-NP cells NNS I-NP COMMA COMMA O but CC O the DT B-NP basis NN I-NP for IN B-PP its PRP$ B-NP selective JJ I-NP expression NN I-NP is VBZ B-VP unknown JJ B-ADJP . . O Within IN B-PP the DT B-NP region NN I-NP between IN B-PP -108 CD B-NP and CC O -40 CD B-NP base NN B-NP pairs NNS I-NP of IN B-PP the DT B-NP IFN-gamma NN I-NP promoter NN I-NP are VBP B-VP two CD B-NP conserved VBN I-NP and CC I-NP essential JJ I-NP regulatory JJ I-NP elements NNS I-NP COMMA COMMA O which WDT B-NP confer VBP B-VP activation-specific JJ B-NP expression NN I-NP in IN B-PP T NN B-NP cells NNS I-NP . . O This DT B-NP report NN I-NP describes VBZ B-VP studies NNS B-NP indicating VBG B-VP that IN B-SBAR the DT B-NP most RBS I-NP proximal JJ I-NP of IN B-PP these DT B-NP two CD I-NP regulatory JJ I-NP elements NNS I-NP is VBZ B-VP an DT B-NP important JJ I-NP determinant NN I-NP of IN B-PP its PRP$ B-NP restricted JJ I-NP expression NN I-NP . . O The DT B-NP proximal JJ I-NP element NN I-NP is VBZ B-VP a DT B-NP composite JJ I-NP site NN I-NP that WDT B-NP binds VBZ B-VP members NNS B-NP of IN B-PP the DT O CREB\/ATF NN B-NP COMMA COMMA O AP-1 NN B-NP COMMA COMMA O and CC O octamer NN B-NP families NNS B-NP of IN B-PP transcription NN B-NP factors NNS I-NP . . O Jun NN B-NP is VBZ B-VP essential JJ B-ADJP for IN B-PP activation-induced JJ B-NP transcription NN I-NP and CC O binds VBZ B-VP preferably RB B-ADVP as IN B-PP a DT B-NP heterodimer NN I-NP with IN B-PP ATF-2 NN B-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O CREB NN B-NP appears VBZ B-VP to TO I-VP dampen VB I-VP transcription NN B-NP from IN B-PP this DT B-NP element NN I-NP . . O The DT B-NP CpG NN I-NP dinucleotide NN I-NP in IN B-PP this DT B-NP element NN I-NP is VBZ B-VP selectively RB I-VP methylated VBN I-VP in IN B-PP Th2 NN B-NP T NN I-NP cells NNS I-NP and CC O other JJ B-NP cells NNS I-NP that WDT B-NP do VBP B-VP not RB I-VP express VB I-VP IFN-gamma NN B-NP COMMA COMMA O and CC O methylation NN B-NP markedly RB B-ADVP reduces VBZ B-VP transcription NN B-NP factor NN I-NP binding NN I-NP . . O As IN B-PP a DT B-NP target NN I-NP for IN B-PP DNA NN B-NP methylation NN I-NP and CC B-PP for IN B-PP binding NN B-NP of IN B-PP transcription NN B-NP factors NNS I-NP that WDT B-NP mediate VBP B-VP or CC O impede VBP B-VP transcription NN B-NP COMMA COMMA O this DT B-NP element NN I-NP appears VBZ B-VP to TO I-VP play VB I-VP a DT B-NP central JJ I-NP role NN I-NP in IN B-PP controlling VBG B-VP IFN-gamma NN B-NP expression NN I-NP . . O Activation NN B-NP of IN B-PP nuclear JJ B-NP factor-kappaB NN I-NP via IN B-PP T NN B-NP cell NN I-NP receptor NN I-NP requires VBZ B-VP a DT O Raf NN B-NP kinase NN I-NP and CC O Ca2+ NN B-NP influx NN B-NP . . O Functional JJ B-NP synergy NN I-NP between IN B-PP Raf NN B-NP and CC O calcineurin NN B-NP . . O Signals NNS B-NP transduced VBN B-VP via IN B-PP the DT B-NP TCR NN I-NP activate VBP B-VP the DT B-NP transcription NN I-NP factor NN I-NP nuclear JJ B-NP factor-kappaB NN I-NP ( ( O NF-kappaB NN B-NP ) ) O COMMA COMMA O which WDT B-NP COMMA COMMA O in IN B-PP turn NN B-NP COMMA COMMA O is VBZ B-VP critical JJ B-ADJP to TO B-PP the DT B-NP transcriptional JJ I-NP induction NN I-NP of IN B-PP many JJ B-NP genes NNS I-NP important JJ B-ADJP for IN B-PP the DT B-NP proliferation NN B-NP and CC O expression NN B-NP of IN B-PP a DT B-NP differentiated VBN I-NP phenotype NN I-NP . . O Treatment NN B-NP of IN B-PP T NN B-NP cells NNS I-NP with IN B-PP the DT B-NP protein NN I-NP kinase NN I-NP C NN I-NP activator NN I-NP PMA NN I-NP in IN B-PP combination NN B-NP with IN B-PP Ca2+ NN B-NP ionophores NNS I-NP mimics VBZ B-VP this DT B-NP process NN I-NP COMMA COMMA O and CC O the DT B-NP two CD I-NP agents NNS I-NP are VBP B-VP often RB I-VP substituted VBN I-VP for IN B-PP TCR NN B-NP stimulation NN I-NP COMMA COMMA O bypassing VBG B-VP the DT B-NP TCR NN I-NP . . O Here RB B-ADVP we PRP B-NP identify VBP B-VP intracellular JJ B-NP signaling VBG I-NP components NNS I-NP involved VBN B-VP in IN B-PP activation NN B-NP of IN B-PP NF-kappaB NN B-NP following VBG B-PP TCR NN B-NP stimulation NN I-NP . . O TCR NN B-NP signaling NN I-NP was VBD B-VP triggered VBN I-VP by IN B-PP treating VBG B-VP Jurkat NN B-NP T NN I-NP cells NNS I-NP with IN B-PP PHA NN B-NP or CC O anti-CD3 JJ B-ADJP Abs NNS B-NP COMMA COMMA O and CC O NF-kappaB NN B-NP activation NN I-NP was VBD B-VP monitored VBN I-VP by IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP and\/or CC B-PP by IN B-PP kappaB-dependent JJ B-NP reporter NN I-NP assays NNS I-NP . . O Contrary JJ B-PP to TO I-PP the DT B-NP idea NN I-NP that IN B-SBAR protein NN B-NP kinase NN I-NP C NN I-NP is VBZ B-VP involved VBN I-VP in IN B-PP TCR-mediated JJ B-NP activation NN I-NP of IN B-PP NF-kappaB NN B-NP COMMA COMMA O high JJ B-NP doses NNS I-NP of IN B-PP staurosporine NN B-NP did VBD B-VP not RB I-VP interfere VB I-VP with IN B-PP activation NN B-NP of IN B-PP NF-kappaB NN B-NP by IN B-PP PHA NN B-NP COMMA COMMA O while IN B-SBAR the DT B-NP same JJ I-NP dose NN I-NP of IN B-PP staurosporine NN B-NP completely RB B-ADVP blocked VBD B-VP activation NN B-NP by IN B-PP PMA NN B-NP . . O PHA-induced JJ B-NP kappaB-dependent JJ I-NP reporter NN I-NP activity NN I-NP was VBD B-VP COMMA COMMA O however RB B-ADVP COMMA COMMA O effectively RB B-VP blocked VBN I-VP by IN B-PP a DT B-NP dominant JJ I-NP negative JJ I-NP form NN I-NP of IN B-PP Raf-1 NN B-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP critical JJ I-NP role NN I-NP for IN B-PP a DT B-NP Raf NN I-NP kinase NN I-NP . . O The DT B-NP TCR-mediated JJ I-NP activation NN I-NP of IN B-PP NF-kappaB NN B-NP was VBD B-VP also RB B-ADVP dependent JJ B-ADJP on IN B-PP a DT B-NP Ca2+ NN I-NP influx NN I-NP COMMA COMMA O because IN B-SBAR the DT B-NP Ca2+ NN I-NP channel NN I-NP blocker NN I-NP COMMA COMMA O SK&F NN B-NP 96365 CD I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP other JJ B-NP agents NNS I-NP that WDT B-NP prevented VBD B-VP the DT B-NP Ca2+ NN I-NP influx NN I-NP COMMA COMMA O inhibited VBD B-VP NF-kappaB NN B-NP activation NN I-NP . . O Cotransfection NN B-NP of IN B-PP a DT B-NP constitutively RB I-NP active JJ I-NP form NN I-NP of IN B-PP calcineurin NN B-NP largely RB B-VP substituted VBD I-VP for IN B-PP the DT B-NP Ca2+ NN I-NP requirement NN I-NP and CC O reversed VBD B-VP the DT B-NP blockade NN I-NP by IN B-PP SK&F NN B-NP 96365 CD I-NP . . O Consistent JJ B-ADJP with IN B-PP these DT B-NP observations NNS I-NP COMMA COMMA O coexpression NN B-NP of IN B-PP constitutively RB B-NP active JJ I-NP forms NNS I-NP of IN B-PP Raf-1 NN B-NP and CC O calcineurin NN B-NP synergistically RB B-ADVP induced VBD B-VP kappaB-dependent JJ B-NP reporter NN I-NP activity NN I-NP COMMA COMMA O suggesting VBG B-VP a DT B-NP physiologically RB I-NP relevant JJ I-NP functional JJ I-NP interaction NN I-NP between IN B-PP the DT B-NP kinase NN I-NP and CC O the DT B-NP phosphatase NN I-NP . . O Induction NN B-NP of IN B-PP the DT B-NP CD11b NN I-NP gene NN I-NP during IN B-PP activation NN B-NP of IN B-PP the DT B-NP monocytic JJ I-NP cell NN I-NP line NN I-NP U937 NN I-NP requires VBZ B-VP a DT B-NP novel JJ I-NP nuclear JJ I-NP factor NN I-NP MS-2 NN I-NP { ( O published VBN B-NP erratum NN I-NP appears VBZ B-VP in IN B-PP J NNP B-NP Immunol NNP I-NP 1999 CD B-NP Jul NNP I-NP 15 CD I-NP ; : O 163 CD B-NP ( ( I-NP 2 CD I-NP ) ) O : : O 1091 CD B-NP } ) O The DT B-NP differentiation NN I-NP of IN B-PP myeloid JJ B-NP precursors NNS I-NP into IN B-PP mature JJ B-NP myelomonocytic JJ I-NP cells NNS I-NP is VBZ B-VP characterized VBN I-VP by IN B-PP the DT B-NP induction NN I-NP of IN B-PP the DT B-NP gene NN I-NP encoding VBG B-VP the DT B-NP beta2 NN I-NP integrin NN I-NP CD11b NN I-NP . . O The DT B-NP transcription NN I-NP factors NNS I-NP Sp1 NN B-NP and CC O PU.1 NN B-NP prime VBP B-VP the DT B-NP CD11b NN I-NP promoter NN I-NP COMMA COMMA O but CC O the DT B-NP nature NN I-NP of IN B-PP the DT B-NP factors NNS I-NP responsible JJ B-ADJP for IN B-PP its PRP$ B-NP inducible JJ I-NP expression NN I-NP are VBP B-VP unknown JJ B-ADJP . . O In IN B-PP addition NN I-PP to TO I-PP the DT B-NP CD11b NN I-NP gene NN I-NP COMMA COMMA O the DT B-NP homologous JJ I-NP genes NNS I-NP encoding VBG B-VP CD11a NN B-NP and CC O CD11c NN B-NP also RB B-ADVP exhibit VBP B-VP inducible JJ B-NP expression NN I-NP during IN B-PP myeloid JJ B-NP differentiation NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O we PRP B-NP compared VBD B-VP the DT B-NP nucleotide JJ I-NP sequences NNS I-NP of IN B-PP the DT O CD11a NN B-NP COMMA COMMA O CD11b NN B-NP COMMA COMMA O and CC O CD11c NN B-NP gene NN B-NP promoters NNS I-NP to TO B-VP identify VB I-VP common JJ B-NP elements NNS I-NP that WDT B-NP might MD B-VP contribute VB I-VP to TO B-PP inducible JJ B-NP expression NN I-NP . . O This DT B-NP analysis NN I-NP identified VBD B-VP one CD B-NP such JJ I-NP element NN I-NP repeated VBN B-VP four CD B-NP times NNS I-NP within IN B-PP the DT B-NP CD11b NN I-NP promoter NN I-NP . . O Mutation NN B-NP of IN B-PP these DT B-NP elements NNS I-NP indicated VBD B-VP that IN B-SBAR two CD B-NP COMMA COMMA O MS-2beta NN B-NP and CC O MS-2gamma NN B-NP COMMA COMMA O are VBP B-VP critical JJ B-ADJP to TO B-PP the DT B-NP induction NN I-NP of IN B-PP the DT B-NP CD11b NN I-NP gene NN I-NP during IN B-PP differentiation NN B-NP of IN B-PP the DT B-NP pro-monocytic JJ I-NP cell NN I-NP line NN I-NP U937 NN I-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP indicate VBP B-VP that IN B-SBAR MS-2beta NN B-NP and CC O MS-2gamma NN B-NP interact VBP B-VP with IN B-PP nuclear JJ B-NP factors NNS I-NP that WDT B-NP are VBP B-VP induced VBN I-VP during IN B-PP U937 NN B-NP differentiation NN I-NP . . O These DT B-NP factors NNS I-NP are VBP B-VP detected VBN I-VP at IN B-PP the DT B-NP time NN I-NP the DT B-NP CD11b NN I-NP promoter NN I-NP is VBZ B-VP activated VBN I-VP . . O The DT B-NP molecular JJ I-NP mass NN I-NP of IN B-PP these DT B-NP factors NNS I-NP is VBZ B-VP approximately RB B-NP 28 CD I-NP kDa NN I-NP COMMA COMMA O and CC O their PRP$ B-NP DNA NN I-NP binding NN I-NP characteristics NNS I-NP are VBP B-VP indistinguishable JJ B-ADJP from IN B-PP those DT B-NP of IN B-PP the DT B-NP novel JJ I-NP nuclear JJ I-NP factor NN I-NP MS-2 NN I-NP . . O Taken VBN B-VP together RB B-ADVP COMMA COMMA O our PRP$ B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR MS-2 NN B-NP mediates VBZ B-VP induction NN B-NP of IN B-PP the DT B-NP CD11b NN I-NP gene NN I-NP as IN B-SBAR cells NNS B-NP of IN B-PP the DT B-NP monocytic JJ I-NP lineage NN I-NP mature VBP B-VP . . O The DT B-NP presence NN I-NP of IN B-PP multiple JJ B-NP potential JJ I-NP binding VBG I-NP sites NNS I-NP for IN B-PP MS-2 NN B-NP in IN B-PP the DT B-NP promoter NN I-NP regions NNS I-NP of IN B-PP a DT B-NP wide JJ I-NP range NN I-NP of IN B-PP genes NNS B-NP expressed VBN B-VP in IN B-PP mature JJ B-NP myeloid JJ I-NP cells NNS I-NP suggests VBZ B-VP this DT B-NP factor NN I-NP plays VBZ B-VP a DT B-NP general JJ I-NP role NN I-NP in IN B-PP myeloid JJ B-NP differentiation NN I-NP . . O HIV-1 NN B-NP LTR NN I-NP activity NN I-NP in IN B-PP human JJ B-NP CD40-activated JJ I-NP B NN I-NP lymphocytes NNS I-NP is VBZ B-VP dependent JJ B-ADJP on IN B-PP NF-kappaB NN B-NP . . O CD40-stimulated JJ B-NP human JJ I-NP B NN I-NP lymphocytes NNS I-NP are VBP B-VP highly RB B-ADJP permissive JJ I-ADJP to TO B-PP a DT B-NP productive JJ I-NP infection NN I-NP by IN B-PP the DT B-NP human JJ I-NP immunodeficiency NN I-NP virus NN I-NP type NN I-NP 1 CD I-NP . . O In IN B-PP these DT B-NP cells NNS I-NP COMMA COMMA O nuclear JJ B-NP factors NNS I-NP involved VBN B-VP in IN B-PP activation NN B-NP of IN B-PP the DT B-NP HIV-1 NN I-NP LTR NN I-NP COMMA COMMA O which WDT B-NP contains VBZ B-VP the DT B-NP transcriptional JJ I-NP control NN I-NP elements NNS I-NP of IN B-PP the DT B-NP virus NN I-NP COMMA COMMA O are VBP B-VP unknown JJ B-ADJP . . O Transient JJ B-NP expression NN I-NP assays NNS I-NP with IN B-PP plasmids NNS B-NP containing VBG B-VP deleted VBN B-NP parts NNS I-NP of IN B-PP the DT B-NP LTR NN I-NP region NN I-NP linked VBN B-VP to TO B-PP a DT B-NP reporter NN I-NP gene NN I-NP showed VBD B-VP that IN B-SBAR the DT B-NP NF-kappaB NN I-NP binding NN I-NP site NN I-NP was VBD B-VP essential JJ B-ADJP for IN B-PP HIV-1 NN B-NP LTR NN I-NP activity NN I-NP in IN B-PP CD40-stimulated JJ B-NP B NN I-NP lymphocytes NNS I-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP and CC O supershift NN B-NP assays NNS B-NP revealed VBD B-VP that IN B-SBAR important JJ B-NP NF-kappaB NN I-NP binding NN I-NP activity NN I-NP composed VBN B-VP of IN B-PP at IN B-ADVP least JJS I-ADVP p50 NN B-NP COMMA COMMA O p65 NN B-NP COMMA COMMA O and CC O c-Rel NN B-NP NF-kappaB NN I-NP subunits NNS B-NP was VBD B-VP present JJ B-ADJP in IN B-PP nuclei NNS B-NP of IN B-PP CD40-stimulated JJ B-NP B NN I-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP confirm VBP B-VP at IN B-PP a DT B-NP molecular JJ I-NP level NN I-NP the DT B-NP ability NN I-NP of IN B-PP HIV-1 NN B-NP to TO B-VP replicate VB I-VP in IN B-PP B NN B-NP cells NNS I-NP and CC O that IN B-SBAR this DT B-NP activity NN I-NP is VBZ B-VP strongly RB I-VP associated VBN I-VP with IN B-PP NF-kappaB NN B-NP . . O Mutation NN B-NP of IN B-PP tyrosines NNS B-NP 492\/493 CD I-NP in IN B-PP the DT B-NP kinase NN I-NP domain NN I-NP of IN B-PP ZAP-70 NN B-NP affects VBZ B-VP multiple JJ B-NP T-cell NN I-NP receptor NN I-NP signaling NN I-NP pathways NNS I-NP . . O The DT B-NP protein-tyrosine JJ I-NP kinase NN I-NP ZAP-70 NN I-NP is VBZ B-VP implicated VBN I-VP COMMA COMMA O together RB B-PP with IN I-PP the DT B-NP Src NN I-NP kinase NN I-NP p56(lck) NN I-NP COMMA COMMA O in IN B-PP controlling VBG B-VP the DT B-NP early JJ I-NP steps NNS I-NP of IN B-PP the DT O T-cell NN B-NP antigen NN I-NP receptor NN I-NP ( ( O TCR NN B-NP ) ) O signaling NN B-NP cascade NN I-NP . . O To TO B-VP help VB I-VP elucidate VB I-VP further RBR B-ADVP the DT B-NP mechanism NN I-NP by IN B-PP which WDT B-NP ZAP-70 NN B-NP regulates VBZ B-VP these DT B-NP initial JJ I-NP events NNS I-NP COMMA COMMA O we PRP B-NP used VBD B-VP a DT B-NP dominant-negative JJ I-NP mutant NN I-NP approach NN I-NP . . O We PRP B-NP overexpressed VBD B-VP in IN B-PP the DT B-NP Jurkat NN I-NP T-cell NN I-NP line NN I-NP ZAP-70 NN B-NP mutated VBN B-VP on IN B-PP Tyr-492 NN B-NP and CC O Tyr-493 NN B-NP in IN B-PP the DT B-NP putative JJ I-NP regulatory JJ I-NP loop NN I-NP of IN B-PP its PRP$ B-NP kinase NN I-NP domain NN I-NP . . O This DT B-NP mutant NN I-NP inhibited VBD B-VP TCR-induced JJ B-NP activation NN I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP by IN B-PP interfering VBG B-VP with IN B-PP both CC O intracellular JJ B-NP calcium NN I-NP increase NN I-NP and CC O Ras-regulated JJ B-NP activation NN I-NP of IN B-PP extracellular JJ B-NP signal-regulated JJ I-NP kinases NNS I-NP . . O Moreover RB B-ADVP COMMA COMMA O TCR-induced JJ B-NP phosphorylation NN I-NP of IN B-PP pp36-38 NN B-NP COMMA COMMA O thought VBN B-VP to TO I-VP play VB I-VP a DT B-NP role NN I-NP upstream RB B-ADVP of IN B-PP these DT B-NP pathways NNS I-NP COMMA COMMA O was VBD B-VP found VBN I-VP to TO I-VP be VB I-VP reduced VBN I-VP . . O In IN B-PP contrast NN B-NP COMMA COMMA O overexpression NN B-NP of IN B-PP wild-type JJ B-NP ZAP-70 NN I-NP induced VBD B-VP constitutive JJ B-NP activation NN I-NP of IN B-PP nuclear JJ B-NP factor NN I-NP of IN B-PP activated VBN B-NP T NN I-NP cells NNS I-NP . . O The DT B-NP ZAP-70 NN I-NP mutant NN I-NP studied VBN B-VP here RB B-ADVP could MD B-VP be VB I-VP phosphorylated VBN I-VP on IN B-PP tyrosine NN B-NP when WRB B-ADVP associated VBN B-VP to TO B-PP the DT B-NP TCR NN I-NP zeta NN I-NP chain NN I-NP and CC O was VBD B-VP able JJ B-ADJP to TO B-VP bind VB I-VP p56(lck) NN B-NP . . O This DT B-NP result NN I-NP demonstrates VBZ B-VP that IN B-SBAR Tyr-492 NN B-NP and CC O Tyr-493 NN B-NP are VBP B-VP not RB O responsible JJ B-ADJP for IN B-PP the DT B-NP Src NN I-NP homology NN I-NP domain NN I-NP 2-mediated JJ I-NP association NN I-NP of IN B-PP p56(lck) NN B-NP with IN B-PP ZAP-70 NN B-NP . . O Our PRP$ B-NP data NNS I-NP are VBP B-VP most RBS B-ADJP consistent JJ I-ADJP with IN B-PP a DT B-NP model NN I-NP in IN B-PP which WDT B-NP recruitment NN B-NP to TO B-PP the DT B-NP TCR NN I-NP allows VBZ B-VP ZAP-70 NN B-NP autophosphorylation NN B-NP and CC O binding NN B-NP to TO B-PP p56(lck) NN B-NP COMMA COMMA O which WDT B-NP in IN B-PP turn NN B-NP phosphorylates VBZ B-VP Tyr-492 NN B-NP and\/or CC O Tyr-493 NN B-NP with IN B-PP consequent JJ B-NP up-regulation NN I-NP of IN B-PP the DT B-NP ZAP-70 NN I-NP kinase NN I-NP activity NN I-NP . . O ZAP-70 NN B-NP will MD B-VP then RB I-VP be VB I-VP able JJ B-ADJP to TO B-VP effectively RB I-VP control VB I-VP phosphorylation NN B-NP of IN B-PP its PRP$ B-NP substrates NNS I-NP and CC O lead VB B-VP to TO B-PP gene NN B-NP activation NN I-NP . . O Dexamethasone NN B-NP suppression NN I-NP test NN I-NP : : O corticosteroid NN B-NP receptors NNS I-NP regulation NN I-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP of IN B-PP young JJ B-NP and CC I-NP aged JJ I-NP subjects NNS I-NP . . O The DT B-NP dexamethasone NN I-NP suppression NN I-NP test NN I-NP ( ( O DST NN B-NP ) ) O is VBZ B-VP considered VBN I-VP an DT B-NP indicator NN I-NP of IN B-PP the DT B-NP function NN I-NP of IN B-PP the DT B-NP adrenal JJ I-NP pituitary JJ I-NP axis NN I-NP . . O The DT B-NP effect NN I-NP of IN B-PP the DT B-NP steroid NN I-NP is VBZ B-VP mediated VBN I-VP by IN B-PP its PRP$ B-NP binding NN I-NP to TO B-PP corticosteroid NN B-NP receptors NNS I-NP . . O We PRP B-NP previously RB B-ADVP suggested VBD B-VP that IN B-SBAR the DT B-NP measurement NN I-NP of IN B-PP corticosteroid NN B-NP receptors NNS I-NP in IN B-PP lymphocytes NNS B-NP is VBZ B-VP an DT B-NP index NN I-NP of IN B-PP an DT B-NP analogous JJ I-NP pattern NN I-NP in IN B-PP brain NN B-NP . . O In IN B-PP the DT B-NP present JJ I-NP study NN I-NP COMMA COMMA O corticosteroid NN O Type NN B-NP I CD I-NP and CC O Type NN B-NP II CD I-NP receptors NNS B-NP in IN B-PP mononuclear JJ B-NP leukocytes NNS I-NP were VBD B-VP measured VBN I-VP in IN B-PP 10 CD B-NP elderly JJ I-NP subjects NNS I-NP and CC B-PP in IN B-PP 9 CD B-NP young JJ I-NP adults NNS I-NP COMMA COMMA O before IN B-PP and CC B-PP after IN B-PP overnight JJ B-NP DST NN I-NP ( ( O 1 CD B-NP mg NN I-NP ) ) O . . O Receptors NNS B-NP were VBD B-VP measured VBN I-VP by IN B-PP radioreceptor NN B-NP assay NN I-NP . . O In IN B-PP all PDT B-NP the DT I-NP subjects NNS I-NP COMMA COMMA O dexamethasone NN B-NP was VBD B-VP able JJ B-ADJP to TO B-VP suppress VB I-VP plasma NN B-NP cortisol NN I-NP . . O The DT B-NP number NN I-NP of IN B-PP Type NN B-NP I CD I-NP and CC O Type NN B-NP II CD I-NP receptors NNS B-NP before IN B-PP the DT B-NP test NN I-NP was VBD B-VP lower JJR B-ADJP in IN B-PP elderly JJ B-NP subjects NNS I-NP than IN B-PP in IN B-PP adults NNS B-NP . . O In IN B-PP the DT B-NP control NN I-NP group NN I-NP COMMA COMMA O dexamethasone NN B-NP produced VBD B-VP a DT B-NP significant JJ I-NP depression NN I-NP of IN B-PP Type NN B-NP I CD I-NP receptors NNS I-NP ( ( O from IN B-PP 267 CD B-NP +\/- CC I-NP 72 CD I-NP to TO B-PP 169 CD B-NP +\/- CC I-NP 71 CD I-NP receptors NNS B-NP per IN B-PP cell NN B-NP ) ) O COMMA COMMA O which WDT B-NP can MD B-VP be VB I-VP interpreted VBN I-VP as IN B-PP a DT B-NP primary JJ I-NP involvement NN I-NP of IN B-PP Type NN B-NP I CD I-NP receptors NNS I-NP in IN B-PP the DT B-NP response NN I-NP to TO B-PP dexamethasone NN B-NP ; : O Type NN B-NP II CD I-NP receptors NNS I-NP decreased VBD B-VP in IN B-PP half PDT B-NP the DT I-NP subjects NNS I-NP ( ( O from IN B-PP 2849 CD B-NP +\/- CC I-NP 703 CD I-NP to TO B-PP 2345 CD B-NP +\/- CC I-NP 569 CD I-NP receptors NNS B-NP per IN B-PP cell NN B-NP ) ) O . . O In IN B-PP elderly JJ B-NP healthy JJ I-NP subjects NNS I-NP COMMA COMMA O Type NN B-NP II CD I-NP receptors NNS I-NP were VBD B-VP also RB I-VP significantly RB I-VP decreased VBN I-VP ( ( O from IN B-PP 1796 CD B-NP +\/- CC I-NP 671 CD I-NP to TO B-PP 720 CD B-NP +\/- CC I-NP 345 CD I-NP ) ) O . . O We PRP B-NP suggest VBP B-VP that IN B-SBAR in IN B-PP young JJ B-NP subjects NNS I-NP Type NN B-NP II CD I-NP receptors NNS I-NP are VBP B-VP initially RB I-VP up-regulated VBN I-VP by IN B-PP dexamethasone NN B-NP COMMA COMMA O and CC O then RB B-VP down-regulated VBN I-VP COMMA COMMA O while IN B-SBAR in RB B-PP aged JJ B-NP subjects NNS I-NP an DT B-NP up-regulation NN I-NP can MD B-VP not RB I-VP be VB I-VP achieved VBN I-VP COMMA COMMA O as IN O suggested VBN B-PP by IN B-NP the DT I-NP higher JJR I-NP values NNS O of IN B-NP plasma NN I-NP cortisol NN B-ADVP usually RB O found VBN B-PP in IN B-NP aging VBG I-NP subjects NNS O Lymphocytes NNS B-NP from IN B-PP CML NN B-NP patients NNS I-NP lack VBP B-VP a DT B-NP 47 CD I-NP kDa NN I-NP factor NN I-NP having VBG B-VP affinity NN B-NP for IN B-PP a DT B-NP genomic JJ I-NP sterol NN I-NP regulatory JJ I-NP sequence NN I-NP . . O Deranged VBN B-NP cellular JJ I-NP cholesterol NN I-NP homeostasis NN I-NP has VBZ B-VP been VBN I-VP widely RB I-VP recognized VBN I-VP in IN B-PP the DT B-NP initiation NN B-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP progression NN B-NP of IN B-PP various JJ B-NP types NNS I-NP of IN B-PP cancers NNS B-NP including VBG B-PP chronic JJ B-NP myeloid JJ I-NP leukaemia NN I-NP ( ( O CML NN B-NP ) ) O . . O Since IN B-SBAR the DT B-NP human JJ I-NP genomic JJ I-NP sterol NN B-NP regulatory JJ I-NP element NN I-NP ( ( O SRE NN B-NP ) ) O has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP regulate VB I-VP various JJ B-NP key JJ I-NP genes NNS I-NP involved VBN B-VP in IN B-PP this DT B-NP phenomenon NN I-NP COMMA COMMA O the DT B-NP present JJ I-NP study NN I-NP revealed VBD B-VP the DT B-NP existence NN I-NP of IN B-PP a DT B-NP unique JJ I-NP 47 CD I-NP kDa NN I-NP protein NN I-NP factor NN I-NP having VBG B-VP affinity NN B-NP for IN B-PP this DT B-NP SRE JJ I-NP sequence NN I-NP in IN B-PP lymphocytes NNS B-NP from IN B-PP normal JJ B-NP subjects NNS I-NP COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP its PRP$ B-NP absence NN I-NP in IN B-PP lymphocytes NNS B-NP from IN B-PP untreated JJ B-NP CML NN I-NP patients NNS I-NP . . O However RB B-ADVP COMMA COMMA O this DT B-NP factor NN I-NP appeared VBD B-VP when WRB B-ADVP these DT B-NP CML NN I-NP patients NNS I-NP achieved VBD B-VP complete JJ B-NP haematological JJ I-NP remission NN I-NP ( ( O CHR NN B-NP ) ) O through IN B-PP alpha-interferon NN B-NP therapy NN I-NP . . O Furthermore RB B-ADVP COMMA COMMA O an DT B-NP inverse JJ I-NP relationship NN I-NP was VBD B-VP also RB I-VP observed VBN I-VP between IN B-PP the DT B-NP LDL NN I-NP receptor NN I-NP gene NN I-NP expression NN I-NP at IN B-PP the DT B-NP transcriptional JJ I-NP level NN I-NP and CC O the DT B-NP binding NN I-NP affinity NN I-NP of IN B-PP this DT B-NP 47 CD I-NP kDa NN I-NP protein NN I-NP factor NN I-NP to TO B-PP the DT B-NP SRE NN I-NP sequence NN I-NP . . O Based VBN B-PP upon IN B-PP these DT B-NP results NNS I-NP we PRP B-NP propose VBP B-VP that IN B-SBAR this DT B-NP factor NN I-NP may MD B-VP have VB I-VP a DT B-NP role NN I-NP in IN B-PP pathophysiology NN B-NP of IN B-PP chronic JJ B-NP myeloid JJ I-NP leukaemia NN I-NP . . O Synergistic JJ B-NP interactions NNS I-NP between IN B-PP overlapping VBG B-NP binding VBG I-NP sites NNS I-NP for IN B-PP the DT B-NP serum NN I-NP response NN I-NP factor NN I-NP and CC O ELK-1 NN B-NP proteins NNS I-NP mediate VBP B-VP both CC O basal JJ B-NP enhancement NN I-NP and CC O phorbol NN B-NP ester NN I-NP responsiveness NN I-NP of IN B-PP primate JJ B-NP cytomegalovirus NN I-NP major JJ I-NP immediate-early JJ I-NP promoters NNS I-NP in IN B-PP monocyte NN B-NP and CC O T-lymphocyte NN B-NP cell NN B-NP types NNS I-NP . . O Cytomegalovirus NN B-NP ( ( O CMV NN B-NP ) ) O infection NN B-NP is VBZ B-VP nonpermissive JJ B-ADJP or CC O persistent JJ B-ADJP in IN B-PP many JJ B-NP lymphoid JJ I-NP and CC I-NP myeloid JJ I-NP cell NN I-NP types NNS I-NP but CC O can MD B-VP be VB I-VP activated VBN I-VP in IN B-PP differentiated VBN B-NP macrophages NNS I-NP . . O We PRP B-NP have VBP B-VP shown VBN I-VP elsewhere RB B-ADVP that IN B-SBAR both CC O the DT O major JJ B-NP immediate-early JJ I-NP gene NN I-NP ( ( O MIE NN B-NP ) ) O and CC O lytic JJ B-NP cycle NN I-NP infectious JJ I-NP progeny NN I-NP virus NN I-NP expression NN B-NP can MD B-VP be VB I-VP induced VBN I-VP in IN B-PP otherwise JJ B-ADVP nonpermissive JJ B-NP monocyte-like JJ I-NP U-937 NN I-NP cell NN I-NP cultures NNS I-NP infected VBN B-VP with IN B-PP either CC O human JJ B-NP CMV NN I-NP ( ( O HCMV NN B-NP ) ) O or CC O simian JJ B-NP CMV NN I-NP ( ( O SCMV NN B-NP ) ) O by IN B-PP treatment NN B-NP with IN B-PP the DT B-NP phorbol NN I-NP ester NN I-NP 12-O-tetradecanoylphorbol-13-acetate NN I-NP ( ( O TPA NN B-NP ) ) O . . O Two CD B-NP multicopy JJ I-NP basal JJ I-NP enhancer NN I-NP motifs NNS I-NP within IN B-PP the DT B-NP SCMV NN I-NP MIE NN I-NP enhancer NN I-NP COMMA COMMA B-NP namely RB I-NP COMMA COMMA O 11 CD B-NP copies NNS I-NP of IN B-PP the DT B-NP 16-bp JJ I-NP cyclic JJ B-NP AMP NN I-NP response NN I-NP element NN I-NP ( ( O CRE NN B-NP ) ) O and CC O 3 CD B-NP copies NNS I-NP of IN B-PP novel JJ O 17-bp JJ O serum NN B-NP response NN I-NP factor NN I-NP ( ( O SRF NN B-NP ) ) O binding NN B-NP sites NNS I-NP referred VBN B-VP to TO B-PP as IN B-PP the DT B-NP SNE NN I-NP ( ( O SRF\/NFkappaB-like JJ B-NP element NN I-NP ) ) O COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP four CD B-NP classical JJ I-NP NFkappaB NN I-NP sites NNS I-NP within IN B-PP the DT B-NP HCMV NN I-NP version NN I-NP COMMA COMMA O contribute VBP B-VP to TO B-PP TPA NN B-NP responsiveness NN I-NP in IN B-PP transient JJ B-NP assays NNS I-NP in IN B-PP monocyte NN B-NP and CC O T-cell NN B-NP types NNS B-NP . . O The DT B-NP SCMV NN I-NP SNE NN I-NP sites NNS I-NP contain VBP B-VP potential JJ B-NP overlapping VBG I-NP core NN I-NP recognition NN I-NP binding NN I-NP motifs NNS I-NP for IN B-PP SRF NN B-NP COMMA COMMA O Rel\/NFkappaB NN B-NP COMMA COMMA O ETS NN B-NP COMMA COMMA O and CC O YY1 NN B-NP class NN B-NP transcription NN I-NP factors NNS I-NP but CC O fail VBP B-VP to TO I-VP respond VB I-VP to TO B-PP either CC O serum NN B-NP or CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP . . O Therefore RB B-ADVP COMMA COMMA O to TO B-VP evaluate VB I-VP the DT B-NP mechanism NN I-NP of IN B-PP TPA NN B-NP responsiveness NN I-NP of IN B-PP the DT B-NP SNE NN I-NP motifs NNS I-NP and CC B-PP of IN B-PP a DT O related JJ O 16-bp JJ O SEE NN B-NP ( ( O SRF\/ETS NN B-NP element NN I-NP ) ) O motif NN B-NP found VBN B-VP in IN B-PP the DT O HCMV NN B-NP and CC O chimpanzee NN B-NP CMV NN I-NP MIE NN B-NP enhancers NNS I-NP COMMA COMMA O we PRP B-NP have VBP B-VP examined VBN I-VP the DT B-NP functional JJ B-NP responses NNS I-NP and CC O protein NN B-NP binding NN I-NP properties NNS I-NP of IN B-PP multimerized JJ B-NP wild-type JJ I-NP and CC I-NP mutant JJ I-NP elements NNS I-NP added VBN B-VP upstream RB B-ADVP to TO B-PP the DT O SCMV NN B-NP MIE NN I-NP or CC O simian JJ B-NP virus NN I-NP 40 CD B-NP minimal JJ I-NP promoter NN I-NP regions NNS I-NP in IN B-PP the DT O U-937 NN B-NP COMMA COMMA O K-562 NN B-NP COMMA COMMA O HL-60 NN B-NP COMMA COMMA O THP-1 NN B-NP COMMA COMMA O and CC O Jurkat NN B-NP cell NN B-NP lines NNS I-NP . . O Unlike IN B-PP classical JJ B-NP NFkappaB NN I-NP sites NNS I-NP COMMA COMMA O neither CC O the DT B-NP SNE NN I-NP nor CC O the DT B-NP SEE NN I-NP motif NN B-NP responded VBD B-VP to TO B-PP phosphatase NN B-NP inhibition NN I-NP by IN B-PP okadaic JJ B-NP acid NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP TPA NN I-NP responsiveness NN I-NP of IN B-PP both DT B-NP CMV NN I-NP elements NNS I-NP proved VBD B-VP to TO I-VP involve VB I-VP synergistic JJ B-NP interactions NNS I-NP between IN B-PP the DT B-NP core NN I-NP SRF NN I-NP binding NN I-NP site NN I-NP ( ( O CCATATATGG NN B-NP ) ) O and CC O the DT B-NP adjacent JJ I-NP inverted VBN I-NP ETS NN I-NP binding NN I-NP motifs NNS I-NP ( ( O TTCC NN B-NP ) ) O COMMA COMMA O which WDT B-NP correlated VBD B-VP directly RB B-ADVP with IN B-PP formation NN B-NP of IN B-PP a DT B-NP bound VBN I-NP tripartite JJ I-NP complex NN I-NP containing VBG B-VP both CC O the DT B-NP cellular JJ I-NP SRF NN I-NP and CC O ELK-1 NN B-NP proteins NNS I-NP . . O This DT B-NP protein NN I-NP complex NN I-NP was VBD B-VP more RBR B-ADJP abundant JJ I-ADJP in IN B-PP U-937 NN B-NP COMMA COMMA O K-562 NN B-NP COMMA COMMA O and CC O HeLa NN B-NP cell NN B-NP extracts NNS I-NP than IN B-PP in IN B-PP Raji NN B-NP COMMA COMMA O HF NN B-NP COMMA COMMA O BALB\/c NN B-NP 3T3 NN I-NP COMMA COMMA O or CC O HL-60 NN B-NP cells NNS B-NP COMMA COMMA O but CC O the DT B-NP binding NN I-NP activity NN I-NP was VBD B-VP altered VBN I-VP only RB B-ADVP twofold RB I-ADVP after IN B-PP TPA NN B-NP treatment NN I-NP . . O A DT B-NP 40-fold JJ I-NP stimulation NN I-NP of IN B-PP chloramphenicol JJ B-NP acetyltransferase NN I-NP activity NN I-NP mediated VBN B-VP by IN B-PP four CD B-NP tandem JJ I-NP repeats NNS I-NP of IN B-PP the DT B-NP SNE NN I-NP could MD B-VP be VB I-VP induced VBN I-VP within IN B-PP 2 CD B-NP h NN I-NP ( ( O and CC O up RB B-ADVP to TO I-ADVP 250-fold JJ I-ADVP within IN B-PP 6 CD B-NP h NN I-NP ) ) O after IN B-PP addition NN B-NP of IN B-PP TPA NN B-NP in IN B-PP DNA-transfected JJ B-NP U-937 NN I-NP cells NNS I-NP COMMA COMMA O indicating VBG B-VP that IN B-SBAR the DT B-NP stimulation NN I-NP appeared VBD B-VP likely JJ B-ADJP to TO B-VP be VB I-VP a DT B-NP true JJ I-NP protein NN I-NP kinase NN I-NP C-mediated JJ I-NP signal NN I-NP transduction NN I-NP event NN I-NP rather RB B-CONJP than IN I-CONJP a DT B-NP differentiation NN I-NP response NN I-NP . . O Slight JJ B-NP differences NNS I-NP in IN B-PP the DT B-NP sequence NN I-NP of IN B-PP the DT B-NP core NN I-NP SRF NN I-NP binding NN I-NP site NN I-NP compared VBN B-PP with IN B-PP that DT B-NP of IN B-PP the DT B-NP classical JJ I-NP c-Fos NN I-NP promoter NN I-NP serum NN I-NP response NN I-NP element NN I-NP COMMA COMMA O together RB B-PP with IN I-PP differences NNS B-NP in IN B-PP the DT B-NP spacing NN I-NP between IN B-PP the DT O SRF NN B-NP and CC O ETS NN B-NP motifs NNS B-NP COMMA COMMA O appear VBP B-VP to TO I-VP account VB I-VP for IN B-PP the DT B-NP inability NN I-NP of IN B-PP the DT B-NP SCMV NN I-NP SNEs NNS I-NP to TO B-VP respond VB I-VP to TO B-PP serum NN B-NP induction NN I-NP . . O Acetylsalicylic JJ B-NP acid NN I-NP and CC O sodium NN B-NP salicylate NN I-NP inhibit VBP B-VP LPS-induced JJ B-NP NF-kappa NN I-NP B\/c-Rel NN I-NP nuclear JJ I-NP translocation NN I-NP COMMA COMMA O and CC O synthesis NN B-NP of IN B-PP tissue NN B-NP factor NN I-NP ( ( O TF NN B-NP ) ) O and CC O tumor NN B-NP necrosis NN I-NP factor NN I-NP alfa NN I-NP ( ( O TNF-alpha NN B-NP ) ) O in IN B-PP human JJ B-NP monocytes NNS I-NP . . O We PRP B-NP have VBP B-VP investigated VBN I-VP the DT B-NP effects NNS I-NP of IN B-PP acetylsalicylic JJ B-NP acid NN I-NP and CC O sodium NN B-NP salicylate NN I-NP on IN B-PP the DT B-NP LPS-induced JJ I-NP synthesis NN I-NP of IN B-PP the DT B-NP pro-coagulant JJ I-NP protein NN I-NP tissue NN B-NP factor NN I-NP ( ( O TF NN B-NP ) ) O and CC O the DT B-NP pro-inflammatory JJ I-NP protein NN I-NP tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O COMMA COMMA O as RB B-CONJP well RB I-CONJP as IN I-CONJP the DT B-NP prostaglandin NN I-NP PGE2 NN I-NP in IN B-PP human JJ B-NP monocytes NNS I-NP . . O Both DT B-NP drugs NNS I-NP dose-dependently RB B-ADVP inhibited VBD B-VP LPS-induced JJ O TF NN B-NP and CC O TNF-alpha NN B-NP synthesis NN B-NP at IN B-PP the DT B-NP mRNA NN I-NP and CC O the DT B-NP protein NN I-NP level NN B-NP COMMA COMMA O and CC O reduced VBD B-VP PGE2 NN B-NP production NN I-NP . . O As IN B-SBAR evidenced VBN B-VP by IN B-PP electro NN B-NP mobility NN I-NP shift NN I-NP assay NN I-NP ( ( O EMSA NN B-NP ) ) O and CC O the DT B-NP use NN I-NP of IN B-PP a DT B-NP NF-kappa NN I-NP B NN I-NP prototypic JJ I-NP probe NN I-NP COMMA COMMA O these DT B-NP drugs NNS I-NP probably RB B-ADVP exert VBP B-VP their PRP$ B-NP inhibitory JJ I-NP effects NNS I-NP by IN B-PP interference NN B-NP with IN B-PP the DT B-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP NF-kappa NN B-NP B\/c-Rel NN I-NP proteins NNS I-NP . . O These DT B-NP data NNS I-NP may MD B-VP expand VB I-VP the DT B-NP understanding NN I-NP of IN B-PP the DT B-NP anti-thrombotic JJ I-NP and CC I-NP anti-inflammatory JJ I-NP effects NNS I-NP of IN B-PP these DT B-NP drugs NNS I-NP when WRB B-ADVP activation NN B-NP of IN B-PP monocytes NNS B-NP occurs VBZ B-VP . . O Octamer NN B-NP independent JJ I-NP activation NN I-NP of IN B-PP transcription NN B-NP from IN B-PP the DT B-NP kappa NN I-NP immunoglobulin NN I-NP germline NN I-NP promoter NN I-NP . . O Previous JJ B-NP analyses NNS I-NP of IN B-PP immunoglobulin NN B-NP V JJ I-NP region NN I-NP promoters NNS I-NP has VBZ B-VP led VBN I-VP to TO B-PP the DT B-NP discovery NN I-NP of IN B-PP a DT B-NP common JJ I-NP octamer NN I-NP motif NN I-NP which WDT B-NP is VBZ B-VP functionally RB B-ADVP important JJ B-ADJP in IN B-PP the DT B-NP tissue-specific JJ I-NP and CC I-NP developmentally RB I-NP regulated VBN I-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP immunoglobulin NN B-NP genes NNS I-NP . . O The DT B-NP germline NN I-NP promoters NNS I-NP ( ( O Ko NN B-NP ) ) O located JJ B-ADJP upstream RB I-ADJP of IN B-PP the DT B-NP J JJ I-NP region NN I-NP gene NN I-NP segments NNS I-NP of IN B-PP the DT B-NP kappa NN I-NP locus NN I-NP also RB B-ADVP contain VBP B-VP an DT B-NP octamer NN I-NP motif NN I-NP ( ( O containing VBG B-VP a DT B-NP single JJ I-NP base NN I-NP pair NN I-NP mutation NN I-NP and CC O referred VBN B-VP to TO B-PP as IN B-PP the DT B-NP variant JJ I-NP octamer NN I-NP ) ) O which WDT B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP previously RB I-VP to TO I-VP bind VB I-VP Oct-1 NN B-NP and CC O Oct-2 NN B-NP transcription NN B-NP factors NNS I-NP in FW B-ADVP vitro FW I-ADVP . . O To TO B-VP further RB I-VP elucidate VB I-VP the DT B-NP role NN I-NP of IN B-PP this DT B-NP variant JJ I-NP octamer NN I-NP motif NN I-NP in IN B-PP the DT B-NP regulation NN I-NP of IN B-PP germline NN B-NP transcription NN I-NP from IN B-PP the DT B-NP unrearranged JJ I-NP kappa NN I-NP locus NN I-NP COMMA COMMA O we PRP B-NP have VBP B-VP quantitated VBN I-VP the DT B-NP relative JJ I-NP binding NN I-NP affinity NN I-NP of IN B-PP Oct-1 NN B-NP and CC O Oct-2 NN B-NP for IN B-PP the DT B-NP variant JJ I-NP octamer NN I-NP motif NN I-NP and CC O determined VBD B-VP the DT B-NP functional JJ I-NP role NN I-NP of IN B-PP this DT B-NP octamer NN I-NP motif NN I-NP in IN B-PP transcriptional JJ B-NP activation NN I-NP . . O We PRP B-NP find VBP B-VP that IN B-SBAR COMMA COMMA O although IN B-SBAR the DT B-NP variant JJ I-NP octamer NN I-NP motif NN I-NP binds VBZ B-VP Oct-1 NN B-NP and CC O Oct-2 NN B-NP in FW B-ADVP vitro FW I-ADVP with IN B-PP 5-fold JJ B-NP lower JJR I-NP affinity NN I-NP than IN B-PP the DT B-NP consensus NN I-NP octamer NN I-NP motif NN I-NP COMMA COMMA O mutation NN B-NP of IN B-PP the DT B-NP variant JJ I-NP octamer NN I-NP motif NN I-NP to TO B-PP either CC O a DT O consensus NN B-NP octamer NN I-NP or CC O non-octamer JJ B-ADJP motif NN B-NP has VBZ B-VP no DT B-NP effect NN I-NP on IN B-PP transcriptional JJ B-NP activation NN I-NP from IN B-PP the DT B-NP germline NN I-NP promoter NN I-NP . . O We PRP B-NP also RB B-ADVP find VBP B-VP significant JJ B-NP differences NNS I-NP in IN B-PP activation NN B-NP of IN B-PP germline NN B-NP and CC O V JJ B-NP region NN I-NP promoters NNS B-NP by IN B-PP kappa NN B-NP enhancers NNS I-NP . . O Our PRP$ B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP germline NN B-NP promoters NNS I-NP and CC O V JJ B-NP region NN I-NP promoters NNS I-NP differ VBP B-VP in IN B-PP their PRP$ B-NP dependence NN I-NP on IN B-PP octamer NN B-NP for IN B-PP activation NN B-NP and CC O respond VBP B-VP differently RB B-ADVP to TO B-PP enhancer NN B-NP activation NN I-NP . . O These DT B-NP findings NNS I-NP have VBP B-VP important JJ B-NP implications NNS I-NP in IN B-PP regulation NN B-NP of IN B-PP germline NN B-NP transcription NN I-NP as RB B-CONJP well RB I-CONJP as IN I-CONJP concomitant JJ B-NP activation NN I-NP of IN B-PP the DT B-NP V-J JJ I-NP recombination NN I-NP of IN B-PP the DT B-NP kappa NN I-NP light JJ I-NP chain NN I-NP locus NN I-NP . . O Characterization NN B-NP of IN B-PP the DT B-NP murine JJ I-NP cyclin-dependent JJ I-NP kinase NN I-NP inhibitor NN I-NP gene NN I-NP p27Kip1 NN I-NP . . O The DT B-NP cyclin-dependent JJ I-NP kinase NN I-NP inhibitor NN I-NP p27Kip1 NN I-NP plays VBZ B-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP regulating VBG B-VP cell-cycle JJ B-NP progression NN I-NP . . O p27Kip1 NN B-NP directly RB B-ADVP inhibits VBZ B-VP the DT B-NP catalytic JJ I-NP activity NN I-NP of IN B-PP cyclin\/cdks NNS O ( ( O cyclin-dependent JJ B-NP kinase NN I-NP ) ) O complexes NNS B-NP and\/or CC O interferes VBZ B-VP physically RB B-ADVP with IN B-PP cyclin\/cdks NN B-NP activation NN I-NP by IN B-PP CAK NN B-NP . . O Interestingly RB B-ADVP COMMA COMMA O the DT B-NP expression NN I-NP level NN I-NP of IN B-PP p27Kip1 NN B-NP mRNA NN I-NP was VBD B-VP maximal JJ B-ADJP in IN B-PP resting VBG B-NP Go NN I-NP T-cells NNS I-NP and CC O rapidly RB B-VP declined VBD I-VP following VBG B-PP anti-CD3 JJ B-NP activation NN I-NP . . O We PRP B-NP report VBP B-VP here RB B-ADVP the DT B-NP cloning NN I-NP of IN B-PP p27Kip1 NN B-NP gene NN I-NP from IN B-PP murine JJ B-NP genomic JJ I-NP DNA NN I-NP and CC O the DT B-NP functional JJ I-NP analysis NN I-NP of IN B-PP the DT B-NP promoter NN I-NP of IN B-PP the DT B-NP p27Kip1 NN I-NP gene NN I-NP . . O The DT B-NP gene NN I-NP consists VBZ B-VP of IN B-PP at IN B-NP least JJS I-NP three CD I-NP exons NNS I-NP and CC O spans NNS B-VP more RBR B-NP than IN I-NP 5.6 CD I-NP kb NN I-NP of IN B-PP DNA NN B-NP . . O Primer NN B-NP extension NN I-NP and CC O nuclease NN B-NP S1 NN I-NP protection NN I-NP analysis NN B-NP revealed VBD B-VP two CD B-NP major JJ I-NP transcription NN I-NP initiation NN I-NP sites NNS I-NP . . O The DT B-NP promoter NN I-NP region NN I-NP lacked VBD B-VP a DT B-NP TATA NN I-NP box NN I-NP but CC O contained VBD B-VP potential JJ B-NP binding VBG I-NP sites NNS I-NP for IN B-PP the DT B-NP transcriptional JJ I-NP factors NNS I-NP including VBG B-PP two CD B-NP Sp1 NN I-NP COMMA COMMA O CRE NN B-NP COMMA COMMA O Myb NN B-NP and CC O NFkB NN B-NP located JJ B-ADJP at IN B-PP positions NNS B-NP -153 CD B-NP COMMA COMMA O -178 CD B-NP COMMA COMMA O -286 CD B-NP COMMA COMMA O -875 CD B-NP COMMA COMMA O and CC O -1011 CD B-NP COMMA COMMA O respectively RB B-ADVP . . O To TO B-VP analyze VB I-VP the DT B-NP regulatory JJ I-NP mechanisms NNS I-NP controlling VBG B-VP p27Kip1 NN B-NP gene NN I-NP expression NN I-NP COMMA COMMA O we PRP B-NP characterized VBD B-VP the DT B-NP 5'-flanking JJ I-NP region NN I-NP from IN B-PP nt NN B-NP -1609 CD I-NP to TO B-PP +178 CD B-NP . . O The DT B-NP -326 CD I-NP to TO I-NP -615 CD I-NP region NN I-NP contained VBD B-VP positive JJ B-NP regulatory JJ I-NP elements NNS I-NP . . O Glucocorticoid-mediated JJ B-NP inhibition NN I-NP of IN B-PP RANTES NN B-NP expression NN I-NP in IN B-PP human JJ B-NP T NN I-NP lymphocytes NNS I-NP . . O The DT B-NP chemokine NN I-NP RANTES NN I-NP has VBZ B-VP been VBN I-VP implicated VBN I-VP in IN B-PP the DT B-NP pathogenesis NN I-NP of IN B-PP allergic JJ B-NP inflammatory JJ I-NP diseases NNS I-NP including VBG B-PP asthma NN B-NP and CC O rhinitis NN B-NP which WDT B-NP are VBP B-VP frequently RB I-VP treated VBN I-VP with IN B-PP glucocorticoids NNS B-NP . . O We PRP B-NP observed VBD B-VP that IN B-SBAR dexamethasone NN B-NP dramatically RB B-ADVP inhibited VBD B-VP RANTES NN B-NP mRNA NN I-NP expression NN I-NP dose NN B-ADVP dependently RB I-ADVP in IN B-PP anti-CD3 NN B-NP activated JJ I-NP Hut-78 NN I-NP T NN I-NP cells NNS I-NP and CC O human JJ B-NP PBMCs NNS I-NP . . O Inhibition NN B-NP of IN B-PP RANTES NNS B-NP expression NN I-NP did VBD B-VP not RB I-VP appear VB I-VP to TO I-VP be VB I-VP secondary JJ B-ADJP to TO B-PP IL-2 NN B-NP inhibition NN I-NP and CC O required VBD B-VP binding VBG B-NP to TO B-PP the DT B-NP intracellular JJ I-NP glucocorticoid NN I-NP receptor NN I-NP . . O The DT B-NP down-regulation NN I-NP of IN B-PP RANTES NN B-NP expression NN I-NP by IN B-PP glucocorticoids NNS B-NP in IN B-PP T NN B-NP cells NNS I-NP may MD B-VP directly RB I-VP contribute VB I-VP to TO B-PP the DT B-NP efficacy NN I-NP of IN B-PP these DT B-NP agents NNS I-NP in IN B-PP suppressing VBG B-VP cellular JJ B-NP infiltration NN I-NP and CC B-PP to TO B-PP their PRP$ B-NP anti-inflammatory JJ I-NP properties NNS I-NP . . O A DT B-NP novel JJ I-NP SP-1 NN I-NP site NN I-NP in IN B-PP the DT B-NP human JJ I-NP interleukin-1 NN I-NP beta NN I-NP promoter NN I-NP confers VBZ B-VP preferential JJ B-NP transcriptional JJ I-NP activity NN I-NP in IN B-PP keratinocytes NNS B-NP . . O To TO B-VP investigate VB I-VP the DT B-NP mechanisms NNS I-NP of IN B-PP transcriptional JJ B-NP activation NN I-NP of IN B-PP interleukin-1beta NN B-NP ( ( O IL-1beta NN B-NP ) ) O in IN B-PP non-monocytic JJ B-NP cells NNS I-NP COMMA COMMA O we PRP B-NP constructed VBD B-VP a DT B-NP series NN I-NP of IN B-PP reporter NN B-NP plasmids NNS I-NP with IN B-PP the DT B-NP bacterial JJ I-NP chloramphenicol NN I-NP acetyltransferase NN I-NP gene NN I-NP linked VBN B-VP to TO B-PP various JJ B-NP parts NNS I-NP of IN B-PP the DT B-NP human JJ I-NP IL-1beta NN I-NP promoter NN I-NP and CC O performed VBD B-VP transient JJ B-NP transfection NN I-NP experiments NNS I-NP . . O We PRP B-NP identified VBD B-VP a DT B-NP promoter NN I-NP segment NN I-NP that WDT B-NP activates VBZ B-VP transcription NN B-NP most RBS B-ADVP efficiently RB I-ADVP in IN B-PP keratinocytes NNS B-NP . . O Electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP ( ( O EMSA NN B-NP ) ) O with IN B-PP a DT B-NP 43-mer NN I-NP oligonucleotide NN I-NP derived VBN B-VP from IN B-PP the DT B-NP functionally RB I-NP identified VBN I-NP cis-acting JJ I-NP element NN I-NP revealed VBD B-VP specific JJ B-NP complexes NNS I-NP . . O By IN B-PP competition NN B-NP analysis NN I-NP with IN B-PP transcription NN B-NP factor NN I-NP consensus NN I-NP sequence NN I-NP oligonucleotides NNS I-NP and CC B-PP by IN B-PP immunosupershift NN B-NP COMMA COMMA O transcription NN B-NP factor NN I-NP SP-1 NN I-NP or CC O a DT B-NP closely RB I-NP related JJ I-NP protein NN I-NP was VBD B-VP shown VBN I-VP to TO I-VP bind VBP I-VP to TO B-PP this DT B-NP regulatory JJ I-NP element NN I-NP . . O The DT B-NP closest JJS I-NP match NN I-NP to TO B-PP the DT B-NP known VBN I-NP SP-1 NN I-NP consensus NN I-NP sequence NN I-NP within IN B-PP the DT B-NP respective JJ I-NP region NN I-NP is VBZ B-VP a DT B-NP TCCCCTCCCCT NN I-NP motif NN I-NP . . O Mutation NN B-NP of IN B-PP this DT B-NP motif NN I-NP almost RB B-ADVP completely RB I-ADVP COMMA COMMA O and CC O specifically RB B-ADVP COMMA COMMA B-VP abolished VBD I-VP the DT B-NP binding NN I-NP of IN B-PP two CD B-NP low-mobility JJ I-NP complexes NNS I-NP and CC O led VBD B-VP to TO B-PP a DT B-NP 95 CD I-NP % NN I-NP decrease NN I-NP of IN B-PP constitutive JJ B-NP transcriptional JJ I-NP activation NN I-NP of IN B-PP a DT B-NP reporter NN I-NP construct NN I-NP IL-1beta NN I-NP ( ( O -170\/+108 CD B-NP ) ) O . . O Likewise RB B-ADVP COMMA COMMA O activation NN B-NP of IN B-PP this DT B-NP reporter NN I-NP construct NN I-NP by IN B-PP tumor NN B-NP necrosis NN I-NP factor-alpha NN I-NP depended VBD B-VP on IN B-PP the DT B-NP SP-1 NN I-NP site NN I-NP . . O These DT B-NP observations NNS I-NP suggest VBP B-VP that IN B-SBAR a DT B-NP so-far-unrecognized JJ I-NP SP-1 NN I-NP site NN I-NP in IN B-PP the DT B-NP human JJ I-NP IL-1beta NN I-NP promoter NN I-NP may MD B-VP participate VB I-VP in IN B-PP the DT B-NP transcriptional JJ I-NP regulation NN I-NP of IN B-PP this DT B-NP gene NN I-NP in IN B-PP keratinocytes NNS B-NP . . O Effects NNS B-NP of IN B-PP glucocorticoids NNS B-NP on IN B-PP lymphocyte NN B-NP activation NN I-NP in IN B-PP patients NNS B-NP with IN B-PP steroid-sensitive JJ B-NP and CC I-NP steroid-resistant JJ I-NP asthma NN I-NP . . O BACKGROUND NN B-NP : : O Glucocorticoids NNS B-NP are VBP B-VP important JJ B-NP medications NNS I-NP used VBN B-VP to TO B-VP control VB I-VP the DT B-NP airway NN I-NP inflammation NN I-NP associated VBN B-VP with IN B-PP asthma NN B-NP . . O Synthetic JJ B-NP glucocorticoids NNS I-NP vary VBP B-VP in IN B-PP their PRP$ B-NP binding NN I-NP affinity NN I-NP for IN B-PP the DT B-NP glucocorticoid NN I-NP receptor NN I-NP ( ( O GCR NN B-NP ) ) O . . O METHODS NNS B-NP : : O We PRP B-NP compared VBD B-VP hydrocortisone NN B-NP COMMA COMMA O beclomethasone NN B-NP dipropionate NN I-NP COMMA COMMA O triamcinolone NN B-NP acetonide NN I-NP COMMA COMMA O flunisolide NN B-NP COMMA COMMA O and CC O budesonide NN B-NP with IN B-PP regard NN B-NP to TO B-PP their PRP$ B-NP capacity NN I-NP to TO B-VP inhibit VB I-VP phytohemagglutinin-induced JJ B-NP peripheral JJ I-NP blood NN I-NP mononuclear JJ I-NP cell NN I-NP proliferation NN I-NP from IN B-PP six CD B-NP patients NNS I-NP with IN B-PP steroid-sensitive JJ B-NP asthma NN I-NP and CC O seven CD B-NP patients NNS I-NP with IN B-PP steroid-resistant JJ B-NP asthma NN I-NP . . O Peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cell NN I-NP GCR NN I-NP binding NN I-NP affinities NNS I-NP for IN B-PP dexamethasone NN B-NP and CC O budesonide NN B-NP were VBD B-VP also RB I-VP determined VBN I-VP for IN B-PP both DT B-NP patient NN I-NP groups NNS I-NP by IN B-PP using VBG B-VP a DT B-NP radioligand NN I-NP binding NN I-NP assay NN I-NP and CC O Scatchard NN B-NP analysis NN I-NP . . O RESULTS NNS B-NP : : O Dose-dependent JJ B-NP inhibition NN I-NP was VBD B-VP demonstrated VBN I-VP for IN B-PP all DT B-NP glucocorticoids NNS I-NP in IN B-PP both DT B-NP patient NN I-NP groups NNS I-NP COMMA COMMA O with IN B-PP the DT B-NP steroid-resistant JJ I-NP group NN I-NP requiring VBG B-VP approximately RB B-NP 2 CD I-NP log-fold JJ I-NP more JJR I-NP glucocorticoids NNS I-NP for IN B-PP an DT B-NP equivalent JJ I-NP degree NN I-NP of IN B-PP inhibition NN B-NP . . O The DT B-NP mean NN I-NP concentrations NNS I-NP necessary JJ B-ADJP to TO B-VP cause VB I-VP 50 CD B-NP % NN I-NP inhibition NN I-NP of IN B-PP lymphocyte NN B-NP proliferation NN I-NP ( ( O IC50s NNS B-NP ) ) O for IN B-PP the DT B-NP steroid-sensitive JJ I-NP group NN I-NP ranged VBD B-VP from IN B-PP 2 CD B-NP x CC I-NP 10(-10) CD I-NP mol\/L NN I-NP for IN B-PP budesonide NN B-NP to TO B-PP 7 CD B-NP x CC I-NP 10(-8) CD I-NP mol\/L NN I-NP for IN B-PP hydrocortisone NN B-NP COMMA COMMA O whereas IN O the DT B-NP mean NN I-NP IC50s NNS I-NP for IN B-PP the DT B-NP steroid-resistant JJ I-NP group NN I-NP ranged VBD B-VP from IN B-PP approximately RB B-NP 2 CD I-NP x CC I-NP 10(-8) CD I-NP mol\/L NN I-NP for IN B-PP budesonide NN B-NP to TO B-PP greater JJR B-NP than IN I-NP 10(-6) CD I-NP mol\/L NN I-NP for IN B-PP hydrocortisone NN B-NP . . O In IN B-PP addition NN B-NP COMMA COMMA O a DT B-NP significant JJ I-NP correlation NN I-NP was VBD B-VP noted VBN I-VP between IN B-PP the DT B-NP degree NN I-NP of IN B-PP inhibition NN B-NP of IN B-PP lymphocyte NN B-NP proliferation NN I-NP ( ( O IC50 NN B-NP ) ) O and CC O the DT B-NP binding NN I-NP affinity NN I-NP of IN B-PP dexamethasone NN B-NP to TO B-PP the DT B-NP GCR NN I-NP . . O Patients NNS B-NP with IN B-PP steroid-resistant JJ B-NP asthma NN I-NP have VBP B-VP been VBN I-VP shown VBN I-VP to TO I-VP have VB I-VP a DT B-NP reduced VBN I-NP GCR NN I-NP binding NN I-NP affinity NN I-NP . . O The DT B-NP GCR NN I-NP binding NN I-NP affinity NN I-NP for IN B-PP budesonide NN B-NP was VBD B-VP significantly RB B-ADJP higher JJR I-ADJP in IN B-PP both DT B-NP groups NNS I-NP ( ( O i.e. FW B-ADVP COMMA COMMA O lower JJR B-NP dissociation NN I-NP constant NN I-NP ) ) O than IN B-PP that DT B-NP obtained VBN B-VP for IN B-PP dexamethasone NN B-NP . . O CONCLUSION NN B-NP : : O These DT B-NP data NNS I-NP suggest VBP B-VP that IN B-SBAR glucocorticoids NNS B-NP such JJ B-PP as IN I-PP budesonide NN B-NP COMMA COMMA O by IN B-PP virtue NN I-PP of IN I-PP their PRP$ B-NP high JJ B-NP GCR NN I-NP binding NN I-NP affinities NNS I-NP and CC O greater JJR B-NP ability NN I-NP to TO B-VP suppress VB I-VP lymphocyte NN B-NP proliferation NN I-NP COMMA COMMA O may MD B-VP therefore RB I-VP be VB I-VP beneficial JJ B-ADJP in IN B-PP the DT B-NP management NN I-NP of IN B-PP difficult-to-control JJ B-NP asthma NN I-NP . . O Involvement NN B-NP of IN B-PP nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP activation NN I-NP in IN B-PP IgE NN B-NP synthesis NN I-NP in IN B-PP human JJ B-NP B NN I-NP cells NNS I-NP . . O Nuclear JJ B-NP factor-kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ) ) O is VBZ B-VP a DT B-NP transcription NN I-NP factor NN I-NP that WDT B-NP binds VBZ B-VP to TO B-PP the DT B-NP consensus NN I-NP DNA NN I-NP sequence NN I-NP in IN B-PP the DT B-NP cis-acting JJ I-NP elements NNS I-NP of IN B-PP various JJ B-NP genes NNS I-NP . . O Although IN B-SBAR NF-kappa NN B-NP B NN I-NP activates VBZ B-VP the DT B-NP expression NN I-NP of IN B-PP many JJ B-NP genes NNS I-NP involved VBN B-VP in IN B-PP immune JJ B-NP and CC I-NP inflammatory JJ I-NP responses NNS I-NP COMMA COMMA O little JJ B-NP is VBZ B-VP known VBN I-VP about IN B-PP the DT B-NP role NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP in IN B-PP the DT B-NP induction NN I-NP of IN B-PP IgE NN B-NP synthesis NN I-NP in IN B-PP human JJ B-NP B NN I-NP cells NNS I-NP . . O Therefore RB B-ADVP we PRP B-NP first RB B-ADVP examined VBD B-VP the DT B-NP participation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP in IN B-PP germline NN B-NP C NN I-NP epsilon NN I-NP transcription NN I-NP in IN B-PP a DT B-NP human JJ I-NP Burkitt NN I-NP lymphoma NN I-NP B NN I-NP cell NN I-NP line NN I-NP COMMA COMMA O DND39 NN B-NP . . O Stimulation NN B-NP of IN B-PP DND39 NN B-NP cells NNS I-NP with IN B-PP IL-4 NN B-NP or CC O anti-CD40 JJ B-NP monoclonal JJ B-NP antibody NN I-NP ( ( O mAb NN B-NP ) ) O activated VBD B-VP phosphatidylinositol NN B-NP 3-kinase NN I-NP and CC O subsequently RB B-VP induced VBD I-VP nuclear JJ B-NP expression NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O which WDT B-NP was VBD B-VP identified VBN I-VP by IN B-PP electrophoretic JJ B-NP mobility NN I-NP shift NN I-NP assays NNS I-NP . . O n-Acetyl-L-cysteine NN B-NP ( ( O NAC NN B-NP ) ) O COMMA COMMA O a DT B-NP potent JJ I-NP antioxidant NN I-NP COMMA COMMA O blocked VBD B-VP NF-kappa NN B-NP B NN I-NP activation NN I-NP caused VBN B-VP by IN B-PP IL-4 NN B-NP and CC B-PP by IN B-PP anti-CD40 JJ B-NP mAb NN I-NP . . O Although IN B-SBAR inhibition NN B-NP of IN B-PP IL-4-driven JJ B-NP germline NN I-NP C NN I-NP epsilon NN I-NP transcription NN I-NP by IN B-PP NAC NN B-NP was VBD B-VP not RB O sufficient JJ B-ADJP COMMA COMMA O the DT B-NP agent NN I-NP remarkably RB B-ADVP diminished VBD B-VP anti-CD40 JJ B-NP mAb-mediated JJ I-NP up-regulation NN I-NP of IN B-PP germline NN B-NP C NN I-NP epsilon NN I-NP transcription NN I-NP . . O Second RB B-ADVP COMMA COMMA O we PRP B-NP studied VBD B-VP the DT B-NP effect NN I-NP of IN B-PP NAC NN B-NP on IN B-PP IgE NN B-NP synthesis NN I-NP in IN B-PP human JJ B-NP normal JJ I-NP B NN I-NP cells NNS I-NP costimulated VBN B-VP with IN B-PP IL-4 NN B-NP and CC O anti-CD40 JJ B-NP mAb NN I-NP . . O NAC NN B-NP was VBD B-VP effective JJ B-ADJP in IN B-PP inhibiting VBG B-VP mature JJ B-NP C NN I-NP epsilon NN I-NP transcription NN I-NP and CC O IgE NN B-NP synthesis NN I-NP in IN B-PP the DT B-NP T NN I-NP cell-independent JJ I-NP culture NN I-NP system NN I-NP . . O However RB B-ADVP COMMA COMMA O NAC NN B-NP did VBD B-VP not RB I-VP significantly RB I-VP affect VB I-VP the DT B-NP spontaneous JJ I-NP production NN I-NP of IN B-PP IgE NN B-NP by IN B-PP atopic JJ B-NP B NN I-NP cells NNS I-NP . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP activity NN I-NP is VBZ B-VP commonly RB B-ADVP inducible JJ B-ADJP in IN B-PP DND39 NN B-NP cells NNS I-NP by IN B-PP IL-4 NN B-NP and CC O anti-CD40 JJ B-NP mAb NN I-NP and CC O suggest VBP B-VP that IN B-SBAR NF-kappa NN B-NP B NN I-NP sensitive JJ B-ADJP to TO B-PP NAC NN B-NP may MD B-VP play VB I-VP a DT B-NP role NN I-NP in IN B-PP regulating VBG B-VP IgE NN B-NP synthesis NN I-NP in IN B-PP B NN B-NP cells NNS I-NP . . O { ( O Molecular JJ B-NP mechanisms NNS I-NP of IN B-PP age-related JJ B-NP lymphocyte NN I-NP dysfunction NN I-NP } ) O Aging NN B-NP is VBZ B-VP classically RB I-VP accompanied VBN I-VP by IN B-PP a DT B-NP dysregulation NN I-NP of IN B-PP the DT B-NP immunologic JJ I-NP machinery NN I-NP . . O As IN B-PP a DT B-NP consequence NN I-NP COMMA COMMA O the DT B-NP immune JJ I-NP response NN I-NP developed VBN B-VP in IN B-PP senescent JJ B-NP organisms NNS I-NP is VBZ B-VP usually RB B-ADVP inappropriate JJ B-ADJP COMMA COMMA O often RB B-ADVP inefficient JJ B-ADJP COMMA COMMA O sometimes RB B-ADVP aberrant JJ B-ADJP COMMA COMMA O and CC O potentially RB B-ADVP detrimental JJ B-ADJP . . O The DT B-NP age-associated JJ I-NP immune JJ I-NP dysfunction NN I-NP may MD B-VP be VB I-VP implicated VBN I-VP to TO B-PP some DT B-NP degree NN I-NP in IN B-PP the DT B-NP extreme JJ I-NP susceptibility NN I-NP of IN B-PP the DT B-NP elderly JJ I-NP to TO B-PP infection NN B-NP and CC O neoplasia NN B-NP and CC O may MD B-VP even RB I-VP participate VB I-VP in IN B-PP various JJ B-NP aspects NNS I-NP of IN B-PP senescence NN B-NP . . O The DT B-NP current JJ I-NP understanding NN I-NP of IN B-PP the DT B-NP molecular JJ I-NP mechanisms NNS I-NP underlying VBG B-VP immunosenescence NN B-NP is VBZ B-VP still RB B-ADVP fragmentary JJ B-ADJP . . O The DT O most RBS B-ADVP extensively RB I-ADVP studied VBN B-NP phenomenon NN I-NP is VBZ B-VP the DT B-NP progressive JJ I-NP decline NN I-NP in IN B-PP the DT B-NP proliferative JJ I-NP capacities NNS I-NP of IN B-PP T NN B-NP lymphocytes NNS I-NP with IN B-PP aging NN B-NP . . O The DT B-NP loss NN I-NP of IN B-PP proliferative JJ B-NP potential NN I-NP in IN B-PP response NN I-PP to TO I-PP antigenic JJ B-NP challenge NN I-NP is VBZ B-VP a DT B-NP characteristic JJ I-NP feature NN I-NP of IN B-PP immune JJ B-NP senescence NN I-NP . . O It PRP B-NP is VBZ B-VP directly RB I-VP implicated VBN I-VP in IN B-PP the DT B-NP emergence NN I-NP of IN B-PP the DT B-NP age-related JJ I-NP immune JJ I-NP deficiency NN I-NP . . O The DT B-NP purpose NN I-NP of IN B-PP this DT B-NP review NN I-NP is VBZ B-VP to TO B-VP show VB I-VP how WRB B-ADVP the DT B-NP accumulation NN I-NP of IN B-PP various JJ B-NP biochemical JJ I-NP lesions NNS I-NP with IN B-PP advancing VBG B-NP age NN I-NP leads VBZ B-VP to TO B-PP the DT B-NP failure NN I-NP of IN B-PP a DT B-NP critical JJ I-NP cell NN I-NP function NN I-NP COMMA COMMA B-NP namely RB I-NP the DT B-NP activation-induced JJ I-NP lymphocyte NN I-NP proliferation NN I-NP . . O The DT B-NP biochemical JJ I-NP modifications NNS I-NP responsible JJ B-ADJP for IN B-PP the DT B-NP defect NN I-NP in IN B-PP transduction NN B-NP and CC O execution NN B-NP of IN B-PP the DT B-NP proliferative JJ I-NP signal NN I-NP are VBP B-VP analyzed VBN I-VP as IN B-PP a DT B-NP function NN I-NP of IN B-PP age NN B-NP . . O The DT B-NP multiple JJ I-NP alterations NNS I-NP observed VBN B-VP on IN B-PP the DT B-NP various JJ I-NP biochemical JJ I-NP pathways NNS I-NP may MD B-VP appear VB I-VP as IN B-PP a DT B-NP consequence NN I-NP of IN B-PP a DT B-NP unique JJ I-NP deleterious JJ I-NP mechanism NN I-NP more RBR B-ADJP fundamentally RB I-ADJP related JJ I-ADJP to TO B-PP the DT B-NP process NN I-NP of IN B-PP senescence NN B-NP such JJ B-PP as IN I-PP the DT B-NP inability NN I-NP to TO B-VP cope VB I-VP with IN B-PP oxidative JJ B-NP stress NN I-NP . . O Stimulation NN B-NP of IN B-PP human JJ B-NP peripheral JJ I-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP by IN B-PP zinc NN B-NP and CC O related JJ B-NP cations NNS I-NP . . O Zinc NN B-NP is VBZ B-VP an DT B-NP important JJ I-NP trace NN I-NP element NN I-NP for IN B-PP immune JJ B-NP function NN I-NP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP show VBP B-VP that IN B-SBAR zinc NN B-NP addition NN I-NP in IN B-PP a DT O serum- NN B-NP and CC O lipopolysaccharide-free JJ B-ADJP cell NN B-NP culture NN I-NP system NN I-NP leads VBZ B-VP to TO B-PP significantly RB B-NP enhanced JJ I-NP levels NNS I-NP of IN B-PP interleukin NN B-NP 1 CD I-NP beta NN I-NP ( ( O IL-1 NN B-NP beta NN I-NP ) ) O and CC O tumour NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP ( ( O TNF-alpha NN B-NP ) ) O and CC B-PP to TO B-PP expression NN B-NP of IN B-PP the DT B-NP corresponding JJ I-NP mRNA NN I-NP in IN B-PP human JJ B-NP peripheral JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP ( ( O PBMC NN B-NP ) ) O . . O Structurally RB B-NP related JJ I-NP divalent JJ I-NP cations NNS I-NP like IN B-PP cobalt NN B-NP COMMA COMMA O nickel NN B-NP COMMA COMMA O and CC O mercury NN B-NP also RB B-ADVP partially RB B-VP increase VBP I-VP monokine NN B-NP secretion NN I-NP but CC O to TO B-PP a DT B-NP much RB I-NP lower JJR I-NP and CC I-NP thus RB I-NP insignificant JJ I-NP extent NN I-NP . . O They PRP B-NP fail VBP B-VP to TO I-VP induce VB I-VP mRNA NN B-NP of IN B-PP TNF-alpha NN B-NP after IN B-PP 3 CD B-NP h NN I-NP of IN B-PP culture NN B-NP . . O Therefore RB B-ADVP COMMA COMMA O monokine NN B-NP induction NN I-NP is VBZ B-VP a DT B-NP zinc-specific JJ I-NP effect NN I-NP influenced VBN B-VP by IN B-PP the DT B-NP physicochemical JJ I-NP properties NNS I-NP of IN B-PP the DT B-NP ion NN I-NP . . O Confirmation NN B-NP of IN B-PP the DT B-NP unique JJ I-NP significance NN I-NP of IN B-PP zinc NN B-NP for IN B-PP immune JJ B-NP function NN I-NP provides VBZ B-VP a DT B-NP better JJR I-NP understanding NN I-NP of IN B-PP the DT B-NP mechanisms NNS I-NP of IN B-PP specific JJ B-NP zinc-mediated JJ I-NP immune JJ I-NP modulation NN I-NP . . O Sequence NN B-NP analysis NN I-NP and CC O expression NN B-NP in IN B-PP cultured VBN B-NP lymphocytes NNS I-NP of IN B-PP the DT B-NP human JJ I-NP FOSB NN I-NP gene NN I-NP ( ( O G0S3 NN B-NP ) ) O . . O G0S3 NN B-NP is VBZ B-VP a DT B-NP member NN I-NP of IN B-PP a DT B-NP set NN I-NP of IN B-PP putative JJ B-NP G0\/G1 NN I-NP switch NN I-NP regulatory JJ I-NP genes NNS I-NP ( ( O G0S NN B-NP genes NNS I-NP ) ) O selected VBN B-VP by IN B-PP screening VBG B-VP cDNA NN B-NP libraries NNS I-NP prepared VBN B-VP from IN B-PP human JJ B-NP blood NN I-NP mononuclear JJ I-NP cells NNS I-NP cultured VBN B-VP for IN B-PP 2 CD B-NP hr NN I-NP with IN B-PP lectin NN B-NP and CC O cycloheximide NN B-NP . . O The DT B-NP sequence NN I-NP shows VBZ B-VP high JJ B-NP homology NN I-NP with IN B-PP the DT B-NP murine JJ I-NP FOSB NN I-NP gene NN I-NP COMMA COMMA O which WDT B-NP encodes VBZ B-VP a DT B-NP component NN I-NP of IN B-PP the DT B-NP AP1 NN I-NP transcriptional JJ I-NP regulator NN I-NP . . O Comparison NN B-NP of IN B-PP cDNA NN B-NP and CC O genomic JJ B-NP sequences NNS I-NP reveals VBZ B-VP a DT B-NP 4-exon JJ I-NP structure NN I-NP characteristic JJ I-NP of IN B-PP the DT B-NP FOS NN I-NP family NN I-NP of IN B-PP genes NNS B-NP . . O Freshly RB B-NP isolated VBN I-NP cells NNS I-NP show VBP B-VP high JJ B-NP levels NNS I-NP of IN B-PP FOSB\/G0S3 NN B-NP and CC O FOS\/G0S7 NN B-NP mRNAs NNS B-NP COMMA COMMA O which WDT B-NP decline VBP B-VP rapidly RB B-ADVP during IN B-PP incubation NN B-NP in IN B-PP culture NN B-NP medium NN I-NP . . O The DT B-NP kinetics NNS I-NP of IN B-PP expression NN B-NP suggest VBP B-VP that IN B-SBAR the DT B-NP high JJ I-NP initial JJ I-NP levels NNS I-NP are VBP B-VP caused VBN I-VP by IN B-PP the DT B-NP isolation NN I-NP procedure NN I-NP COMMA COMMA O and CC O do VBP B-VP not RB I-VP reflect VB I-VP constitutive JJ B-NP expression NN I-NP . . O In IN B-PP cells NNS B-NP preincubated VBN B-VP for IN B-PP a DT B-NP day NN I-NP COMMA COMMA O levels NNS B-NP of IN B-PP FOS NN B-NP mRNA NN I-NP reach VBP B-VP a DT B-NP maximum NN I-NP 20 CD B-NP min NN I-NP after IN B-PP the DT B-NP addition NN I-NP of IN B-PP lectin NN B-NP and CC O decline VBP B-VP to TO B-PP control NN B-NP levels NNS I-NP over IN B-PP the DT B-NP next JJ I-NP 3 CD I-NP hr NN I-NP . . O Levels NNS B-NP of IN B-PP FOSB NN B-NP mRNA NN I-NP reach VBP B-VP a DT B-NP maximum JJ I-NP 40 CD B-NP min NN I-NP after IN B-PP the DT B-NP addition NN I-NP of IN B-PP lectin NN B-NP and CC O decline VBP B-VP to TO B-PP control NN B-NP levels NNS I-NP over IN B-PP the DT B-NP next JJ I-NP 6 CD I-NP hr NN I-NP . . O In IN B-PP freshly RB B-NP isolated VBN I-NP cells NNS I-NP COMMA COMMA O both CC O FOS NNS B-NP and CC O FOSB NN B-NP mRNAs NNS B-NP increase VBP B-VP dramatically RB B-ADVP in IN B-PP response NN I-PP to TO I-PP the DT B-NP protein NN I-NP synthesis NN I-NP inhibitor NN I-NP cycloheximide NN I-NP . . O In IN B-PP preincubated JJ B-NP cells NNS I-NP COMMA COMMA O the DT B-NP cycloheximide NN I-NP response NN I-NP is VBZ B-VP decreased VBN I-VP COMMA COMMA O especially RB B-PP in IN I-PP the DT B-NP case NN I-NP of IN B-PP FOSB NN B-NP . . O These DT B-NP differences NNS I-NP in IN B-PP expression NN B-NP of IN B-PP FOS NN B-NP and CC O FOSB NN B-NP suggest VBP B-VP different JJ B-NP roles NNS B-NP and CC O regulation NN B-NP . . O Regions NNS B-NP of IN B-PP low JJ B-NP base NN I-NP order-dependent JJ I-NP stem-loop JJ I-NP potential NN I-NP in IN B-PP the DT B-NP region NN I-NP of IN B-PP the DT B-NP gene NN I-NP are VBP B-VP defined VBN I-VP . . O These DT B-NP indicate VBP B-VP where WRB B-ADVP base NN B-NP order NN I-NP has VBZ B-VP been VBN I-VP adapted VBN I-VP for IN B-PP purposes NNS B-NP other JJ B-PP than IN I-PP stem-loop JJ B-NP stability NN I-NP ( ( O e.g. FW B-ADVP COMMA COMMA O encoding VBG B-VP proteins NNS B-NP or CC O gene NN B-NP regulation NN I-NP ) ) O . . O Regions NNS B-NP of IN B-PP low JJ B-NP potential NN I-NP in IN B-PP a DT B-NP 68.5-kb JJ I-NP genomic JJ I-NP segment NN I-NP containing VBG B-VP the DT B-NP FOSB NN I-NP gene NN I-NP suggest VBP B-VP that IN B-SBAR the DT B-NP potential NN I-NP may MD B-VP help VB I-VP locate VB I-VP genes NNS B-NP in IN B-PP uncharted JJ B-NP DNA NN I-NP sequences NNS I-NP . . O Signaling NN B-NP via IN B-PP IL-2 NN B-NP and CC O IL-4 NN B-NP in IN B-PP JAK3-deficient JJ B-NP severe JJ I-NP combined JJ I-NP immunodeficiency NN I-NP lymphocytes NNS I-NP : : O JAK3-dependent JJ B-NP and CC I-NP independent JJ I-NP pathways NNS I-NP . . O Both CC O IL-2 NN B-NP and CC O IL-4 NN B-NP bind VBP B-VP to TO B-PP receptors NNS B-NP containing VBG B-VP the DT B-NP common JJ I-NP gamma NN I-NP chain NN I-NP and CC O JAK3 NN B-NP . . O Although IN B-SBAR JAK3 NN B-NP is VBZ B-VP required VBN I-VP for IN B-PP proper JJ B-NP lymphoid JJ I-NP development NN I-NP COMMA COMMA O the DT B-NP precise JJ I-NP roles NNS I-NP of IN B-PP this DT B-NP kinase NN I-NP in IN B-PP IL-2 NN B-NP and CC O IL-4 NN B-NP signaling NN B-NP in IN B-PP lymphocytes NNS B-NP have VBP B-VP not RB I-VP been VBN I-VP defined VBN I-VP . . O Here RB B-ADVP COMMA COMMA O we PRP B-NP have VBP B-VP studied VBN I-VP IL-2 NN B-NP and CC O IL-4 NN B-NP signaling NN B-NP in IN B-PP B NN B-NP cell NN I-NP lines NNS I-NP lacking VBG B-VP JAK3 NN B-NP . . O Although IN B-SBAR IL-2-induced JJ B-NP phosphorylation NN I-NP of IN B-PP IL-2R NN B-NP beta NN I-NP COMMA COMMA O JAK1 NN B-NP COMMA COMMA O and CC O STAT5 NN B-NP all DT B-ADVP required VBN B-VP the DT B-NP presence NN I-NP of IN B-PP JAK3 NN B-NP COMMA COMMA O IL-4-mediated JJ B-NP phosphorylation NN I-NP of IN B-PP JAK1 NN B-NP COMMA COMMA O STAT6 NN B-NP COMMA COMMA O and CC O insulin NN B-NP receptor NN I-NP substrates NNS I-NP 1 CD B-NP and CC O 2 CD B-NP did VBD B-VP not RB O . . O However RB B-ADVP COMMA COMMA O IL-4-induced JJ B-NP effects NNS I-NP were VBD B-VP clearly RB I-VP improved VBN I-VP following VBG B-PP JAK3 NN B-NP expression NN I-NP . . O These DT B-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR IL-4 NN B-NP signaling NN I-NP occurs VBZ B-VP in IN B-PP the DT I-PP absence NN I-PP of IN I-PP of IN I-PP JAK3 NN B-NP COMMA COMMA O but CC O is VBZ B-VP comparatively RB B-ADJP inefficient JJ I-ADJP . . O These DT B-NP findings NNS I-NP may MD B-VP help VB I-VP in RP B-PP understanding VBG B-VP the DT B-NP pathogenesis NN I-NP of IN B-PP the DT B-NP immunodeficiency NN I-NP that WDT B-NP occurs VBZ B-VP with IN B-PP mutations NNS B-NP of IN B-PP JAK3 NN B-NP and CC O may MD B-VP suggest VB I-VP a DT B-NP mechanism NN I-NP for IN B-PP the DT B-NP pleiotropic JJ I-NP effects NNS I-NP of IN B-PP IL-4 NN B-NP . . O Identification NN B-NP of IN B-PP Bcd NN B-NP COMMA COMMA O a DT B-NP novel JJ I-NP proto-oncogene NN I-NP expressed VBN B-VP in IN B-PP B-cells NNS B-NP . . O A DT O novel JJ O B-cell NN O derived JJ O ( ( O Bcd NN B-ADJP ) ) O oncogene NN B-NP has VBZ B-VP been VBN I-VP isolated VBN I-VP from IN B-PP the DT B-NP peripheral JJ I-NP blood NN I-NP lymphocytes NNS I-NP of IN B-PP one CD O B-cell NN B-NP chronic JJ I-NP lymphocytic JJ I-NP leukemia NN I-NP ( ( O B-CLL NN B-NP ) ) O patient NN B-NP using VBG B-VP DNA NN B-NP transfer NN I-NP and CC O a DT B-NP mouse NN I-NP tumorigenicity NN I-NP assay NN I-NP . . O The DT B-NP Bcd NN I-NP proto-oncogene NN I-NP was VBD B-VP activated VBN I-VP by IN B-PP a DT B-NP truncation NN I-NP in IN B-PP the DT B-NP 5' JJ I-NP UTR NN I-NP . . O It PRP B-NP predicts VBZ B-VP for IN B-PP two CD B-NP open JJ B-NP reading NN I-NP frames NNS I-NP ( ( O ORFs NNS B-NP ) ) O . . O ORF1 NN B-NP consists VBZ B-VP of IN B-PP 240 CD B-NP bp NN I-NP that WDT B-NP would MD B-VP encode VB I-VP 80 CD B-NP amino NN I-NP acids NNS I-NP COMMA COMMA O while IN B-SBAR the DT B-NP major JJ I-NP ORF2 NN I-NP consists VBZ B-VP of IN B-PP 648 CD B-NP bp NN I-NP capable JJ B-ADJP of IN B-PP coding VBG B-VP for IN B-PP 216 CD B-NP amino NN I-NP acids NNS I-NP . . O Predicted VBN B-NP peptide NN I-NP sequence NN I-NP of IN B-PP ORF2 NN B-NP contained VBD B-VP a DT B-NP zinc NN I-NP finger NN I-NP domain NN I-NP which WDT B-NP showed VBD B-VP significant JJ B-NP homology NN I-NP to TO B-PP GC NN B-NP box NN I-NP binding NN I-NP proteins NNS I-NP BTEB2 NN B-NP and CC O SP1 NN B-NP . . O Transfection NN B-NP of IN B-PP an DT B-NP expression NN I-NP vector NN I-NP containing VBG B-VP ORF2 NN B-NP but CC B-CONJP not RB I-CONJP full JJ B-NP length NN I-NP cDNA NN I-NP was VBD B-VP able JJ B-ADJP to TO B-VP transform VB I-VP NIH3T3 NN B-NP cells NNS I-NP and CC O induce VB B-VP tumors NNS B-NP in IN B-PP nude JJ B-NP mice NNS I-NP . . O Bcd NN B-NP mRNA NN I-NP transcripts NNS I-NP of IN B-PP < JJR B-NP or CC I-NP = JJ I-NP 2.6 CD I-NP kb NN I-NP were VBD B-VP selectively RB I-VP expressed VBN I-VP in IN B-PP PBL NN B-NP and CC O testis NN B-NP of IN B-PP healthy JJ B-NP individuals NNS I-NP . . O Within IN B-PP the DT B-NP PBL NN I-NP COMMA COMMA O Bcd NN B-NP gene NN I-NP expression NN I-NP was VBD B-VP restricted JJ B-ADJP to TO B-PP CD19+ JJ B-NP B-cells NNS I-NP and CC O absent JJ B-ADJP from IN B-PP CD14+ JJ B-NP monocytes NNS I-NP and CC O T-cells NNS B-NP . . O Bcd NN B-NP transcripts NNS I-NP were VBD B-VP detected VBN I-VP in IN B-PP all DT B-NP normal JJ I-NP PBL NN I-NP samples NNS I-NP tested VBN B-VP but CC O not RB B-PP in IN I-PP several JJ B-NP malignant JJ I-NP human JJ I-NP B-cell NN I-NP lines NNS I-NP and CC B-PP not RB B-PP in IN I-PP 50 CD B-NP % NN I-NP of IN B-PP B-cells NNS B-NP from IN B-PP B-CLL NN B-NP patients NNS I-NP . . O However RB B-ADVP COMMA COMMA O stimulation NN B-NP of IN B-PP B-cells NNS B-NP from IN B-PP B-CLL NN B-NP patients NNS I-NP under IN B-PP conditions NNS B-NP which WDT B-NP induced VBD B-VP differentiation NN B-NP into IN B-PP plasma NN B-NP cells NNS I-NP was VBD B-VP associated VBN I-VP with IN B-PP induction NN B-NP of IN B-PP Bcd NN B-NP gene NN I-NP expression NN I-NP . . O The DT B-NP Bcd NN I-NP gene NN I-NP may MD B-VP therefore RB I-VP play VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP B-cell NN B-NP growth NN B-NP and CC O development NN B-NP . . O Pancreatic JJ B-NP development NN B-NP and CC O maturation NN B-NP of IN B-PP the DT B-NP islet NN I-NP B NN I-NP cell NN I-NP . . O Studies NNS B-NP of IN B-PP pluripotent JJ B-NP islet NN I-NP cultures NNS I-NP . . O Pancreas NN B-NP organogenesis NN I-NP is VBZ B-VP a DT B-NP highly RB I-NP regulated VBN I-NP process NN I-NP COMMA COMMA O in IN B-PP which WDT B-NP two CD B-NP anlage NNS I-NP evaginate VBP B-VP from IN B-PP the DT B-NP primitive JJ I-NP gut NN I-NP . . O They PRP B-NP later RB B-ADVP fuse VBP B-VP COMMA COMMA O and CC O COMMA COMMA O under IN B-PP the DT B-NP influence NN I-NP of IN B-PP the DT B-NP surrounding VBG I-NP mesenchyme NN I-NP COMMA COMMA O the DT B-NP mature JJ I-NP organ NN I-NP develops VBZ B-VP COMMA COMMA O being VBG B-VP mainly RB I-VP composed VBN I-VP of IN B-PP ductal JJ B-NP COMMA COMMA I-NP exocrine JJ I-NP and CC I-NP endocrine JJ I-NP compartments NNS I-NP . . O Early JJ B-NP buds NNS I-NP are VBP B-VP characterized VBN I-VP by IN B-PP a DT B-NP branching VBG I-NP morphogenesis NN I-NP of IN B-PP the DT B-NP ductal JJ I-NP epithelium NN I-NP from IN B-PP which WDT B-NP endocrine JJ B-NP and CC I-NP exocrine JJ I-NP precursor NN I-NP cells NNS I-NP bud VBP B-VP to TO B-VP eventually RB I-VP form VB I-VP the DT B-NP two CD I-NP other JJ I-NP compartments NNS I-NP . . O The DT B-NP three CD I-NP compartments NNS I-NP are VBP B-VP thought VBN I-VP to TO I-VP be VB I-VP of IN B-PP common JJ B-NP endodermal JJ I-NP origin NN I-NP ; : O in IN B-PP contrast NN I-PP to TO I-PP earlier JJR B-NP hypotheses NNS I-NP COMMA COMMA O which WDT B-NP suggested VBD B-VP that IN B-SBAR the DT B-NP endocrine JJ I-NP compartment NN I-NP was VBD B-VP of IN B-PP neuroectodermal JJ B-NP origin NN I-NP . . O It PRP B-NP is VBZ B-VP thus RB I-VP generally RB I-VP believed VBN I-VP that IN B-SBAR the DT B-NP pancreatic JJ I-NP endocrine-lineage NN I-NP possesses VBZ B-VP the DT B-NP ability NN I-NP to TO B-VP mature VB I-VP along IN B-PP a DT B-NP differentiation NN I-NP pathway NN I-NP that WDT B-NP shares VBZ B-VP many JJ B-NP characteristics NNS I-NP with IN B-PP those DT B-NP of IN B-PP neuronal JJ B-NP differentiation NN I-NP . . O During IN B-PP recent JJ B-NP years NNS I-NP COMMA COMMA O studies NNS B-NP of IN B-PP insulin-gene JJ B-NP regulation NN I-NP and CC O COMMA COMMA O in IN B-PP particular JJ B-NP COMMA COMMA O the DT B-NP tissue-specific JJ I-NP transcriptional JJ I-NP control NN I-NP of IN B-PP insulin-gene JJ B-NP activity NN I-NP have VBP B-VP provided VBN I-VP information NN B-NP on IN B-PP pancreas NN B-NP development NN I-NP in IN B-PP general JJ B-NP . . O The DT B-NP present JJ I-NP review NN I-NP summarizes VBZ B-VP these DT B-NP findings NNS I-NP COMMA COMMA O with IN B-PP a DT B-NP special JJ I-NP focus NN I-NP on IN B-PP our PRP$ B-NP own JJ I-NP studies NNS I-NP on IN B-PP pluripotent JJ B-NP endocrine JJ I-NP cultures NNS I-NP of IN B-PP rat NN B-NP pancreas NN I-NP . . O Induction NN B-NP of IN B-PP vascular JJ B-NP cell NN I-NP adhesion NN I-NP molecule-1 NN I-NP by IN B-PP low-density JJ B-NP lipoprotein NN I-NP . . O Low-density JJ B-NP lipoprotein NN I-NP ( ( O LDL NN B-NP ) ) O is VBZ B-VP a DT B-NP well-established JJ I-NP risk NN I-NP factor NN I-NP for IN B-PP atherosclerosis NN B-NP . . O When WRB B-ADVP endothelial JJ B-NP cells NNS I-NP are VBP B-VP incubated VBN I-VP with IN B-PP this DT B-NP lipoprotein NN I-NP in IN B-PP pathophysiologic JJ B-NP amounts NNS I-NP COMMA COMMA O the DT B-NP cells NNS I-NP are VBP B-VP activated VBN I-VP . . O Among IN B-PP the DT B-NP documented VBN I-NP cellular JJ I-NP responses NNS I-NP to TO B-PP LDL NN B-NP is VBZ B-VP increased VBN B-NP recruitment NN I-NP of IN B-PP monocytes NNS B-NP COMMA COMMA O which WDT B-NP are VBP B-VP believed VBN I-VP to TO I-VP play VB I-VP a DT B-NP major JJ I-NP role NN I-NP in IN B-PP promoting VBG B-VP intimal JJ B-NP plaque NN I-NP formation NN I-NP . . O The DT B-NP findings NNS I-NP presented VBN B-VP here RB B-ADVP link VB B-VP an DT B-NP atheogenic JJ I-NP lipoprotein NN I-NP COMMA COMMA O LDL NN B-NP COMMA COMMA O with IN B-PP the DT B-NP induction NN I-NP of IN B-PP an DT B-NP adhesion NN I-NP molecule NN I-NP important JJ B-ADJP in IN B-PP atherogenesis NN B-NP Human JJ B-NP LDL NN I-NP induces VBZ B-VP the DT B-NP vascular JJ I-NP cell NN I-NP adhesion NN I-NP molecule-1 NN I-NP ( ( O VCAM-1 NN B-NP ) ) O transcriptionally RB B-ADVP with IN B-PP an DT B-NP increase NN I-NP in IN B-PP mRNA NN B-NP levels NNS I-NP through IN B-PP activation NN B-NP of IN B-PP the DT B-NP VCAM NN I-NP promoter NN I-NP . . O This DT B-NP effect NN I-NP is VBZ B-VP blocked VBN I-VP by IN B-PP anti-VCAM JJ B-NP antibodies NNS I-NP . . O After IN B-PP a DT B-NP 2-day JJ I-NP incubation NN I-NP in IN B-PP LDL NN B-NP COMMA COMMA O the DT B-NP binding NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O which WDT B-NP is VBZ B-VP believed VBN I-VP to TO I-VP be VB I-VP a DT B-NP key JJ I-NP oxidative-stress JJ I-NP sensor NN I-NP for IN B-PP VCAM NN B-NP regulation NN I-NP COMMA COMMA O remains VBZ B-VP at IN B-PP basal JJ B-NP level NN I-NP . . O In IN B-PP contrast NN B-NP COMMA COMMA O the DT B-NP binding NN I-NP activities NNS I-NP of IN B-PP AP-1 NN B-NP and CC O GATA NN B-NP COMMA COMMA O on IN B-PP the DT B-NP other JJ I-NP hand NN I-NP COMMA COMMA O are VBP B-VP increased VBN I-VP by IN B-PP LDL NN B-NP . . O Thus RB B-ADVP COMMA COMMA O a DT B-NP component NN I-NP of IN B-PP LDL-enhanced JJ B-NP endothelial JJ I-NP recruitment NN I-NP of IN B-PP monocytes NNS B-NP is VBZ B-VP attributed VBN I-VP to TO B-PP VCAM-1 JJ B-NP expression NN I-NP COMMA COMMA O which WDT B-NP appears VBZ B-VP to TO I-VP be VB I-VP mediated VBN I-VP through IN B-PP AP-1 NN B-NP and CC O GATA NN B-NP . . O These DT B-NP data NNS I-NP identify VBP B-VP LDL NN B-NP as IN B-PP a DT B-NP VCAM-inducer NN I-NP possibly RB B-ADJP distinct JJ I-ADJP from IN B-PP cytokines NNS B-NP and CC O endotoxin NN B-NP . . O The DT B-NP NF-kappa NN I-NP B NN I-NP inhibitor NN I-NP COMMA COMMA O tepoxalin NN B-NP COMMA COMMA O suppresses VBZ B-VP surface NN B-NP expression NN I-NP of IN B-PP the DT B-NP cell NN I-NP adhesion NN I-NP molecules NNS I-NP CD62E NN B-NP COMMA COMMA O CD11b\/CD18 NN B-NP and CC O CD106 NN B-NP . . O Tepoxalin NN B-NP COMMA COMMA O a DT B-NP dual JJ I-NP enzyme NN I-NP inhibitor NN I-NP of IN B-PP cyclooxygenase NN B-NP and CC O 5-lipoxygenase NN B-NP has VBZ B-VP been VBN I-VP shown VBN I-VP to TO I-VP inhibit VB I-VP T-cell NN B-NP activation NN I-NP . . O Its PRP$ B-NP immunosuppressive JJ I-NP property NN I-NP is VBZ B-VP distinct JJ B-ADJP from IN B-PP cyclosporin NN B-NP because IN B-SBAR only RB B-NP tepoxalin NN I-NP COMMA COMMA O but CC B-CONJP not RB I-CONJP cyclosporin NN B-NP COMMA COMMA O suppresses VBZ B-VP NF-kappa NN B-NP B NN I-NP activation NN I-NP . . O Here RB B-ADVP we PRP B-NP report VBP B-VP that IN B-SBAR tepoxalin NN B-NP selectively RB B-ADVP inhibits VBZ B-VP intercellular JJ B-NP adhesion NN I-NP molecule-1 NN I-NP ( ( I-NP ICAM-1 NN I-NP COMMA COMMA I-NP CD54 NN I-NP ) ) I-NP \/MAC-1 NN I-NP ( ( I-NP CD11b\/CD18 NN I-NP ) ) O dependent JJ B-NP adhesion NN I-NP of IN B-PP polymorphonuclear JJ B-NP cells NNS I-NP to TO B-PP IL-1 NN B-NP activated JJ I-NP human JJ I-NP umbilical JJ I-NP vein NN I-NP endothelial JJ I-NP cells NNS I-NP . . O The DT B-NP mechanism NN I-NP of IN B-PP inhibition NN B-NP is VBZ B-VP related JJ B-ADJP to TO B-PP the DT B-NP surface NN I-NP expression NN I-NP of IN B-PP several JJ B-NP cell NN I-NP adhesion NN I-NP molecules NNS I-NP . . O Flow NN B-NP cytometry NN I-NP analyses NNS I-NP on IN B-PP cultured VBN B-NP cells NNS I-NP that WDT B-NP were VBD B-VP treated VBN I-VP with IN B-PP tepoxalin NN B-NP or CC O antisense JJ B-NP oligonucleotides NNS I-NP to TO B-PP the DT B-NP P65\/p50 NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP COMMA COMMA O and CC O then RB O stimulated VBN B-VP with IN B-PP PMA NN B-NP COMMA COMMA O revealed VBD B-VP a DT B-NP reduced VBN I-NP expression NN I-NP of IN B-PP CD11b\/CD18 NN B-NP on IN B-PP monocytic JJ B-NP HL60 NN I-NP cells NNS I-NP COMMA COMMA O and CC O endothelial JJ B-NP adhesion NN I-NP molecule-1 NN I-NP ( ( O CD62E NN B-NP ) ) O and CC O vascular JJ B-NP adhesion NN I-NP molecule-1 NN I-NP ( ( O CD106 NN B-NP ) ) O on IN B-PP human JJ B-NP umbilical JJ I-NP vein NN I-NP endothelial JJ I-NP cells NNS I-NP . . O Expression NN B-NP of IN B-PP other JJ B-NP adhesion NN I-NP molecules NNS I-NP such JJ B-PP as IN I-PP lymphocyte NN B-NP function NN I-NP associated-antigen-1 NN I-NP ( ( O CD11a\/CD18 NN B-NP ) ) O and CC O CD54 NN B-NP were VBD B-VP unaffected JJ B-ADJP . . O Tepoxalin NN B-NP also RB B-ADVP inhibited VBD B-VP the DT B-NP secretion NN I-NP of IN B-PP a DT O NF-kappa NN B-NP B NN I-NP regulated JJ B-NP chemokine NN I-NP COMMA COMMA O IL-8 NN B-NP COMMA COMMA O a DT B-NP known JJ I-NP inducer NN I-NP of IN B-PP CD11b\/CD18 NN B-NP expression NN I-NP . . O Thus RB B-ADVP the DT B-NP suppression NN I-NP of IN B-PP CD11b\/CD18 NN B-NP expression NN I-NP by IN B-PP tepoxalin NN B-NP may MD B-VP involve VB I-VP IL-8 NN B-NP . . O Our PRP$ B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR by IN B-PP inhibiting VBG B-VP NF-kappa NN B-NP B NN I-NP activation NN I-NP COMMA COMMA O surface NN B-NP expression NN I-NP of IN B-PP several JJ B-NP adhesion NN I-NP molecules NNS I-NP can MD B-VP be VB I-VP modulated VBN I-VP and CC O that IN B-SBAR tepoxalin NN B-NP may MD B-VP be VB I-VP useful JJ B-ADJP in IN B-PP treating VBG B-VP selected VBN B-NP adhesion NN I-NP mediated JJ I-NP events NNS I-NP such JJ B-PP as IN I-PP leukocyte NN B-NP migration NN I-NP or CC O atherosclerotic JJ B-NP plaque NN I-NP formation NN I-NP . . O Expression NN B-NP of IN B-PP erythroid-specific JJ B-NP genes NNS I-NP in IN B-PP megakaryoblastic JJ B-NP disorders NNS I-NP . . O Currently RB B-NP available JJ I-NP data NNS I-NP indicate VBP B-VP that IN B-SBAR erythroid JJ B-NP and CC I-NP megakaryocytic JJ I-NP differentiation NN I-NP pathways NNS I-NP are VBP B-VP closely RB B-ADJP related JJ I-ADJP to TO B-PP each DT B-NP other JJ I-NP COMMA COMMA O and CC O there EX B-NP may MD B-VP exist VB I-VP progenitor NN B-NP cells NNS I-NP common JJ B-ADJP to TO B-PP those DT B-NP two CD I-NP lineages NNS I-NP may MD O exist VB O . . O Acute JJ B-NP megakaryoblastic JJ I-NP leukemia NN I-NP ( ( O AML-M7 NN B-NP ) ) O and CC O transient JJ B-NP myeloproliferative JJ I-NP disorder NN I-NP in IN B-PP Down NN B-NP 's POS B-NP syndrome NN I-NP ( ( O TMD NN B-NP ) ) O are VBP B-VP characterized VBN I-VP by IN B-PP rapid JJ B-NP growth NN I-NP of IN B-PP abnormal JJ B-NP blast NN I-NP cells NNS I-NP which WDT B-NP express VBP B-VP megakaryocytic JJ B-NP markers NNS I-NP . . O These DT B-NP blast NN I-NP cells NNS I-NP express VBP B-VP lineage-specific JJ B-NP transcription NN I-NP factors NNS I-NP such JJ B-PP as IN I-PP GATA-1 NN B-NP common JJ B-ADJP to TO B-PP these DT B-NP lineages NNS I-NP and CC O frequently RB B-VP express VBP I-VP erythroid-specific JJ B-NP mRNAs NNS I-NP such JJ B-PP as IN I-PP gamma-globin NN B-NP and CC O erythroid JJ B-NP delta-aminolevulinate NN I-NP synthase NN I-NP ( ( O ALAS-E NN B-NP ) ) O COMMA COMMA O indicating VBG B-VP that IN B-SBAR most JJS B-NP of IN B-PP the DT B-NP blasts NNS I-NP in IN B-PP M7 NN B-NP and CC O TMD NN B-NP cases NNS B-NP have VBP B-VP erythroid JJ B-NP and CC I-NP megakaryocytic JJ I-NP phenotypes NNS I-NP . . O These DT B-NP results NNS I-NP suggest VBP B-VP that IN B-SBAR blasts NNS B-NP in IN B-PP M7 NN B-NP and CC O TMD NN B-NP may MD B-VP correspond VB I-VP to TO B-PP progenitors NNS B-NP of IN B-PP both CC B-NP erythroid JJ I-NP and CC I-NP megakaryocytic JJ I-NP lineages NNS I-NP . . O Nuclear JJ B-NP NF-ATp NN I-NP is VBZ B-VP a DT B-NP hallmark NN I-NP of IN B-PP unstimulated JJ B-NP B NN I-NP cells NNS I-NP from IN B-PP B-CLL NN B-NP patients NNS I-NP . . O B NN B-NP lymphocytes NNS I-NP from IN B-PP the DT B-NP peripheral JJ I-NP blood NN I-NP of IN B-PP patients NNS B-NP with IN B-PP chronic JJ B-NP lymphocytic JJ I-NP leukaemia NN I-NP ( ( O CLL NN B-NP ) ) O were VBD B-VP analysed VBN I-VP for IN B-PP the DT B-NP nuclear JJ B-NP presence NN I-NP and CC O DNA NN B-NP binding NN I-NP of IN B-PP a DT B-NP panel NN I-NP of IN B-PP transcription NN B-NP factors NNS I-NP which WDT B-NP are VBP B-VP involved VBN I-VP in IN B-PP the DT B-NP gene NN I-NP control NN I-NP of IN B-PP lymphoid JJ B-NP cells NNS I-NP . . O The DT B-NP following JJ I-NP transcription NN I-NP factors NNS I-NP were VBD B-VP studied VBN I-VP : : O the DT B-NP Octamer NN I-NP factors NNS I-NP Oct-1 NN B-NP and CC O Oct-2 NN B-NP COMMA COMMA O members NNS B-NP of IN B-PP the DT B-NP AP-1 NN I-NP factor NN I-NP family NN I-NP COMMA COMMA O NF-AT NN B-NP factors NNS I-NP COMMA COMMA O in IN B-PP particular JJ B-NP NF-ATp NN B-NP COMMA COMMA O and CC O members NNS B-NP of IN B-PP the DT B-NP Rel\/NF-kB NN I-NP family NN I-NP . . O We PRP B-NP show VBP B-VP that IN B-SBAR the DT B-NP constitutive JJ I-NP nuclear JJ I-NP translocation NN I-NP of IN B-PP NF-ATp NN B-NP COMMA COMMA O a DT B-NP member NN I-NP of IN B-PP the DT B-NP growing VBG I-NP family NN I-NP of IN B-PP NF-AT NN B-NP factors NNS I-NP COMMA COMMA O is VBZ B-VP a DT B-NP hallmark NN I-NP of IN B-PP nonstimulated JJ B-NP B NN I-NP cells NNS I-NP from IN B-PP CLL NN B-NP patients NNS I-NP that WDT B-NP distinguishes VBZ B-VP B-CLL NN B-NP cells NNS I-NP from IN B-PP ' `` B-NP normal JJ I-NP ' '' I-NP B NN I-NP lymphocytes NNS I-NP . . O Constitutive JJ B-NP nuclear JJ I-NP appearance NN I-NP was VBD B-VP also RB I-VP observed VBN I-VP for IN B-PP NF-kB2\/p52 NN B-NP . . O Constitutive JJ B-NP binding NN I-NP of IN B-PP further JJ B-NP factor NN I-NP proteins NNS I-NP to TO B-PP DNA NN B-NP COMMA COMMA O such JJ B-PP as IN I-PP JunD NN B-NP COMMA COMMA O c-Fos NN B-NP and CC O FosB NN B-NP COMMA COMMA O was VBD B-VP detected VBN I-VP in IN B-PP several JJ B-NP patients NNS I-NP whereas IN B-SBAR the DT B-NP localisation NN B-NP and CC O DNA NN B-NP binding NN I-NP of IN B-PP other JJ B-NP factors NNS I-NP such JJ B-PP as IN I-PP c-Jun NN B-NP COMMA COMMA O RelA\/p65 NN B-NP and CC O c-Rel NN B-NP was VBD B-VP unaltered JJ B-ADJP . . O It PRP B-NP is VBZ B-VP remarkable JJ B-ADJP that IN B-SBAR in IN B-PP B-CLL JJ B-NP cells NNS I-NP the DT B-NP nuclear JJ B-NP appearance NN I-NP and CC O DNA NN B-NP binding NN I-NP of IN B-PP specific JJ B-NP transcription NN I-NP factors NNS I-NP is VBZ B-VP dramatically RB I-VP affected JJ I-VP whereas IN B-SBAR other JJ B-NP members NNS I-NP of IN B-PP the DT B-NP same JJ I-NP factor NN I-NP family NN I-NP remained VBD B-VP unaltered JJ B-ADJP in IN B-PP these DT B-NP leukemic JJ I-NP cells NNS I-NP . . O It PRP B-NP remains VBZ B-VP to TO I-VP be VB I-VP shown VBN I-VP which WDT B-NP molecular JJ I-NP events NNS I-NP lead VBP B-VP to TO B-PP the DT B-NP specific JJ I-NP ' `` I-NP pre-activation NN I-NP ' '' O COMMA COMMA O i.e. FW B-ADVP constitutive JJ B-NP nuclear JJ I-NP translocation NN I-NP and CC O DNA NN B-NP binding NN I-NP COMMA COMMA O of IN B-PP these DT B-NP members NNS I-NP of IN B-PP NF-AT NN B-NP COMMA COMMA O NF-kB NN B-NP and CC O AP-1 NN B-NP factor NN B-NP families NNS I-NP . . O { ( O The DT B-NP value NN I-NP of IN B-PP the DT B-NP clinical JJ I-NP test NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP chronic JJ B-NP pulmonary JJ I-NP heart NN I-NP disease NN I-NP } ) O In IN B-SBAR order NN O to TO O inquire VB B-VP into IN B-PP the DT B-NP functional JJ I-NP state NN I-NP of IN B-PP adrenal JJ B-NP cortex NN I-NP in IN B-PP patients NNS B-NP with IN B-PP pulmonary JJ B-NP heart NN I-NP disease NN I-NP COMMA COMMA O the DT B-NP number NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP ( ( O GCR NN B-NP ) ) O of IN B-PP peripheral JJ B-NP blood NN I-NP leukocytes NNS I-NP in IN B-PP patients NNS B-NP with IN B-PP chronic JJ B-NP pulmonary JJ I-NP heart NN I-NP disease NN I-NP was VBD B-VP determined VBN I-VP with IN B-PP radioligand-binding JJ B-NP assay NN I-NP and CC O the DT B-NP corresponding JJ I-NP plasma NN I-NP cortisol NN I-NP levels NNS I-NP were VBD B-VP assessed VBN I-VP with IN B-PP radioimmune JJ B-NP assays NNS I-NP . . O The DT B-NP results NNS I-NP showed VBD B-VP that IN B-SBAR the DT B-NP number NN I-NP of IN B-PP GCR NN B-NP in IN B-PP the DT B-NP patients NNS I-NP was VBD B-VP significantly RB I-VP reduced VBN I-VP ( ( O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O and CC O it PRP B-NP was VBD B-VP increased VBN I-VP when WRB B-ADVP their PRP$ B-NP health NN I-NP state NN I-NP was VBD B-VP improved VBN I-VP . . O However RB B-ADVP COMMA COMMA O it PRP B-NP was VBD B-VP still RB B-ADVP lower JJR B-ADJP than IN B-PP that DT B-NP in IN B-PP healthy JJ B-NP subjects NNS I-NP ( ( O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O . . O The DT B-NP number NN I-NP of IN B-PP GCR NN B-NP in IN B-PP the DT B-NP patients NNS I-NP was VBD B-VP greatly RB I-VP increased VBN I-VP when WRB B-ADVP these DT B-NP patients NNS I-NP were VBD B-VP treated VBN I-VP with IN B-PP oxygen NN B-NP ( ( O P NN B-NP < JJR B-NP 0.01 CD I-NP ) ) O . . O No DT B-NP difference NN I-NP in IN B-PP plasma NN B-NP cortisol NN I-NP was VBD B-VP found VBN I-VP between IN B-PP the DT B-NP patients NNS I-NP and CC O the DT B-NP healthy JJ I-NP subjects NNS I-NP ( ( O P NN B-NP > JJR B-NP 0.05 CD I-NP ) ) O . . O These DT B-NP results NNS I-NP indicate VBP B-VP that IN B-SBAR the DT B-NP function NN I-NP of IN B-PP adrenal JJ B-NP cortex NN I-NP may MD B-VP be VB I-VP improved VBN I-VP by IN B-PP the DT B-NP compensation NN I-NP mechanism NN I-NP of IN B-PP the DT B-NP patients NNS I-NP COMMA COMMA O but CC O the DT B-NP lower JJR I-NP GCR NN I-NP number NN I-NP was VBD B-VP the DT B-NP result NN I-NP of IN B-PP lacking NN B-NP of IN B-PP oxygen NN B-NP in IN B-PP the DT B-NP patients NNS I-NP . . O The DT B-NP number NN I-NP of IN B-PP GCR NN B-NP may MD B-VP be VB I-VP improved VBN I-VP by IN B-PP inhalation NN B-NP of IN B-PP oxygen NN B-NP . . O Therefore RB B-ADVP oxygen NN B-NP therapy NN I-NP is VBZ B-VP helpful JJ B-ADJP in IN B-PP raising VBG B-VP the DT B-NP activity NN I-NP of IN B-PP glucocorticoid NN B-NP receptors NNS I-NP and CC O controlling VBG B-VP the DT B-NP development NN I-NP of IN B-PP the DT B-NP disease NN I-NP . . O Inhibition NN B-NP of IN B-PP nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP subunit NN I-NP p65 NN I-NP mRNA NN I-NP accumulation NN I-NP in IN B-PP lipopolysaccharide-stimulated JJ B-NP human JJ I-NP monocytic JJ I-NP cells NNS I-NP treated VBN B-VP with IN B-PP sodium NN B-NP salicylate NN I-NP . . O Lipopolysaccharide NN B-NP is VBZ B-VP one CD B-NP of IN B-PP the DT B-NP most RBS I-NP potent JJ I-NP trigger NN I-NP substances NNS I-NP for IN B-PP monocytes NNS B-NP and CC O macrophages NNS B-NP causing VBG B-VP secretion NN B-NP of IN B-PP inflammatory JJ B-NP mediators NNS I-NP such JJ B-PP as IN I-PP tumor NN B-NP necrosis NN I-NP factor NN I-NP and CC O interleukin-1 NN B-NP . . O The DT B-NP nature NN I-NP of IN B-PP the DT B-NP nuclear JJ I-NP factors NNS I-NP involved VBN B-VP in IN B-PP regulation NN B-NP of IN B-PP these DT B-NP cytokine NN I-NP genes NNS I-NP is VBZ B-VP still RB B-ADVP unknown JJ B-ADJP . . O Nuclear JJ B-NP factor NN I-NP kappa NN I-NP B NN I-NP ( ( O NF-kappa NN B-NP B NN I-NP ; : O heterodimer NN B-NP of IN B-PP p50 NN B-NP and CC O p65 NN B-NP ) ) O proteins NNS B-NP have VBP B-VP been VBN I-VP suggested VBN I-VP to TO I-VP play VB I-VP an DT B-NP important JJ I-NP role NN I-NP in IN B-PP gene NN B-NP transcription NN I-NP of IN B-PP inflammatory JJ B-NP mediators NNS I-NP when WRB B-ADVP monocytes NNS B-NP are VBP B-VP stimulated VBN I-VP with IN B-PP lipopolysaccharide NN B-NP . . O Nonsteroidal JJ B-NP anti-inflammatory JJ I-NP drugs NNS I-NP such JJ B-PP as IN I-PP salicylates NNS B-NP have VBP B-VP been VBN I-VP used VBN I-VP to TO B-VP treat VB I-VP symptoms NNS B-NP of IN B-PP inflammation NN B-NP COMMA COMMA O and CC O a DT B-NP new JJ I-NP mechanism NN I-NP of IN B-PP drug NN B-NP action NN I-NP was VBD B-VP suggested VBN I-VP recently RB B-ADVP . . O Salicylates NNS B-NP have VBP B-VP been VBN I-VP shown VBN I-VP to TO I-VP inhibit VB I-VP lipopolysaccharide-induced JJ B-NP gene NN I-NP transcription NN I-NP via IN B-PP inhibition NN B-NP of IN B-PP NF-kappa NN B-NP B NN I-NP activation NN I-NP by IN B-PP preventing VBG B-VP the DT B-NP degradation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP inhibitor NN I-NP " `` I-NP I NN I-NP kappa NN I-NP B NN I-NP " '' O COMMA COMMA O blocking VBG B-VP the DT B-NP translocation NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP into IN B-PP the DT B-NP nuclear JJ I-NP compartment NN I-NP . . O However RB B-ADVP COMMA COMMA O the DT B-NP nature NN I-NP of IN B-PP the DT B-NP subunit NN I-NP involved VBN B-VP in IN B-PP this DT B-NP mechanism NN I-NP has VBZ B-VP not RB I-VP been VBN I-VP defined VBN I-VP . . O To TO B-VP examine VB I-VP the DT B-NP mechanisms NNS I-NP by IN B-PP which WDT B-NP salicylates NNS B-NP affect VBP B-VP cytokine NN B-NP gene NN I-NP transcription NN I-NP COMMA COMMA O the DT B-NP amount NN I-NP of IN B-PP active JJ B-NP and CC I-NP inactive JJ I-NP NF-kappa NN I-NP B NN I-NP and CC O NF-kappa NN B-NP B NN I-NP mRNA NN I-NP COMMA COMMA O in IN B-PP Porphyromonas NN B-NP gingivalis NN I-NP lipopolysaccharide-stimulated JJ I-NP human JJ I-NP monocytic JJ I-NP cells NNS I-NP was VBD B-VP assessed VBN I-VP . . O High JJ B-NP doses NNS I-NP of IN B-PP sodium NN B-NP salicylate NN I-NP suppressed VBD B-VP NF-kappa NN B-NP B NN I-NP p65 NN I-NP mRNA NN I-NP accumulation NN I-NP COMMA COMMA O resulting VBG B-VP in IN B-PP suppression NN B-NP of IN B-PP total JJ B-NP NF-kappa NN I-NP B NN I-NP COMMA COMMA O p50 NN B-NP on IN B-PP tissue NN B-NP oligonucleotide NN I-NP had VBD B-VP no DT B-NP effects NNS I-NP on IN B-PP lipopolysaccharide-induced JJ B-NP NF-kappa NN I-NP B NN I-NP activation NN I-NP . . O The DT B-NP data NNS I-NP demonstrate VBP B-VP that IN B-SBAR the DT B-NP p65 NN I-NP subunit NN I-NP of IN B-PP NF-kappa NN B-NP B NN I-NP is VBZ B-VP inhibited VBN I-VP by IN B-PP salicylate NN B-NP treatment NN I-NP and CC O highlight VBP B-VP the DT B-NP role NN I-NP of IN B-PP salicylate NN B-NP in IN B-PP the DT B-NP control NN I-NP of IN B-PP gene NN B-NP expression NN I-NP of IN B-PP inflammatory JJ B-NP mediators NNS I-NP . . O Lack NN B-NP of IN B-PP T-cell-mediated JJ B-NP recognition NN I-NP of IN B-PP the DT B-NP fusion NN I-NP region NN I-NP of IN B-PP the DT B-NP pml\/RAR-alpha NN I-NP hybrid NN I-NP protein NN I-NP by IN B-PP lymphocytes NNS B-NP of IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP patients NNS I-NP . . O In IN B-PP previous JJ B-NP studies NNS I-NP COMMA COMMA O it PRP B-NP was VBD B-VP shown VBN I-VP that IN B-SBAR the DT B-NP fusion NN I-NP region NN I-NP of IN B-PP the DT B-NP pml\/RAR-alpha NN I-NP protein NN I-NP COMMA COMMA O expressed VBN B-VP by IN B-PP acute JJ B-NP promyelocytic JJ I-NP leukemia NN I-NP ( ( O APL NN B-NP ) ) O cells NNS B-NP COMMA COMMA O can MD B-VP be VB I-VP specifically RB I-VP recognized VBN I-VP in FW B-ADVP vitro FW I-ADVP by IN B-PP donor NN B-NP ( ( O D. NNP B-NP E. NNP I-NP ) ) O CD4 NN B-NP T NN I-NP cells NNS I-NP in IN B-PP a DT B-NP HLA NN I-NP class NN I-NP II CD I-NP DR11-restricted JJ I-NP fashion NN I-NP . . O We PRP B-NP present VBP B-VP here RB B-ADVP the DT B-NP results NNS I-NP on IN B-PP the DT B-NP recognition NN I-NP of IN B-PP several JJ B-NP pml\/RAR-alpha NN I-NP peptides NNS I-NP by IN B-PP APL NN B-NP patients NNS I-NP expressing VBG B-VP HLA NN B-NP DR11 NN I-NP . . O The DT B-NP in FW I-NP vitro FW I-NP immunization NN I-NP of IN B-PP peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP from IN B-PP four CD B-NP patients NNS I-NP in IN B-PP remission NN B-NP ( ( O S.R. NNP B-NP COMMA COMMA O F.R. NNP B-NP COMMA COMMA O M.M. NNP B-NP COMMA COMMA O P. NNP B-NP G. NNP I-NP ) ) O with IN B-PP BCR1\/25 NN B-NP COMMA COMMA O a DT B-NP 25-mer NN I-NP pml\/RAR-alpha NN I-NP COMMA COMMA O did VBD B-VP not RB I-VP elicit VB I-VP either CC O a DT B-NP polyclonal JJ I-NP or CC O a DT B-NP clonal JJ I-NP immune JJ B-NP response NN I-NP specific JJ B-ADJP to TO B-PP the DT B-NP peptide NN I-NP . . O We PRP B-NP then RB B-ADVP generated VBD B-VP new JJ B-NP donor NN I-NP anti-pml\/RAR-alpha JJ I-NP CD4(+) JJ I-NP T-cell NN I-NP clones NNS I-NP . . O These DT B-NP clones NNS I-NP were VBD B-VP tested VBN I-VP for IN B-PP their PRP$ B-NP recognition NN I-NP of IN B-PP BCR1\/25 NN B-NP . . O One CD B-NP clone NN I-NP ( ( O C3\/5 NN B-NP COMMA COMMA O CD3(+) JJ B-ADJP COMMA COMMA O CD4(+) JJ B-ADJP COMMA COMMA O CD8(-) JJ B-ADJP ) ) O was VBD B-VP selected VBN I-VP for IN B-PP further JJ B-NP analysis NN I-NP . . O Clone NN B-NP C3\/5 NN I-NP showed VBD B-VP specific JJ B-NP proliferation NN B-NP COMMA COMMA O cytotoxicity NN B-NP COMMA COMMA O and CC O cytokine NN B-NP ( ( O tumor NN B-NP necrosis NN I-NP factor NN I-NP alpha NN I-NP COMMA COMMA O granulocyte-macrophage JJ B-ADJP colony-stimulating JJ I-ADJP factor NN B-NP ) ) O production NN B-NP when WRB B-ADVP challenged VBN B-VP with IN B-PP autologous JJ B-NP lymphoblastic JJ I-NP cell NN I-NP lines NNS I-NP pulsed VBN B-VP with IN B-PP peptide NN B-NP BCR1\/25 NN I-NP . . O C3\/5 NN B-NP cells NNS I-NP developed VBD B-VP specific JJ B-NP proliferation NN B-NP and CC O cytotoxicity NN B-NP when WRB B-ADVP challenged VBN B-VP with IN B-PP peptide-pulsed JJ B-NP lymphoblastic JJ B-NP cell NN I-NP lines NNS I-NP and CC O peripheral JJ B-NP blood NN I-NP lymphocytes NNS I-NP from IN B-PP the DT B-NP four CD I-NP DR11(+) JJ I-NP APL NN I-NP patients NNS I-NP . . O APL NN B-NP blasts NNS I-NP COMMA COMMA O available JJ B-ADJP only RB B-PP from IN I-PP patients NNS B-NP F.R. NNP B-NP and CC O P.G. NNP B-NP COMMA COMMA O were VBD B-VP not RB I-VP lysed VBN I-VP by IN B-PP C3\/5 NN B-NP and CC O were VBD B-VP unable JJ B-ADJP to TO B-VP present VB I-VP peptide NN B-NP BCR1\/25 NN I-NP . . O Incubation NN B-NP of IN B-PP APL NN B-NP cells NNS I-NP with IN B-PP IFN-gamma NN B-NP failed VBD B-VP to TO I-VP induce VB I-VP HLA NN B-NP class NN I-NP II CD I-NP molecules NNS I-NP and CC O recognition NN B-NP by IN B-PP the DT B-NP C3\/5 NN I-NP clone NN I-NP . . O Since IN B-SBAR APL NN B-NP cells NNS I-NP do VBP B-VP not RB I-VP express VB I-VP HLA NN B-NP class NN I-NP II CD I-NP molecules NNS I-NP COMMA COMMA O we PRP B-NP tested VBD B-VP in IN B-PP two CD B-NP donors NNS I-NP ( ( O D.E. NNP B-NP and CC O C.H.R. NNP B-NP ) ) O and CC B-PP in IN B-PP patients NNS B-NP S.R. NN B-NP and CC O P.G. NN B-NP whether CC O the DT B-NP use NN I-NP of IN B-PP 9-mer NN B-NP peptides NNS I-NP ( ( O BCR1\/9 NN B-NP ) ) O would MD B-VP generate VB I-VP a DT B-NP CD8\/HLA NN I-NP class NN I-NP I-restricted JJ I-NP response NN I-NP . . O No DT B-NP peptide-specific JJ I-NP T-cell NN I-NP line NN B-NP or CC O clone NN B-NP could MD B-VP be VB I-VP generated VBN I-VP from IN B-PP both CC O donors NNS B-NP and CC O patients NNS B-NP . . O These DT B-NP findings NNS I-NP are VBP B-VP discussed VBN I-VP in IN B-PP relation NN I-PP to TO I-PP possible JJ B-NP therapeutic JJ I-NP approaches NNS I-NP to TO B-PP the DT B-NP immunotherapy NN I-NP of IN B-PP APL NN B-NP . . O