The nonobese patient with diabetes ( NOD ) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex ( MHC ) region of the genome .

The nonobese patient with diabetes ( NOD ) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the <dna>major histocompatibility complex ( MHC ) region</dna> of the <dna>genome</dna> .


A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down-regulation of expression of the proteasome subunit LMP2 , which is encoded by a gene in the MHC genomic region .

A specific <protein>proteasome</protein> defect has been identified in NOD mouse in select <cell_line>lymphocytic and monocytic lineages</cell_line> that results from down-regulation of expression of the <protein>proteasome subunit LMP2</protein> , which is encoded by a gene in the <dna>MHC genomic region</dna> .


This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB ( NF-kappaB ) , which plays important roles in immune and inflammatory responses , as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha ( TNF-alpha ) .

This defect prevents the proteolytic processing required for the production and activation of the <protein>transcription factor nuclear factor-kappaB</protein> ( <protein>NF-kappaB</protein> ) , which plays important roles in immune and inflammatory responses , as well as increases the susceptibility of the affected cells to apoptosis induced by <protein>tumor necrosis factor-alpha</protein> ( <protein>TNF-alpha</protein> ) .


The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific .

The novel role of the <protein>proteasome</protein> in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific .


We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting .

We propose a role of the <protein>proteasome</protein> as a step in disease pathogenesis and tissue targeting .


Down-regulation of TDT transcription in CD4 ( + ) CD8 ( + ) thymocytes by Ikaros proteins in direct competition with an Ets activator .

Down-regulation of TDT transcription in <cell_type>CD4 ( + ) CD8 ( + ) thymocytes</cell_type> by <protein>Ikaros proteins</protein> in direct competition with an <protein>Ets activator</protein> .


Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation .

<protein>Ikaros</protein> is a unique regulator of lymphopoiesis that associates with <dna>pericentromeric heterochromatin</dna> and has been implicated in heritable gene inactivation .


Binding and competition experiments demonstrate that Ikaros dimers compete with an Ets activator for occupancy of the lymphocyte-specific TdT promoter .

Binding and competition experiments demonstrate that <protein>Ikaros dimers</protein> compete with an <protein>Ets activator</protein> for occupancy of the <dna>lymphocyte-specific TdT promoter</dna> .


Mutations that selectively disrupt Ikaros binding to an integrated TdT promoter had no effect on promoter function in a CD4 ( + ) CD8 ( + ) thymocyte line .

Mutations that selectively disrupt Ikaros binding to an <dna>integrated TdT promoter</dna> had no effect on promoter function in a <cell_line>CD4 ( + ) CD8 ( + ) thymocyte line</cell_line> .


However , these mutations abolished down-regulation on differentiation , providing evidence that Ikaros plays a direct role in repression .

However , these mutations abolished down-regulation on differentiation , providing evidence that <protein>Ikaros</protein> plays a direct role in repression .


Reduced access to restriction enzyme cleavage suggested that chromatin alterations accompany down-regulation .


The Ikaros-dependent down-regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning .


Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA-binding domain .

Current models propose that the functions of <protein>Ikaros</protein> should be disrupted by a small <protein>isoform</protein> that retains the <protein>dimerization domain</protein> and lacks the <protein>DNA-binding domain</protein> .


Surprisingly , in the CD4 ( + ) CD8 ( + ) thymocyte line , overexpression of a small Ikaros isoform had no effect on differentiation or on the pericentromeric targeting and DNA-binding properties of Ikaros .

Surprisingly , in the <cell_line>CD4 ( + ) CD8 ( + ) thymocyte line</cell_line> , overexpression of a <protein>small Ikaros isoform</protein> had no effect on differentiation or on the pericentromeric targeting and DNA-binding properties of <protein>Ikaros</protein> .


Rather , the small isoform assembled into multimeric complexes with DNA-bound Ikaros at the pericentromeric foci .

Rather , the small <protein>isoform</protein> assembled into <protein>multimeric complexes</protein> with <protein>DNA-bound Ikaros</protein> at the pericentromeric foci .


The capacity for in vivo multimer formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may contribute to the pericentromeric repositioning of the inactive gene .

The capacity for in vivo multimer formation suggests that interactions between <protein>Ikaros dimers</protein> bound to the <dna>TdT promoter</dna> and those bound to <dna>pericentromeric repeat sequences</dna> may contribute to the pericentromeric repositioning of the <dna>inactive gene</dna> .


Type I interferons and IL-12 : convergence and cross-regulation among mediators of cellular immunity .

<protein>Type I interferons</protein> and <protein>IL-12</protein> : convergence and cross-regulation among mediators of cellular immunity .


Therapeutic use of type I IFN ( IFN-alpha/beta ) has become common .

Therapeutic use of <protein>type I IFN</protein> ( <protein>IFN-alpha/beta</protein> ) has become common .


Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity ( CMI ) , these cellular immune responses either causing injury to the host , lacking sufficient vigor for virus or tumor clearance , or both .


In general , therapeutic efficacy is limited .


It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood .

It is thus notable that the pleiotropic effects of <protein>type I IFN</protein> on CMI remain poorly understood .


We characterized the effects of type I IFN on the production of IL-12 , the central immunoregulatory cytokine of the CD4 ( + ) T cell arm of CMI .

We characterized the effects of <protein>type I IFN</protein> on the production of <protein>IL-12</protein> , the <protein>central immunoregulatory cytokine</protein> of the <protein>CD4 ( + ) T cell arm</protein> of CMI .


We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages .

We show that <protein>type I IFN</protein> are potent inhibitors of IL-12 production by <cell_type>human monocytes/macrophages</cell_type> .


The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene , marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter .

The underlying mechanism involves transcriptional inhibition of the <dna>IL-12p40 gene</dna> , marked by down-regulation of PU.1 binding activity at the <dna>upstream Ets site</dna> of the <dna>IL-12p40 promoter</dna> .


Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-gamma production from T and NK cells .

<protein>Type I IFN</protein> have previously been shown to be able to substitute for <protein>IL-12</protein> in driving IFN-gamma production from <cell_type>T and NK cells</cell_type> .


The ability of IFN-alpha/beta to suppress IL-12 production while up-regulating IFN-gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI .

The ability of <protein>IFN-alpha/beta</protein> to suppress IL-12 production while up-regulating IFN-gamma production suggests a possible mechanistic basis for the difficulties of employing these <protein>cytokines</protein> in diseases involving abnormalities of CMI .


Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes : evidence of an antiinflammatory action ?

<protein>Nuclear factor-kappaB</protein> suppressive and <protein>inhibitor-kappaB</protein> stimulatory effects of troglitazone in obese patients with type 2 diabetes : evidence of an antiinflammatory action ?


It has been shown recently that troglitazone exerts an anti-inflammatory effect , in vitro , and in experimental animals .


To test these properties in humans , we investigated the effect of troglitazone on the proinflammatory transcription factor nuclear factor-kappaB and its inhibitory protein IkappaB in mononuclear cells ( MNC ) and plasma soluble intracellular adhesion molecule-1 , monocyte chemoattractant protein-1 , plasminogen activator inhibitor-1 , and C-reactive protein .

To test these properties in humans , we investigated the effect of troglitazone on the <protein>proinflammatory transcription factor nuclear factor-kappaB</protein> and its <protein>inhibitory protein IkappaB</protein> in <cell_type>mononuclear cells</cell_type> ( <cell_type>MNC</cell_type> ) and <protein>plasma soluble intracellular adhesion molecule-1</protein> , <protein>monocyte chemoattractant protein-1</protein> , <protein>plasminogen activator inhibitor-1</protein> , and <protein>C-reactive protein</protein> .


We also examined the effect of troglitazone on reactive oxygen species generation , p47 ( phox ) subunit expression , 9-hydroxyoctadecadienoic acid ( 9-HODE ) , 13-HODE , o-tyrosine , and m-tyrosine in obese patients with type 2 diabetes .


Seven obese patients with type 2 diabetes were treated with troglitazone ( 400 mg/day ) for 4 weeks .


Blood samples were obtained at weekly intervals .


Nuclear factor-kappaB binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4 .

<protein>Nuclear factor-kappaB</protein> binding activity in <cell_type>MNC</cell_type> nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4 .


On the other hand , IkappaB protein levels increased significantly after troglitazone treatment at week 1 , and this increase persisted throughout the study .


Plasma monocyte chemoattractant protein-1 and soluble intracellular adhesion molecule-1 concentrations did not decrease significantly after troglitazone treatment , although there was a trend toward inhibition .

<protein>Plasma monocyte chemoattractant protein-1</protein> and <protein>soluble intracellular adhesion molecule-1</protein> concentrations did not decrease significantly after troglitazone treatment , although there was a trend toward inhibition .


Reactive oxygen species generation by polymorphonuclear cells and MNC , p47 ( phox ) subunit protein quantities , plasminogen activator inhibitor-1 , and C-reactive protein levels decreased significantly after troglitazone intake .

Reactive oxygen species generation by <cell_type>polymorphonuclear cells</cell_type> and <cell_type>MNC</cell_type> , <protein>p47 ( phox ) subunit protein</protein> quantities , <protein>plasminogen activator inhibitor-1</protein> , and <protein>C-reactive protein</protein> levels decreased significantly after troglitazone intake .


13-HODE/linoleic acid and 9-HODE/linoleic acid ratios also decreased after troglitazone intake .


However , o-tyrosine/phenylalanine and m-tyrosine/phenylalanine ratios did not change significantly .


These data show that troglitazone has profound antiinflammatory effects in addition to antioxidant effects in obese type 2 diabetics ; these effects may be relevant to the recently described beneficial antiatherosclerotic effects of troglitazone at the vascular level .


OX40 stimulation by gp34/OX40 ligand enhances productive human immunodeficiency virus type 1 infection .

OX40 stimulation by <protein>gp34/OX40 ligand</protein> enhances productive human immunodeficiency virus type 1 infection .


OX40 is a member of the tumor necrosis factor ( TNF ) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells .

<protein>OX40</protein> is a member of the <protein>tumor necrosis factor ( TNF ) receptor superfamily</protein> and known to be an important <protein>costimulatory molecule</protein> expressed on <cell_type>activated T cells</cell_type> .


To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 ( HIV-1 ) infection by its natural ligand , gp34 , the OX40-transfected ACH-2 cell line , ACH-2/OX40 , chronically infected with HIV-1 , was cocultured with paraformaldehyde ( PFA ) -fixed gp34-transfected mouse cell line , SV-T2/gp34 .

To investigate the role of costimulation of <protein>OX40</protein> in human immunodeficiency virus type 1 ( HIV-1 ) infection by its natural ligand , <protein>gp34</protein> , the <cell_line>OX40-transfected ACH-2 cell line , ACH-2/OX40</cell_line> , chronically infected with HIV-1 , was cocultured with paraformaldehyde ( PFA ) -fixed <cell_line>gp34-transfected mouse cell line , SV-T2/gp34</cell_line> .


The results showed that HIV-1 production was strongly induced .


This was followed by apparent apoptosis , and both processes were specifically inhibited by the gp34 -specific neutralizing monoclonal antibody 5A8 .

This was followed by apparent apoptosis , and both processes were specifically inhibited by the <protein>gp34</protein> -specific <protein>neutralizing monoclonal antibody 5A8</protein> .


Endogenous TNF alpha ( TNF-alpha ) and TNF-beta production were not involved in the enhanced HIV-1 production .

Endogenous <protein>TNF alpha</protein> ( <protein>TNF-alpha</protein> ) and <protein>TNF-beta</protein> production were not involved in the enhanced HIV-1 production .


Furthermore , enhanced HIV-1 transcription in gp34 -stimulated ACH-2/OX40 cells was dependent on the kappa B site of the HIV-1 long terminal repeat , and the OX40-gp34 interaction activated NF-kappa B consisting of p50 and p65 subunits .

Furthermore , enhanced HIV-1 transcription in <protein>gp34</protein> -stimulated <cell_line>ACH-2/OX40 cells</cell_line> was dependent on the <dna>kappa B site</dna> of the <dna>HIV-1 long terminal repeat</dna> , and the OX40-gp34 interaction activated <protein>NF-kappa B</protein> consisting of <protein>p50 and p65 subunits</protein> .


When primary activated CD4 ( + ) T cells acutely infected with HIV-1 ( NL4-3 ) ( CXCR4-using T-cell-line-tropic ) were cocultured with PFA-fixed gp34 ( + ) human T-cell leukemia virus type 1-bearing MT-2 cells or SV-T2/gp34 cells , HIV-1 production was also markedly enhanced .

When primary activated <cell_type>CD4 ( + ) T cells</cell_type> acutely infected with HIV-1 ( NL4-3 ) ( <cell_line>CXCR4-using T-cell-line-tropic</cell_line> ) were cocultured with PFA-fixed <cell_type>gp34 ( + ) human T-cell</cell_type> leukemia virus type 1-bearing <cell_line>MT-2 cells</cell_line> or <cell_line>SV-T2/gp34 cells</cell_line> , HIV-1 production was also markedly enhanced .


The enhancement was again significantly inhibited by 5A8 .

The enhancement was again significantly inhibited by <protein>5A8</protein> .


The present study first shows that OX40-gp34 interaction stimulates HIV-1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV-1 production in both acutely and latently infected CD4 ( + ) T cells in vivo .

The present study first shows that OX40-gp34 interaction stimulates HIV-1 expression and suggests that OX40 triggering by <protein>gp34</protein> may play an important role in enhancing HIV-1 production in both acutely and latently infected <cell_type>CD4 ( + ) T cells</cell_type> in vivo .


Troglitazone , a PPARgamma ligand , inhibits osteopontin gene expression in human monocytes/macrophage THP-1 cells .

Troglitazone , a PPARgamma ligand , inhibits osteopontin gene expression in <cell_type>human monocytes/macrophage THP-1 cells</cell_type> .


Peroxizome proliferator-activated receptor-gamma ( PPARgamma ) is a member of the nuclear receptor family of transcription factors that regulate adipocyte differentiation .

<protein>Peroxizome proliferator-activated receptor-gamma</protein> ( <protein>PPARgamma</protein> ) is a member of the <protein>nuclear receptor family</protein> of <protein>transcription factors</protein> that regulate adipocyte differentiation .


Recent studies indicate that liganded PPARgamma not only promotes differentiation but also inhibits the activation of macrophages .

Recent studies indicate that <protein>liganded PPARgamma</protein> not only promotes differentiation but also inhibits the activation of <cell_type>macrophages</cell_type> .


Osteopontin , a component of extracellular matrix , is synthesized by macrophages in atherosclerotic plaques .

<protein>Osteopontin</protein> , a component of extracellular matrix , is synthesized by <cell_type>macrophages</cell_type> in atherosclerotic plaques .


In this study , we examined whether PPARgamma ligand regulates osteopontin gene expression in THP-1 cells , a cell line derived from human monocytic leukemia cells which can differentiate to macrophage upon stimulation with phorbol ester PMA .

In this study , we examined whether <protein>PPARgamma</protein> ligand regulates osteopontin gene expression in <cell_line>THP-1 cells</cell_line> , a cell line derived from <cell_type>human monocytic leukemia cells</cell_type> which can differentiate to <cell_type>macrophage</cell_type> upon stimulation with phorbol ester PMA .


Northern blot analysis showed that osteopontin expression is markedly induced in response to PMA .


Troglitazone , a PPARgamma ligand , dramatically attenuated the PMA-induced osteopontin expression .

Troglitazone , a <protein>PPARgamma</protein> ligand , dramatically attenuated the PMA-induced osteopontin expression .


Transient transfection assays of the human osteopontin promoter/luciferase construct which contains a 5'-flanking region between -1500 and +87 relative to the transcription start site demonstrate that either treatment with troglitazone or cotransfection of PPARgamma expression vector inhibits osteopontin promoter activity .

Transient transfection assays of the <dna>human osteopontin promoter/luciferase construct</dna> which contains a <dna>5'-flanking region</dna> between -1500 and +87 relative to the <dna>transcription start site</dna> demonstrate that either treatment with troglitazone or cotransfection of <dna>PPARgamma expression vector</dna> inhibits osteopontin promoter activity .


These data indicate that troglitazone reduces osteopontin gene expression at transcriptional level through PPARgamma activation , and suggest the role of troglitazone in inhibiting the ability of macrophages to produce extracellular matrix , which is particularly relevant to atherosclerotic plaque formation .

These data indicate that troglitazone reduces osteopontin gene expression at transcriptional level through <protein>PPARgamma</protein> activation , and suggest the role of troglitazone in inhibiting the ability of <cell_type>macrophages</cell_type> to produce extracellular matrix , which is particularly relevant to atherosclerotic plaque formation .


Transcription factor NF-kappa B regulates Ig lambda light chain gene rearrangement .

<protein>Transcription factor NF-kappa B</protein> regulates <protein>Ig lambda</protein> light chain gene rearrangement .


The tissue- and stage-specific assembly of Ig and TCR genes is mediated by a common V ( D ) J recombinase complex in precursor lymphocytes .

The tissue- and stage-specific assembly of <dna>Ig and TCR genes</dna> is mediated by a common <protein>V ( D ) J recombinase complex</protein> in <cell_type>precursor lymphocytes</cell_type> .


Directed alterations in the accessibility of V , D , and J gene segments target the recombinase to specific Ag receptor loci .

Directed alterations in the accessibility of <dna>V , D , and J gene segments</dna> target the <protein>recombinase</protein> to specific <dna>Ag receptor loci</dna> .


Accessibility within a given locus is regulated by the functional interaction of transcription factors with cognate enhancer elements and correlates with the transcriptional activity of unrearranged gene segments .

Accessibility within a given <dna>locus</dna> is regulated by the functional interaction of <protein>transcription factors</protein> with <dna>cognate enhancer elements</dna> and correlates with the transcriptional activity of unrearranged <dna>gene segments</dna> .


As demonstrated in our prior studies , rearrangement of the Igkappa locus is regulated by the inducible transcription factor NF-kappaB .

As demonstrated in our prior studies , rearrangement of the <dna>Igkappa locus</dna> is regulated by the <protein>inducible transcription factor</protein> <protein>NF-kappaB</protein> .


In contrast to the Igkappa locus , known transcriptional control elements in the Iglambda locus lack functional NF-kappaB binding sites .

In contrast to the <dna>Igkappa locus</dna> , known <dna>transcriptional control elements</dna> in the <dna>Iglambda locus</dna> lack functional <dna>NF-kappaB binding sites</dna> .


Consistent with this observation , the expression of assembled Iglambda genes in mature B cells has been shown to be NF-kappaB independent .

Consistent with this observation , the expression of assembled <dna>Iglambda genes</dna> in <cell_type>mature B cells</cell_type> has been shown to be <protein>NF-kappaB</protein> independent .


Nonetheless , we now show that specific repression of NF-kappaB inhibits germline transcription and recombination of Iglambda gene segments in precursor B cells .

Nonetheless , we now show that specific repression of <protein>NF-kappaB</protein> inhibits germline transcription and recombination of <dna>Iglambda gene segments</dna> in <cell_type>precursor B cells</cell_type> .


Molecular analyses indicate that the block in NF-kappaB impairs Iglambda rearrangement at the level of recombinase accessibility .

Molecular analyses indicate that the block in <protein>NF-kappaB</protein> impairs Iglambda rearrangement at the level of <protein>recombinase</protein> accessibility .


In contrast , the activities of known Iglambda promoter and enhancer elements are unaffected in the same cellular background .

In contrast , the activities of known <dna>Iglambda promoter</dna> and <dna>enhancer elements</dna> are unaffected in the same cellular background .


These findings expand the range of NF-kappaB action in precursor B cells beyond Igkappa to include the control of recombinational accessibility at both L chain loci .

These findings expand the range of <protein>NF-kappaB</protein> action in <cell_type>precursor B cells</cell_type> beyond <protein>Igkappa</protein> to include the control of recombinational accessibility at both <dna>L chain loci</dna> .


Moreover , our results strongly suggest the existence of a novel Iglambda regulatory element that is either directly or indirectly activated by NF-kappaB during the early stages of B cell development .

Moreover , our results strongly suggest the existence of a novel <dna>Iglambda regulatory element</dna> that is either directly or indirectly activated by <protein>NF-kappaB</protein> during the early stages of B cell development .


Transcription factor STAT5A is a substrate of Bruton 's tyrosine kinase in B cells .

<protein>Transcription factor</protein> <protein>STAT5A</protein> is a substrate of <protein>Bruton 's tyrosine kinase</protein> in <cell_type>B cells</cell_type> .


STAT5A is a molecular regulator of proliferation , differentiation , and apoptosis in lymphohematopoietic cells .

<protein>STAT5A</protein> is a molecular regulator of proliferation , differentiation , and apoptosis in <cell_type>lymphohematopoietic cells</cell_type> .


Here we show that STAT5A can serve as a functional substrate of Bruton 's tyrosine kinase ( BTK ) .

Here we show that <protein>STAT5A</protein> can serve as a functional substrate of <protein>Bruton 's tyrosine kinase</protein> ( <protein>BTK</protein> ) .


Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity ( K ( d ) = 44 nm ) , as determined by surface plasmon resonance using a BIAcore biosensor system .

<protein>Purified recombinant BTK</protein> was capable of directly binding <protein>purified recombinant STAT5A</protein> with high affinity ( K ( d ) = 44 nm ) , as determined by surface plasmon resonance using a BIAcore biosensor system .


BTK was also capable of tyrosine-phosphorylating ectopically expressed recombinant STAT5A on Tyr ( 694 ) both in vitro and in vivo in a Janus kinase 3 -independent fashion .

<protein>BTK</protein> was also capable of tyrosine-phosphorylating ectopically expressed <protein>recombinant STAT5A</protein> on Tyr ( 694 ) both in vitro and in vivo in a <protein>Janus kinase 3</protein> -independent fashion .


BTK phosphorylated the Y665F , Y668F , and Y682F , Y683F mutants but not the Y694F mutant of STAT5A .

<protein>BTK</protein> phosphorylated the <protein>Y665F , Y668F , and Y682F , Y683F mutants</protein> but not the <protein>Y694F mutant</protein> of <protein>STAT5A</protein> .


STAT5A mutations in the Src homology 2 ( SH2 ) and SH3 domains did not alter the BTK -mediated tyrosine phosphorylation .

STAT5A mutations in the <protein>Src homology 2 ( SH2 ) and SH3 domains</protein> did not alter the <protein>BTK</protein> -mediated tyrosine phosphorylation .


Recombinant BTK proteins with mutant pleckstrin homology , SH2 , or SH3 domains were capable of phosphorylating STAT5A , whereas recombinant BTK proteins with SH1/kinase domain mutations were not .

<protein>Recombinant BTK proteins</protein> with mutant pleckstrin homology , <protein>SH2 , or SH3 domains</protein> were capable of phosphorylating <protein>STAT5A</protein> , whereas <protein>recombinant BTK proteins</protein> with SH1/kinase domain mutations were not .


In pull-down experiments , only full-length BTK and its SH1/kinase domain ( but not the pleckstrin homology , SH2 , or SH3 domains ) were capable of binding STAT5A .

In pull-down experiments , only <protein>full-length BTK</protein> and its <protein>SH1/kinase domain</protein> ( but not the pleckstrin homology , <protein>SH2 , or SH3 domains</protein> ) were capable of binding <protein>STAT5A</protein> .


Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo .

Ectopically expressed <protein>BTK kinase domain</protein> was capable of tyrosine-phosphorylating <protein>STAT5A</protein> both in vitro and in vivo .


BTK -mediated tyrosine phosphorylation of ectopically expressed wild type ( but not Tyr ( 694 ) mutant ) STAT5A enhanced its DNA binding activity .

<protein>BTK</protein> -mediated tyrosine phosphorylation of ectopically expressed wild type ( but not <protein>Tyr ( 694 ) mutant</protein> ) <protein>STAT5A</protein> enhanced its DNA binding activity .


In BTK -competent chicken B cells , anti-IgM-stimulated tyrosine phosphorylation of STAT5 protein was prevented by pretreatment with the BTK inhibitor LFM-A13 but not by pretreatment with the JAK3 inhibitor HI-P131 .

In <protein>BTK</protein> -competent chicken <cell_type>B cells</cell_type> , anti-IgM-stimulated tyrosine phosphorylation of <protein>STAT5 protein</protein> was prevented by pretreatment with the <protein>BTK</protein> inhibitor LFM-A13 but not by pretreatment with the JAK3 inhibitor HI-P131 .


B cell antigen receptor ligation resulted in enhanced tyrosine phosphorylation of STAT5 in BTK -deficient chicken B cells reconstituted with wild type human BTK but not in BTK -deficient chicken B cells reconstituted with kinase-inactive mutant BTK .

B cell antigen receptor ligation resulted in enhanced tyrosine phosphorylation of <protein>STAT5</protein> in <protein>BTK</protein> -deficient chicken <cell_type>B cells</cell_type> reconstituted with <protein>wild type human BTK</protein> but not in <protein>BTK</protein> -deficient chicken <cell_type>B cells</cell_type> reconstituted with <protein>kinase-inactive mutant BTK</protein> .


Similarly , anti-IgM stimulation resulted in enhanced tyrosine phosphorylation of STAT5A in BTK -competent B cells from wild type mice but not in BTK -deficient B cells from XID mice .

Similarly , anti-IgM stimulation resulted in enhanced tyrosine phosphorylation of <protein>STAT5A</protein> in <protein>BTK</protein> -competent <cell_type>B cells</cell_type> from wild type mice but not in <protein>BTK</protein> -deficient <cell_type>B cells</cell_type> from XID mice .


In contrast to B cells from XID mice , B cells from JAK3 knockout mice showed a normal STAT5A phosphorylation response to anti-IgM stimulation .

In contrast to <cell_type>B cells</cell_type> from XID mice , <cell_type>B cells</cell_type> from JAK3 knockout mice showed a normal STAT5A phosphorylation response to anti-IgM stimulation .


These findings provide unprecedented experimental evidence that BTK plays a nonredundant and pivotal role in B cell antigen receptor-mediated STAT5A activation in B cells

These findings provide unprecedented experimental evidence that <protein>BTK</protein> plays a nonredundant and pivotal role in B cell antigen receptor-mediated STAT5A activation in <cell_type>B cells</cell_type>


Role of T-bet in commitment of TH1 cells before IL-12 -dependent selection .

Role of <protein>T-bet</protein> in commitment of <cell_type>TH1 cells</cell_type> before <protein>IL-12</protein> -dependent selection .


How cytokines control differentiation of helper T ( TH ) cells is controversial .

How <protein>cytokines</protein> control differentiation of <cell_type>helper T ( TH ) cells</cell_type> is controversial .


We show that T-bet , without apparent assistance from interleukin 12 ( IL-12 ) / STAT4 , specifies TH1 effector fate by targeting chromatin remodeling to individual interferon-gamma ( IFN-gamma ) alleles and by inducing IL-12 receptor beta2 expression .

We show that <protein>T-bet</protein> , without apparent assistance from <protein>interleukin 12 ( IL-12 )</protein> / <protein>STAT4</protein> , specifies <cell_type>TH1</cell_type> effector fate by targeting chromatin remodeling to individual <dna>interferon-gamma ( IFN-gamma ) alleles</dna> and by inducing <dna>IL-12 receptor beta2</dna> expression .


Subsequently , it appears that IL-12 / STAT4 serves two essential functions in the development of TH1 cells : as growth signal , inducing survival and cell division ; and as trans-activator , prolonging IFN-gamma synthesis through a genetic interaction with the coactivator , CREB-binding protein .

Subsequently , it appears that <protein>IL-12</protein> / <protein>STAT4</protein> serves two essential functions in the development of <cell_type>TH1 cells</cell_type> : as <protein>growth signal</protein> , inducing survival and cell division ; and as <protein>trans-activator</protein> , prolonging <protein>IFN-gamma</protein> synthesis through a genetic interaction with the <protein>coactivator</protein> , <protein>CREB-binding protein</protein> .


These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage .

These results suggest that a <protein>cytokine</protein> does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage .


Stat6 is necessary and sufficient for IL-4 's role in Th2 differentiation and cell expansion .

<protein>Stat6</protein> is necessary and sufficient for IL-4 's role in Th2 differentiation and cell expansion .


IL-4 plays a critical role in the differentiation of T CR-stimulated naive CD4 T cells to the Th2 phenotype .

<protein>IL-4</protein> plays a critical role in the differentiation of T <cell_type>CR-stimulated naive CD4 T cells</cell_type> to the Th2 phenotype .


In response to IL-4 , the IL-4R activates a set of phosphotyrosine binding domain-containing proteins , including insulin receptor substrate 1/2 , Shc , and IL-4R interacting protein , as well as Stat6 .

In response to <protein>IL-4</protein> , the <protein>IL-4R</protein> activates a set of <protein>phosphotyrosine binding domain-containing proteins</protein> , including <protein>insulin receptor substrate 1/2</protein> , <protein>Shc</protein> , and <protein>IL-4R interacting protein</protein> , as well as <protein>Stat6</protein> .


Stat6 has been shown to be required for Th2 differentiation .

<protein>Stat6</protein> has been shown to be required for Th2 differentiation .


To determine the roles of the phosphotyrosine binding adaptors in Th2 differentiation , we prepared a retrovirus containing a mutant of the human ( h ) IL-4R alpha-chain , Y497F , which is unable to recruit these adaptors .

To determine the roles of the <protein>phosphotyrosine binding adaptors</protein> in Th2 differentiation , we prepared a retrovirus containing a mutant of the <protein>human ( h ) IL-4R alpha-chain</protein> , <protein>Y497F</protein> , which is unable to recruit these adaptors .


The mutant hIL-4Ralpha , as well as the wild-type ( WT ) hIL-4Ralpha , was introduced into naive CD4 T cells .

The <protein>mutant hIL-4Ralpha</protein> , as well as the <protein>wild-type ( WT ) hIL-4Ralpha</protein> , was introduced into <cell_type>naive CD4 T cells</cell_type> .


Upon hIL-4 stimulation , Y497F worked as well as the WT hIL-4Ralpha in driving Th2 differentiation , as measured by Gata3 up-regulation and IL-4 production .

Upon hIL-4 stimulation , <protein>Y497F</protein> worked as well as the <protein>WT hIL-4Ralpha</protein> in driving Th2 differentiation , as measured by Gata3 up-regulation and IL-4 production .


Furthermore , IL-4-driven cell expansion was also normal in the cells infected with Y497F , although cells infected with Y497F were not capable of phosphorylating insulin receptor substrate 2 .

Furthermore , IL-4-driven cell expansion was also normal in the cells infected with <protein>Y497F</protein> , although cells infected with <protein>Y497F</protein> were not capable of phosphorylating <protein>insulin receptor substrate 2</protein> .


These results suggest that the signal pathway mediated by Y497 is dispensable for both IL-4 -driven Th2 differentiation and cell expansion .

These results suggest that the signal pathway mediated by <protein>Y497</protein> is dispensable for both <protein>IL-4</protein> -driven Th2 differentiation and cell expansion .


Both WT and Y497F hIL-4Ralpha lose the ability to drive Th2 differentiation and cell expansion in Stat6-knockout CD4 T cells .

Both <protein>WT and Y497F hIL-4Ralpha</protein> lose the ability to drive Th2 differentiation and cell expansion in <cell_type>Stat6-knockout CD4 T cells</cell_type> .


A constitutively activated form of Stat6 introduced into CD4 T cells resulted in both Th2 differentiation and enhanced cell expansion .

A constitutively activated form of <protein>Stat6</protein> introduced into <cell_type>CD4 T cells</cell_type> resulted in both Th2 differentiation and enhanced cell expansion .


Thus , activated Stat6 is necessary and sufficient to mediate both IL-4 -driven Th2 differentiation and cell expansion in CD4 T cells .

Thus , <protein>activated Stat6</protein> is necessary and sufficient to mediate both <protein>IL-4</protein> -driven Th2 differentiation and cell expansion in <cell_type>CD4 T cells</cell_type> .


The effect of HIV-1 regulatory proteins on cellular genes : derepression of the IL-2 promoter by Tat .

The effect of <protein>HIV-1 regulatory proteins</protein> on cellular genes : derepression of the <dna>IL-2 promoter</dna> by <protein>Tat</protein> .


In HIV-infected individuals dysregulation of the immune system is characterized by severe disorders of the cytokine network .


Increase secretion of IL-2 , the major T cell growth and differentiation cytokine , may play a decisive role in sensitization of T cells for activation induced apoptosis and indirect death of activated T cells through augmented virus replication .

Increase secretion of <protein>IL-2</protein> , the major <cell_type>T cell</cell_type> growth and differentiation <protein>cytokine</protein> , may play a decisive role in sensitization of <cell_type>T cells</cell_type> for activation induced apoptosis and indirect death of <cell_type>activated T cells</cell_type> through augmented virus replication .


We investigated the cause of enhanced IL-2 secretion and found that the HIV Tat induces this effect .

We investigated the cause of enhanced IL-2 secretion and found that the <protein>HIV Tat</protein> induces this effect .


We demonstrate that increased IL-2 secretion is due to Tat -enhanced IL-2 promoter activation .

We demonstrate that increased IL-2 secretion is due to <protein>Tat</protein> -enhanced <dna>IL-2 promoter</dna> activation .


Tat derepresses and activates the distal AP-1 site ( position -185 to -177 ) in the IL-2 promoter .

<protein>Tat</protein> derepresses and activates the <dna>distal AP-1 site</dna> ( <dna>position -185 to -177</dna> ) in the <dna>IL-2 promoter</dna> .


In nonstimulated T cells a repressor complex containing NF-IL6 , JunB , c-Fos and Fra-1 is formed on the AP-1 ( IL-2/d ) site and represses IL-2 promoter activity .

In <cell_type>nonstimulated T cells</cell_type> a repressor complex containing <protein>NF-IL6</protein> , <protein>JunB</protein> , <protein>c-Fos</protein> and <protein>Fra-1</protein> is formed on the <dna>AP-1 ( IL-2/d ) site</dna> and represses <dna>IL-2 promoter</dna> activity .


After T cell activation , a heterodimeric activator containing p65 and c-Jun binds to the AP-1 ( IL-2/d ) site .

After T cell activation , a <protein>heterodimeric activator</protein> containing <protein>p65</protein> and <protein>c-Jun</protein> binds to the <dna>AP-1 ( IL-2/d ) site</dna> .


HIV Tat enhances activation of NF-kappaB and consequently , activates the AP-1 ( IL-2/d ) site .

<protein>HIV Tat</protein> enhances activation of <protein>NF-kappaB</protein> and consequently , activates the <dna>AP-1 ( IL-2/d ) site</dna> .


Our data provide evidence for a novel mechanism by which HIV Tat dysregulates IL-2 production and therefore may contribute to the HIV-1 infection in a way yet to be clarified .

Our data provide evidence for a novel mechanism by which <protein>HIV Tat</protein> dysregulates IL-2 production and therefore may contribute to the HIV-1 infection in a way yet to be clarified .


Transforming growth factor-beta1 interferes with thrombopoietin-induced signal transduction in megakaryoblastic and erythroleukemic cells .

<protein>Transforming growth factor-beta1</protein> interferes with thrombopoietin-induced signal transduction in <cell_type>megakaryoblastic and erythroleukemic cells</cell_type> .


OBJECTIVE : Thrombopoietin ( TPO ) and transforming growth factor-beta ( 1 ) ( TGF-beta ( 1 ) ) have been shown to exert opposite effects on proliferation and megakaryocytic differentiation of hematopoietic cells .

OBJECTIVE : <protein>Thrombopoietin</protein> ( <protein>TPO</protein> ) and <protein>transforming growth factor-beta ( 1 )</protein> ( <protein>TGF-beta ( 1 )</protein> ) have been shown to exert opposite effects on proliferation and megakaryocytic differentiation of <cell_type>hematopoietic cells</cell_type> .


To determine whether TGF-beta ( 1 ) interferes directly with TPO -induced signal transduction in hematopoietic cells , we compared the regulatory effects in the TPO -responsive cell lines Mo-7e and HEL .

To determine whether <protein>TGF-beta ( 1 )</protein> interferes directly with <protein>TPO</protein> -induced signal transduction in <cell_type>hematopoietic cells</cell_type> , we compared the regulatory effects in the <protein>TPO</protein> -responsive cell lines Mo-7e and HEL .


MATERIALS AND METHODS : The cells were stimulated by 100 ng/mL TPO and/or 100 ng/mL TGF-beta1 and analyzed for proliferation ( 3H thymidine incorporation ) , viability ( trypan blue exclusion ) , and protein expression and phosphorylation ( Western blot ) .

MATERIALS AND METHODS : The cells were stimulated by 100 ng/mL <protein>TPO</protein> and/or 100 ng/mL <protein>TGF-beta1</protein> and analyzed for proliferation ( 3H thymidine incorporation ) , viability ( trypan blue exclusion ) , and protein expression and phosphorylation ( Western blot ) .


RESULTS : TPO enhanced the proliferation of Mo-7e cells as determined by 3H-thymidine incorporation , whereas TGF-beta1 suppressed baseline cell growth and antagonized the proliferative effect of TPO .

RESULTS : <protein>TPO</protein> enhanced the proliferation of <cell_line>Mo-7e cells</cell_line> as determined by 3H-thymidine incorporation , whereas <protein>TGF-beta1</protein> suppressed baseline cell growth and antagonized the proliferative effect of <protein>TPO</protein> .


TPO -induced proliferation also was reduced by a specific inhibitor of the mitogen-activated protein kinase ( MAPK ) pathway ( PD098059 ) , which inhibits activation of the MAPK extracellular signal-regulated kinases ( ERK ) ERK1 and ERK2 , and AG490 , an inhibitor of Janus kinase-2 , which completely blocked TPO -induced proliferation .

<protein>TPO</protein> -induced proliferation also was reduced by a specific inhibitor of the <protein>mitogen-activated protein kinase</protein> ( <protein>MAPK</protein> ) pathway ( PD098059 ) , which inhibits activation of the <protein>MAPK extracellular signal-regulated kinases</protein> ( <protein>ERK</protein> ) <protein>ERK1</protein> and <protein>ERK2</protein> , and AG490 , an inhibitor of <protein>Janus kinase-2</protein> , which completely blocked <protein>TPO</protein> -induced proliferation .


As demonstrated by Western blotting , TGF-beta1 reduced the TPO -stimulated ERK1 / ERK2 and STAT5 phosphorylation in Mo-7e and HEL cells .

As demonstrated by Western blotting , <protein>TGF-beta1</protein> reduced the <protein>TPO</protein> -stimulated <protein>ERK1</protein> / <protein>ERK2</protein> and STAT5 phosphorylation in <cell_line>Mo-7e and HEL cells</cell_line> .


This effect was completely reversed by preincubation with a tyrosine phosphatase inhibitor ( Na3VO4 ) , which suggests that TGF-beta1 activated a phosphatase .

This effect was completely reversed by preincubation with a tyrosine phosphatase inhibitor ( Na3VO4 ) , which suggests that <protein>TGF-beta1</protein> activated a <protein>phosphatase</protein> .


Although STAT3 also was activated by TPO , STAT3 activation remained unaltered by TGF-beta1 .

Although <protein>STAT3</protein> also was activated by <protein>TPO</protein> , <protein>STAT3</protein> activation remained unaltered by <protein>TGF-beta1</protein> .


CONCLUSION : Taken together , these data suggest that TGF-beta1 modulates TPO -mediated effects on megakaryocytic proliferation by interfering with TPO -induced signal transduction , particularly by reducing the activities of MAPK ERK1/ERK2 and STAT5 .

CONCLUSION : Taken together , these data suggest that <protein>TGF-beta1</protein> modulates <protein>TPO</protein> -mediated effects on megakaryocytic proliferation by interfering with <protein>TPO</protein> -induced signal transduction , particularly by reducing the activities of <protein>MAPK ERK1/ERK2 and STAT5</protein> .


Invariant chain induces B cell maturation by activating a TAF ( II ) 105-NF-kappaB -dependent transcription program .

<protein>Invariant chain</protein> induces B cell maturation by activating a <protein>TAF ( II ) 105-NF-kappaB</protein> -dependent transcription program .


Early stages of B cell development occur in the bone marrow , resulting in formation of immature B cells .

Early stages of B cell development occur in the bone marrow , resulting in formation of <cell_type>immature B cells</cell_type> .


From there these immature cells migrate to the spleen where they differentiate to mature cells .

From there these <cell_type>immature cells</cell_type> migrate to the spleen where they differentiate to <cell_type>mature cells</cell_type> .


This final maturation step is crucial for the B cells to become responsive to antigens and to participate in the immune response .

This final maturation step is crucial for the <cell_type>B cells</cell_type> to become responsive to <protein>antigens</protein> and to participate in the immune response .


Recently , invariant chain ( Ii ) , a major histocompatibility complex class II chaperone , as well as the transcription factors c-Rel and p65/RelA , were found to play a role in the final antigen-independent differentiation stage of B cells in the spleen .

Recently , <protein>invariant chain</protein> ( <protein>Ii</protein> ) , a <protein>major histocompatibility complex class II chaperone</protein> , as well as the <protein>transcription factors</protein> <protein>c-Rel</protein> and <protein>p65/RelA</protein> , were found to play a role in the final antigen-independent differentiation stage of <cell_type>B cells</cell_type> in the spleen .


In this study , we investigated a possible link between Ii -dependent B cell maturation and the NF-kappaB pathway .

In this study , we investigated a possible link between <protein>Ii</protein> -dependent B cell maturation and the NF-kappaB pathway .


Our studies indicate that Ii -induced B cell maturation involves activation of transcription mediated by the NF-kappaB p65/RelA homodimer and requires the B cell-enriched coactivator TBP-associated factor ( II ) 105 .

Our studies indicate that <protein>Ii</protein> -induced B cell maturation involves activation of transcription mediated by the <protein>NF-kappaB p65/RelA homodimer</protein> and requires the <protein>B cell-enriched coactivator</protein> <protein>TBP-associated factor ( II ) 105</protein> .


Androgens indirectly accelerate thymocyte apoptosis .

Androgens indirectly accelerate <cell_type>thymocyte</cell_type> apoptosis .


Apoptotic processes , or the disturbance of the natural regulation of these processes , may be involved in the pathogenesis of autoimmune diseases ( AID ) .


Women are , in general , more susceptible than men to develop AID like rheumatoid arthritis .


Androgens and glucocorticoids , in contrast to oestrogens , have favourable effects in AID models as well as in human AID .


It is known that glucocorticoids ( GC ) , used for treatment of AID , increase apoptosis in the thymus resulting in decreased numbers of CD4+ CD8+ thymocytes .

It is known that glucocorticoids ( GC ) , used for treatment of AID , increase apoptosis in the thymus resulting in decreased numbers of <cell_type>CD4+ CD8+ thymocytes</cell_type> .


It was asked whether androgens , in contrast to oestrogens , exert their favourable effects in the treatment of AID by a mechanism comparable to that described for GC by eliminating the apoptosis prone CD4+ CD8+ population in the thymus .

It was asked whether androgens , in contrast to oestrogens , exert their favourable effects in the treatment of AID by a mechanism comparable to that described for GC by eliminating the apoptosis prone <cell_type>CD4+ CD8+ population</cell_type> in the thymus .


Although both androgens and oestrogens proved thymolytic , a significantly decreased percentage of CD4+ CD8+ thymocytes was observed by flow cytometry after treatment of mice with the androgen methyltestosterone , but not with the oestrogen ethinylestradiol .

Although both androgens and oestrogens proved thymolytic , a significantly decreased percentage of <cell_type>CD4+ CD8+ thymocytes</cell_type> was observed by flow cytometry after treatment of mice with the androgen methyltestosterone , but not with the oestrogen ethinylestradiol .


To investigate whether the observed thymolytic effects were due to the presence of hormone receptors on thymocytes , cells were isolated from the thymus and incubated with androgens or oestrogens to measure apoptosis .

To investigate whether the observed thymolytic effects were due to the presence of <protein>hormone receptors</protein> on <cell_type>thymocytes</cell_type> , cells were isolated from the thymus and incubated with androgens or oestrogens to measure apoptosis .


Several techniques were used to determine thymocyte apoptosis in vitro , but no enhanced apoptotic signal was observed .

Several techniques were used to determine <cell_type>thymocyte</cell_type> apoptosis in vitro , but no enhanced apoptotic signal was observed .


Using the very sensitive TUNEL assay , no direct effect of androgens on thymocytes in vitro could be observed .

Using the very sensitive TUNEL assay , no direct effect of androgens on <cell_type>thymocytes</cell_type> in vitro could be observed .


This is in sharp contrast to the high signal observed with GC .


Therefore , upon in vivo androgen treatment , other cells containing androgen receptors than thymocytes are probably involved in inducing the increase in thymic apoptosis .

Therefore , upon in vivo androgen treatment , other cells containing <protein>androgen receptors</protein> than <cell_type>thymocytes</cell_type> are probably involved in inducing the increase in thymic apoptosis .


To study the role of the androgen receptor on thymocyte apoptosis , androgen receptor mutant ( Tfm/Y ) mice were treated with androgens .

To study the role of the <protein>androgen receptor</protein> on <cell_type>thymocyte</cell_type> apoptosis , <protein>androgen receptor</protein> mutant ( Tfm/Y ) mice were treated with androgens .


No alterations of thymocyte subpopulations were seen , suggesting that changes in the percentage of CD4+ CD8+ thymocytes after administration of androgens depend on the presence of functional androgen receptors .

No alterations of <cell_type>thymocyte subpopulations</cell_type> were seen , suggesting that changes in the percentage of <cell_type>CD4+ CD8+ thymocytes</cell_type> after administration of androgens depend on the presence of functional <protein>androgen receptors</protein> .


Thus , it is concluded that androgens indirectly accelerate thymocyte apoptosis in vivo .

Thus , it is concluded that androgens indirectly accelerate <cell_type>thymocyte</cell_type> apoptosis in vivo .


Inhibition of the transcription factors AP-1 and NF-kappaB in CD4 T cells by peroxisome proliferator-activated receptor gamma ligands .

Inhibition of the <protein>transcription factors</protein> <protein>AP-1</protein> and <protein>NF-kappaB</protein> in <cell_type>CD4 T cells</cell_type> by <protein>peroxisome proliferator-activated receptor gamma ligands</protein> .


The peroxisome proliferator-activated receptor gamma ( PPARgamma ) , a member of the nuclear hormone receptor superfamily , is essential for adipocyte differentiation and glucose homeostasis .

The <protein>peroxisome proliferator-activated receptor gamma</protein> ( <protein>PPARgamma</protein> ) , a member of the <protein>nuclear hormone receptor superfamily</protein> , is essential for adipocyte differentiation and glucose homeostasis .


PPARgamma has been found recently to regulate macrophage activation in response to mitogens and inflammation .

<protein>PPARgamma</protein> has been found recently to regulate macrophage activation in response to <protein>mitogens</protein> and inflammation .


Our study shows PPARgamma to be preferentially expressed in the nuclei of resting T cells and to increase upon activation of T cells by either anti-CD3 and anti-CD28 or phorbol myristyl acetate ( PMA ) .

Our study shows <protein>PPARgamma</protein> to be preferentially expressed in the nuclei of <cell_type>resting T cells</cell_type> and to increase upon activation of <cell_type>T cells</cell_type> by either <protein>anti-CD3</protein> and <protein>anti-CD28</protein> or phorbol myristyl acetate ( PMA ) .


We also found the PPARgamma ligand ciglitizone to attenuate the activation of T cells by inhibiting cytokine gene expression and anti-CD3 and anti-CD28 or PMA-induced proliferative responses .

We also found the <protein>PPARgamma ligand</protein> ciglitizone to attenuate the activation of <cell_type>T cells</cell_type> by inhibiting cytokine gene expression and <protein>anti-CD3</protein> and <protein>anti-CD28</protein> or PMA-induced proliferative responses .


Inhibition of both the proliferative response and inflammatory cytokine expression in CD4 T cells was correlated with suppression of the activated transcription factors AP1 and NF-kappaB .

Inhibition of both the proliferative response and inflammatory cytokine expression in <cell_type>CD4 T cells</cell_type> was correlated with suppression of the activated <protein>transcription factors</protein> <protein>AP1</protein> and <protein>NF-kappaB</protein> .


PPARgamma ligands also strongly inhibited SEA-induced Vbeta3 T cell activation in vivo .

<protein>PPARgamma ligands</protein> also strongly inhibited SEA-induced Vbeta3 T cell activation in vivo .


These results , together with previous findings of the inhibitory effect of PPARgamma ligands on activated macrophages , provide clear evidence for PPARgamma as a negative regulator of the inflammatory activation of both macrophage and T cells .

These results , together with previous findings of the inhibitory effect of <protein>PPARgamma ligands</protein> on <cell_type>activated macrophages</cell_type> , provide clear evidence for <protein>PPARgamma</protein> as a <protein>negative regulator</protein> of the inflammatory activation of both <cell_type>macrophage</cell_type> and <cell_type>T cells</cell_type> .


PPARgamma may thus be a potential therapeutic target for the treatment of autoimmunity .

<protein>PPARgamma</protein> may thus be a potential therapeutic target for the treatment of autoimmunity .


A prominent role for activator protein-1 in the transcription of the human 2B4 ( CD244 ) gene in NK cells .

A prominent role for <protein>activator protein-1</protein> in the transcription of the <dna>human 2B4 ( CD244 ) gene</dna> in <cell_type>NK cells</cell_type> .


The cell surface glycoprotein 2B4 ( CD244 ) of the Ig superfamily is involved in the regulation of NK and T lymphocyte functions .

The <protein>cell surface glycoprotein 2B4</protein> ( <protein>CD244</protein> ) of the <protein>Ig superfamily</protein> is involved in the regulation of <cell_type>NK</cell_type> and <cell_type>T lymphocyte</cell_type> functions .


We have recently identified CD48 as the high affinity counterreceptor for 2B4 in both mice and humans .

We have recently identified <protein>CD48</protein> as the <protein>high affinity counterreceptor</protein> for <protein>2B4</protein> in both mice and humans .


The cytoplasmic domain of 2B4 associates with src homology 2 domain-containing protein or signaling lymphocyte activation molecule-associated protein , whose mutation is the underlying genetic defect in the X-linked lymphoproliferative syndrome .

The <protein>cytoplasmic domain</protein> of <protein>2B4</protein> associates with <protein>src homology 2 domain-containing protein</protein> or <protein>signaling lymphocyte activation molecule-associated protein</protein> , whose mutation is the underlying genetic defect in the X-linked lymphoproliferative syndrome .


In this study , we report the molecular cloning and characterization of the human 2B4 ( h2B4 ) promoter .

In this study , we report the molecular cloning and characterization of the <dna>human 2B4 ( h2B4 ) promoter</dna> .


Through primer extension analysis , we found that the transcription of the h2B4 gene initiates at multiple start sites .

Through primer extension analysis , we found that the transcription of the <dna>h2B4 gene</dna> initiates at multiple start sites .


We isolated h2B4 genomic clones and PCR amplified the 5 ' untranslated region containing the promoter elements .

We isolated <dna>h2B4 genomic clones</dna> and PCR amplified the <dna>5 ' untranslated region</dna> containing the <dna>promoter elements</dna> .


We have identified a functional AP-1 site that lies between ( -106 to -100 ) through transient transfection analysis in YT cells , a human NK cell line .

We have identified a functional <dna>AP-1 site</dna> that lies between ( -106 to -100 ) through transient transfection analysis in <cell_line>YT cells</cell_line> , a <cell_line>human NK cell line</cell_line> .


EMSAs with Abs specific for various protein factors of the AP-1 family revealed that multiple members of the Jun family are involved in the regulation of the h2B4 gene .

EMSAs with <protein>Abs</protein> specific for various <protein>protein factors</protein> of the <protein>AP-1 family</protein> revealed that multiple members of the <protein>Jun family</protein> are involved in the regulation of the <dna>h2B4 gene</dna> .


Mutation of the AP-1 site not only abolishes protein/DNA interactions but also promoter activity .

Mutation of the <dna>AP-1 site</dna> not only abolishes protein/DNA interactions but also promoter activity .


These results demonstrate a significant role for AP-1 in the transcriptional regulation of the h2B4 gene .

These results demonstrate a significant role for <protein>AP-1</protein> in the transcriptional regulation of the <dna>h2B4 gene</dna> .


Functional correction of FA-C cells with FANCC suppresses the expression of interferon gamma-inducible genes .

Functional correction of <cell_type>FA-C cells</cell_type> with <protein>FANCC</protein> suppresses the expression of <dna>interferon gamma-inducible genes</dna> .


Because hematopoietic cells derived from Fanconi anemia ( FA ) patients of the C-complementation group ( FA-C ) are hypersensitive to the inhibitory effects of interferon gamma ( IFNgamma ) , the products of certain IFNgamma-inducible genes known to influence hematopoietic cell survival were quantified .

Because <cell_type>hematopoietic cells</cell_type> derived from Fanconi anemia ( FA ) patients of the C-complementation group ( FA-C ) are hypersensitive to the inhibitory effects of <protein>interferon gamma</protein> ( <protein>IFNgamma</protein> ) , the products of certain <dna>IFNgamma-inducible genes</dna> known to influence hematopoietic cell survival were quantified .


High constitutive expression of the IFNgamma-inducible genes , IFN-stimulated gene factor 3 gamma subunit ( ISGF3gamma ) , IFN regulatory factor-1 ( IRF-1 ) , and the cyclin-dependent kinase inhibitor p21 ( WAF1 ) was found in FANCC mutant B lymphoblasts , low-density bone marrow cells , and murine embryonic fibroblasts .

High constitutive expression of the <dna>IFNgamma-inducible genes</dna> , <protein>IFN-stimulated gene factor 3 gamma subunit</protein> ( <protein>ISGF3gamma</protein> ) , <protein>IFN regulatory factor-1</protein> ( <protein>IRF-1</protein> ) , and the <protein>cyclin-dependent kinase inhibitor p21</protein> ( <protein>WAF1</protein> ) was found in <protein>FANCC</protein> mutant <cell_type>B lymphoblasts</cell_type> , <cell_type>low-density bone marrow cells</cell_type> , and <cell_type>murine embryonic fibroblasts</cell_type> .


Paradoxically , these cells do not activate signal transducer and activator of transcription ( STAT ) 1 properly .

Paradoxically , these cells do not <protein>activate signal transducer and activator of transcription ( STAT ) 1</protein> properly .


In an attempt to clarify mechanisms by which FA-C cells overexpress IFNgamma-inducible genes in the face of defective STAT1 phosphorylation , it was reasoned that decreased levels of activated STAT1 might result in reduced expression of a hematopoietic IFNgamma-responsive protein that normally modulates expression of other IFNgamma-responsive genes .

In an attempt to clarify mechanisms by which <cell_type>FA-C cells</cell_type> overexpress <dna>IFNgamma-inducible genes</dna> in the face of defective STAT1 phosphorylation , it was reasoned that decreased levels of <protein>activated STAT1</protein> might result in reduced expression of a <protein>hematopoietic IFNgamma-responsive protein</protein> that normally modulates expression of other <dna>IFNgamma-responsive genes</dna> .


Levels of the IFNgamma -inducible factor IFN consensus sequence binding protein ( ICSBP ) , a negative trans-acting regulator of some IFNgamma-inducible genes , were quantified .

Levels of the <protein>IFNgamma</protein> -inducible factor <protein>IFN consensus sequence binding protein</protein> ( <protein>ICSBP</protein> ) , a <protein>negative trans-acting regulator</protein> of some <dna>IFNgamma-inducible genes</dna> , were quantified .


ICSBP levels were reduced in FA-C B lymphoblasts and MEFs .

<protein>ICSBP</protein> levels were reduced in <cell_type>FA-C B lymphoblasts</cell_type> and <cell_type>MEFs</cell_type> .


However , enforced expression of ICSBP failed to down-regulate IRF-1 , ISGF3gamma , and p21 ( WAF1 ) .

However , enforced expression of <protein>ICSBP</protein> failed to down-regulate <protein>IRF-1</protein> , <protein>ISGF3gamma</protein> , and <protein>p21 ( WAF1 )</protein> .


Thus , the FANCC protein functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibition , but it does so independently of the classic IFN-STAT1 pathway and is not the direct result of reduced ICSBP expression .

Thus , the <protein>FANCC protein</protein> functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibition , but it does so independently of the classic IFN-STAT1 pathway and is not the direct result of reduced <protein>ICSBP</protein> expression .


A genetic investigation of E2A function in lymphocyte development .


Lymphocytes are derived from hematopoietic stem cells ( HSC ) following a series of regulated differentiation events .

<cell_type>Lymphocytes</cell_type> are derived from <cell_type>hematopoietic stem cells</cell_type> ( <cell_type>HSC</cell_type> ) following a series of regulated differentiation events .


Multipotent HSCs become committed to the B cell lineage in bone marrow and the T cell lineage in the thymus after receiving appropriate signals from the corresponding microenvironment .

<cell_type>Multipotent HSCs</cell_type> become committed to the <cell_line>B cell lineage</cell_line> in bone marrow and the <cell_line>T cell lineage</cell_line> in the thymus after receiving appropriate signals from the corresponding microenvironment .


These committed lymphoid cells must then undergo V ( D ) J recombination at the immunoglobulin gene or T cell receptor gene locus resulting in clonal production of functional B or T lymphocytes , respectively .

These committed <cell_type>lymphoid cells</cell_type> must then undergo V ( D ) J recombination at the <dna>immunoglobulin gene</dna> or <dna>T cell receptor gene locus</dna> resulting in clonal production of functional <cell_type>B or T lymphocytes</cell_type> , respectively .


Lymphocyte commitment and differentiation are accompanied by programmed gene expression or repression events which are driven by lineage and stage specific transcription factors .

Lymphocyte commitment and differentiation are accompanied by programmed gene expression or repression events which are driven by <protein>lineage and stage specific transcription factors</protein> .


The basic-helix-loop-helix ( bHLH ) transcription factors encoded by the E2A gene are involved in several differentiation events during B and T cell development , including lineage commitment , initiation of V ( D ) J recombination , and antigen receptor mediated proliferation and differentiation .

The <protein>basic-helix-loop-helix ( bHLH ) transcription factors</protein> encoded by the <dna>E2A gene</dna> are involved in several differentiation events during B and T cell development , including lineage commitment , initiation of V ( D ) J recombination , and antigen receptor mediated proliferation and differentiation .


Several recent reviews have provided a comprehensive discussion of biochemical , cellular , and genetic research on E2A function in lymphocyte development ( 1 , 2 ) .


Here , we only discuss some of the genetic approaches our laboratory ( except where it is noted ) has undertaken to investigate the molecular pathways mediated by E2A transcription factors in lymphocyte development

Here , we only discuss some of the genetic approaches our laboratory ( except where it is noted ) has undertaken to investigate the molecular pathways mediated by <protein>E2A transcription factors</protein> in lymphocyte development


D609 inhibits ionizing radiation-induced oxidative damage by acting as a potent antioxidant .


Tricyclodecan-9-yl-xanthogenate ( D609 ) has been extensively studied in biological systems and exhibits a variety of biological functions , including antiviral , antitumor , and anti-inflammatory activities .


Most of these activities have been largely attributed to the inhibitory effect of D609 on phosphatidylcholine-specific phospholipase C .

Most of these activities have been largely attributed to the inhibitory effect of D609 on phosphatidylcholine-specific <protein>phospholipase C</protein> .


However , as a xanthate derivative , D609 is a strong electrolyte and readily dissociates to xanthate anions and cations of alkali metals in solution .


Xanthate anions and protonated xanthic acid contain a free thiol moiety and are highly reductive .


This implies that D609 and other xanthate derivatives may function as potent antioxidants .


Indeed , we found that D609 inhibited the Fenton reaction-induced oxidation of dihydrorhodamine 123 in a dose-dependent manner similar to that of pyrrolidinedithiocarbamate , a well known antioxidant .


In addition , D609 inhibited the formation of the alpha-phenyl-tert-butylnitrone-free radical spin adducts and lipid peroxidation of synaptosomal membranes by the Fenton reagents .


Furthermore , preincubation of lymphocytes with D609 resulted in a significant diminution of ionizing radiation ( IR ) -induced 1 ) production of reactive oxygen species ; 2 ) decrease in intracellular reduced glutathione ; 3 ) oxidative damage to proteins and lipids ; and 4 ) activation of nuclear factor-kappaB .

Furthermore , preincubation of <cell_type>lymphocytes</cell_type> with D609 resulted in a significant diminution of ionizing radiation ( IR ) -induced 1 ) production of reactive oxygen species ; 2 ) decrease in intracellular reduced glutathione ; 3 ) oxidative damage to proteins and lipids ; and 4 ) activation of <protein>nuclear factor-kappaB</protein> .


Moreover , when D609 ( 50 mg/kg i.v. ) was administered to mice 10 min prior to total body IR ( 6.5 and 8.5 Gy ) , it protected the mice from IR-induced lethality .


Thus , these results indicate that D609 is a potent antioxidant and has the ability to inhibit IR-induced cellular oxidative stress .


Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ .

Inhibition of <protein>AP-1</protein> by the glucocorticoid-inducible <protein>protein GILZ</protein> .


The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression , which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP-1 and NF-kappa B as well as by competition for common coactivators .

The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression , which has been ascribed to interference between the <protein>glucocorticoid receptor</protein> and <protein>transcription factors</protein> such as <protein>AP-1</protein> and <protein>NF-kappa B</protein> as well as by competition for common coactivators .


Here we show that glucocorticoid-induced inhibition of interleukin-2 mRNA expression in activated normal T cells required new protein synthesis , suggesting that this phenomenon is secondary to expression of glucocorticoid-regulated genes .

Here we show that glucocorticoid-induced inhibition of interleukin-2 mRNA expression in <cell_type>activated normal T cells</cell_type> required new protein synthesis , suggesting that this phenomenon is secondary to expression of glucocorticoid-regulated <dna>genes</dna> .


One of the most prominent glucocorticoid-induced genes is glucocorticoid-induced leucine zipper ( GILZ ) , which has been reported to inhibit activation-induced up-regulation of Fas ligand ( FasL ) mRNA .

One of the most prominent glucocorticoid-induced <dna>genes</dna> is <dna>glucocorticoid-induced leucine zipper</dna> ( <dna>GILZ</dna> ) , which has been reported to inhibit activation-induced up-regulation of <rna>Fas ligand ( FasL ) mRNA</rna> .


Indeed , transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter .

Indeed , transient expression of <dna>GILZ</dna> in <cell_line>Jurkat T cells</cell_line> blocked induction of a <dna>reporter construct</dna> driven by the <dna>FasL promoter</dna> .


This could be accounted for by GILZ -mediated inhibition of Egr-2 and Egr-3 , NFAT/AP-1 -inducible transcription factors that bind a regulatory element in the FasL promoter and up-regulate FasL expression .

This could be accounted for by <protein>GILZ</protein> -mediated inhibition of <protein>Egr-2</protein> and <protein>Egr-3</protein> , <protein>NFAT/AP-1</protein> -inducible <protein>transcription factors</protein> that bind a <dna>regulatory element</dna> in the <dna>FasL promoter</dna> and up-regulate FasL expression .


GILZ also potently inhibited AP-1-driven and IL-2 promoter-driven reporter constructs , and recombinant GILZ specifically interacted with c-Fos and c-Jun in vitro and inhibited the binding of active AP-1 to its target DNA .

<protein>GILZ</protein> also potently inhibited <dna>AP-1-driven and IL-2 promoter-driven reporter constructs</dna> , and recombinant <protein>GILZ</protein> specifically interacted with <protein>c-Fos</protein> and <protein>c-Jun</protein> in vitro and inhibited the binding of <protein>active AP-1</protein> to its target DNA .


Whereas homodimerization of GILZ required the presence of its leucine zipper , the interaction with c-Fos and c-Jun occurred through the N-terminal 60-amino acid region of GILZ .

Whereas homodimerization of <protein>GILZ</protein> required the presence of its <protein>leucine zipper</protein> , the interaction with <protein>c-Fos</protein> and <protein>c-Jun</protein> occurred through the <protein>N-terminal</protein> <protein>60-amino acid region</protein> of <protein>GILZ</protein> .


Thus , GILZ represents a glucocorticoid-induced gene product that can inhibit a variety of activation-induced events , at least in part by direct interference with AP-1 , and is therefore a candidate for a mediator of glucocorticoid-induced immunosuppression .

Thus , <protein>GILZ</protein> represents a glucocorticoid-induced gene product that can inhibit a variety of activation-induced events , at least in part by direct interference with <protein>AP-1</protein> , and is therefore a candidate for a mediator of glucocorticoid-induced immunosuppression .


Pharmacokinetic differences between a T cell-tolerizing and a T cell-activating peptide .


Vaccination with a peptide representing a CTL epitope from the human papillomavirus ( HPV ) 16 E7 protein induces a specific CTL response that prevents the outgrowth of HPV16 E7-expressing tumors .

Vaccination with a peptide representing a CTL epitope from the human papillomavirus ( HPV ) 16 <protein>E7 protein</protein> induces a specific CTL response that prevents the outgrowth of HPV16 E7-expressing tumors .


In contrast , vaccination with a peptide encoding an adenovirus type 5 ( Ad5 ) E1A CTL epitope results in CTL tolerance and enhanced growth of an Ad5 E1A-expressing tumor .


It is unclear why these peptides induce such opposite effects .


To determine whether a difference in pharmacokinetics can explain the functional contrasts , tritiated Ad5 E1A and HPV16 E7 peptides were injected into mice .


Results show that the tolerizing peptide spread through the body 16 times faster than the activating peptide and was cleared at least 2 times faster .


The HPV16 E7 peptide kinetics correlated with the kinetics of HPV16 E7 -specific CTL induction .

The HPV16 E7 peptide kinetics correlated with the kinetics of <protein>HPV16 E7</protein> -specific CTL induction .


In contrast , Ad5 E1A peptide injection resulted in physical deletion of preexisting Ad5 E1A -specific CTLs within 24 h after injection .

In contrast , Ad5 E1A peptide injection resulted in physical deletion of preexisting <protein>Ad5 E1A</protein> -specific <protein>CTLs</protein> within 24 h after injection .


This tolerization occurred at the time when the peptide reached its maximum peptide concentration in the organs .


These data suggest that ubiquitous expression of the tolerizing Ad5 E1A peptide within a short period of time causes activation-induced cell death of Ad5 E1A -specific CTLs .

These data suggest that ubiquitous expression of the tolerizing Ad5 E1A peptide within a short period of time causes activation-induced cell death of <protein>Ad5 E1A</protein> -specific <protein>CTLs</protein> .


Therefore , information on the pharmacokinetics of peptides is vital for the safety and efficacy of peptide-based vaccines .


Smad3 and Smad4 mediate transforming growth factor-beta1 -induced IgA expression in murine B lymphocytes .

<protein>Smad3</protein> and <protein>Smad4</protein> mediate <protein>transforming growth factor-beta1</protein> -induced IgA expression in <cell_type>murine B lymphocytes</cell_type> .


Transforming growth factor ( TGF ) -beta1 is well established as a critical IgA isotype switching factor and Smad molecules have been reported to act as transducers and transcriptional factors in the expression of TGF-beta1 -targeted genes .

<protein>Transforming growth factor ( TGF ) -beta1</protein> is well established as a critical <protein>IgA isotype switching factor</protein> and <protein>Smad molecules</protein> have been reported to act as <protein>transducers</protein> and <protein>transcriptional factors</protein> in the expression of <protein>TGF-beta1</protein> -targeted <dna>genes</dna> .


We examined the involvement of Smad proteins in TGF-beta1 -induced IgA expression .

We examined the involvement of <protein>Smad proteins</protein> in <protein>TGF-beta1</protein> -induced IgA expression .


First , we found that TGF-beta1 significantly increases endogenous germ-line ( GL ) alpha transcripts by LPS-stimulated CH12.LX.4933 ( mu ( + ) ) B lymphoma cells .

First , we found that <protein>TGF-beta1</protein> significantly increases <rna>endogenous germ-line ( GL ) alpha transcripts</rna> by LPS-stimulated <cell_line>CH12.LX.4933 ( mu ( + ) ) B lymphoma cells</cell_line> .


To investigate its signaling mechanisms , the lymphoma cell line was transfected with pFL3 that contains the TGF-beta-responsive element of the GLalpha promoter , and stimulated with TGF-beta1 .

To investigate its signaling mechanisms , the <cell_line>lymphoma cell line</cell_line> was transfected with <dna>pFL3</dna> that contains the <dna>TGF-beta-responsive element</dna> of the <dna>GLalpha promoter</dna> , and stimulated with <protein>TGF-beta1</protein> .


Similar to endogenous GLalpha transcripts , TGF-beta1 induces GLalpha promoter activity and overexpression of Smad3 markedly enhances the promoter activity .

Similar to <rna>endogenous GLalpha transcripts</rna> , <protein>TGF-beta1</protein> induces <dna>GLalpha promoter</dna> activity and overexpression of <protein>Smad3</protein> markedly enhances the promoter activity .


This activity is further augmented by cotransfected Smad4 .

This activity is further augmented by <protein>cotransfected Smad4</protein> .


On the other hand , Smad7 substantially abrogates the synergistic effect of Smad3/4 on GLalpha promoter activity .

On the other hand , <protein>Smad7</protein> substantially abrogates the synergistic effect of <protein>Smad3/4</protein> on <dna>GLalpha promoter</dna> activity .


In addition , overexpression of Smad3/4 enhances TGF-beta1 -induced endogenous GLalpha transcripts in normal spleen B cell s .

In addition , overexpression of <protein>Smad3/4</protein> enhances <protein>TGF-beta1</protein> -induced <rna>endogenous GLalpha transcripts</rna> in <cell_type>normal spleen B cell</cell_type> s .


Finally , in the presence of TGF-beta1 , overexpression of Smad3/4 selectively increases both surface IgA expression and IgA production .

Finally , in the presence of <protein>TGF-beta1</protein> , overexpression of <protein>Smad3/4</protein> selectively increases both surface IgA expression and IgA production .


The results from the present study indicate that Smad3 , Smad4 , and Smad7 , at least in part , serve as mediators linking TGF-beta1 to transcriptional regulation of IgA switching related gene and regulation of IgA class switching .

The results from the present study indicate that <protein>Smad3</protein> , <protein>Smad4</protein> , and <protein>Smad7</protein> , at least in part , serve as mediators linking <protein>TGF-beta1</protein> to transcriptional regulation of <dna>IgA switching related gene</dna> and regulation of IgA class switching .


The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation .

The <protein>translesion DNA polymerase zeta</protein> plays a major role in Ig and bcl-6 somatic hypermutation .


Ig somatic mutations would be introduced by a polymerase ( pol ) while repairing DNA outside main DNA replication .

Ig somatic mutations would be introduced by a <protein>polymerase</protein> ( <protein>pol</protein> ) while repairing DNA outside main DNA replication .


We show that human B cells constitutively express the translesion pol zeta , which effectively extends DNA past mismatched bases ( mispair extender ) , and pol eta , which bypasses DNA lesions in an error-free fashion .

We show that <cell_type>human B cells</cell_type> constitutively express the <protein>translesion pol zeta</protein> , which effectively extends DNA past mismatched bases ( mispair extender ) , and <protein>pol eta</protein> , which bypasses DNA lesions in an error-free fashion .


Upon B cell receptor ( BCR ) engagement and coculture with activated CD4+ T cells , these lymphocytes upregulated pol zeta , downregulated pol eta , and mutated the Ig and bcl-6 genes .

Upon <protein>B cell receptor</protein> ( <protein>BCR</protein> ) engagement and coculture with <cell_type>activated CD4+ T cells</cell_type> , these <cell_type>lymphocytes</cell_type> upregulated <protein>pol zeta</protein> , downregulated <protein>pol eta</protein> , and mutated the <dna>Ig and bcl-6 genes</dna> .


Inhibition of the pol zeta REV3 catalytic subunit by specific phosphorothioate-modified oligonucleotides impaired Ig and bcl-6 hypermutation and UV damage-induced DNA mutagenesis , without affecting cell cycle or viability .

Inhibition of the <protein>pol zeta</protein> <protein>REV3 catalytic subunit</protein> by specific phosphorothioate-modified oligonucleotides impaired Ig and bcl-6 hypermutation and UV damage-induced DNA mutagenesis , without affecting cell cycle or viability .


Thus , pol zeta plays a critical role in Ig and bcl-6 hypermutation , perhaps facilitated by the downregulation of pol eta .

Thus , <protein>pol zeta</protein> plays a critical role in Ig and bcl-6 hypermutation , perhaps facilitated by the downregulation of <protein>pol eta</protein> .


Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I .

Molecular mechanism of cell cycle progression induced by the <protein>oncogene product Tax</protein> of human T-cell leukemia virus type I .


The trans-activator protein Tax of human T-cell leukemia virus type I ( HTLV-I ) plays an important role in the development of adult T-cell leukemia through , at least in part , its ability to stimulate cell growth .

The <protein>trans-activator protein Tax</protein> of human T-cell leukemia virus type I ( HTLV-I ) plays an important role in the development of adult T-cell leukemia through , at least in part , its ability to stimulate cell growth .


We previously reported that Tax induced cell cycle progression from G0/G1 phase to S and G2/M phases in human T-cell line Kit 225 cells .

We previously reported that <protein>Tax</protein> induced cell cycle progression from G0/G1 phase to S and G2/M phases in <cell_line>human T-cell line Kit 225 cells</cell_line> .


To elucidate molecular mechanism of Tax -induced cell cycle progression , we systematically examined the effects of Tax on biochemical events associated with cell cycle progression .

To elucidate molecular mechanism of <protein>Tax</protein> -induced cell cycle progression , we systematically examined the effects of <protein>Tax</protein> on biochemical events associated with cell cycle progression .


Introduction of Tax into resting Kit 225 cells induced activation of the G1/S transition regulation cascade consisting of activation of cyclin dependent kinase 2 ( CDK2 ) and CDK4 , phosphorylation of the Rb family proteins and an increase in free E2F .

Introduction of <protein>Tax</protein> into <cell_line>resting Kit 225 cells</cell_line> induced activation of the G1/S transition regulation cascade consisting of activation of <protein>cyclin dependent kinase 2</protein> ( <protein>CDK2</protein> ) and <protein>CDK4</protein> , phosphorylation of the <protein>Rb family proteins</protein> and an increase in free <protein>E2F</protein> .


The kinase activation was found to result from Tax -induced expression of genes for cell cycle regulatory molecules including cyclin D2 , cyclin E , E2F1 , CDK2 , CDK4 and CDK6 , and Tax -induced reduction of CDK inhibitors p19 ( INK4d ) and p27 ( Kip1 ) .

The kinase activation was found to result from <protein>Tax</protein> -induced expression of genes for <protein>cell cycle regulatory molecules</protein> including <protein>cyclin D2</protein> , <protein>cyclin E</protein> , <protein>E2F1</protein> , <protein>CDK2</protein> , <protein>CDK4</protein> and <protein>CDK6</protein> , and <protein>Tax</protein> -induced reduction of <protein>CDK inhibitors p19</protein> ( <protein>INK4d</protein> ) and <protein>p27 ( Kip1 )</protein> .


These modulations by Tax always paralleled the ability of Tax to activate the NF-kappaB transcription pathway .

These modulations by <protein>Tax</protein> always paralleled the ability of <protein>Tax</protein> to activate the NF-kappaB transcription pathway .


These results indicate the important role of Tax -mediated trans-activation of the genes for cell cycle regulatory molecules in Tax -induced cell cycle progression .

These results indicate the important role of <protein>Tax</protein> -mediated trans-activation of the genes for <protein>cell cycle regulatory molecules</protein> in <protein>Tax</protein> -induced cell cycle progression .


Cot kinase induces cyclooxygenase-2 expression in T cells through activation of the nuclear factor of activated T cells .

<protein>Cot kinase</protein> induces cyclooxygenase-2 expression in <cell_type>T cells</cell_type> through activation of the <protein>nuclear factor of activated T cells</protein> .


Cyclooxygenase-2 ( COX-2 ) is induced in human T lymphocytes upon T cell receptor triggering .

<protein>Cyclooxygenase-2</protein> ( <protein>COX-2</protein> ) is induced in <cell_type>human T lymphocytes</cell_type> upon <protein>T cell receptor</protein> triggering .


Here we report that Cot kinase , a mitogen-activated protein kinase kinase kinase involved in T cell activation , up-regulates COX-2 gene expression in Jurkat T cells .

Here we report that <protein>Cot kinase</protein> , a <protein>mitogen-activated protein kinase kinase kinase</protein> involved in T cell activation , up-regulates <dna>COX-2 gene</dna> expression in <cell_line>Jurkat T cells</cell_line> .


Induction of COX-2 promoter activity by Cot kinase occurred mainly through activation of the nuclear factor of activated T cells ( NFAT ) .

Induction of COX-2 promoter activity by <protein>Cot kinase</protein> occurred mainly through activation of the <protein>nuclear factor of activated T cells</protein> ( <protein>NFAT</protein> ) .


Mutation of the distal ( -105/-97 ) and proximal ( -76/-61 ) NFAT response elements in the COX-2 promoter abolished the activation induced by Cot kinase .

Mutation of the <dna>distal ( -105/-97 )</dna> and <dna>proximal ( -76/-61 )</dna> <dna>NFAT response elements</dna> in the <dna>COX-2 promoter</dna> abolished the activation induced by <protein>Cot kinase</protein> .


Even more , coexpression of a dominant negative version of NFAT inhibited Cot kinase -mediated COX-2 promoter activation , whereas cotransfection of a constitutively active version of the calcium-dependent phosphatase calcineurin synergizes with Cot kinase in the up-regulation of COX-2 promoter -driven transcription .

Even more , coexpression of a dominant negative version of <protein>NFAT</protein> inhibited <protein>Cot kinase</protein> -mediated <dna>COX-2 promoter</dna> activation , whereas cotransfection of a constitutively active version of the <protein>calcium-dependent phosphatase calcineurin</protein> synergizes with <protein>Cot kinase</protein> in the up-regulation of <dna>COX-2 promoter</dna> -driven transcription .


Strikingly , Cot kinase increased transactivation mediated by a GAL4-NFAT fusion protein containing the N-terminal transactivation domain of NFATp .

Strikingly , <protein>Cot kinase</protein> increased transactivation mediated by a <protein>GAL4-NFAT fusion protein</protein> containing the <protein>N-terminal transactivation domain</protein> of <protein>NFATp</protein> .


In contrast to phorbol ester plus calcium ionophore A23187 , Cot kinase increases both COX-2 promoter activity and NFAT -mediated transactivation in a cyclosporin A-independent manner .

In contrast to phorbol ester plus calcium ionophore A23187 , <protein>Cot kinase</protein> increases both <dna>COX-2 promoter</dna> activity and <protein>NFAT</protein> -mediated transactivation in a cyclosporin A-independent manner .


These data indicate that Cot kinase up-regulates COX-2 promoter -driven transcription through the NFAT response elements , being the Cot kinase -induced NFAT -dependent transactivation presumably implicated in this up-regulation .

These data indicate that <protein>Cot kinase</protein> up-regulates <dna>COX-2 promoter</dna> -driven transcription through the <dna>NFAT response elements</dna> , being the <protein>Cot kinase</protein> -induced <protein>NFAT</protein> -dependent transactivation presumably implicated in this up-regulation .


Positive and negative roles of the trans-acting T cell factor-1 for the acquisition of distinct Ly-49 MHC class I receptors by NK cells .

Positive and negative roles of the <protein>trans-acting T cell factor-1</protein> for the acquisition of distinct <protein>Ly-49 MHC class I receptors</protein> by <cell_type>NK cells</cell_type> .


Members of the Ly-49 gene family code for class I MHC-specific receptors that regulate NK cell function .

Members of the <dna>Ly-49 gene family</dna> code for <protein>class I MHC-specific receptors</protein> that regulate NK cell function .


Due to a combinatorial distribution of Ly-49 receptors , NK cells display considerable clonal heterogeneity .

Due to a combinatorial distribution of <protein>Ly-49 receptors</protein> , <cell_type>NK cells</cell_type> display considerable clonal heterogeneity .


The acquisition of one Ly-49 receptor , Ly-49A is strictly dependent on the transcriptional trans-acting factor T cell-specific factor-1 ( TCF-1 ) .

The acquisition of one <protein>Ly-49 receptor</protein> , <protein>Ly-49A</protein> is strictly dependent on the <protein>transcriptional trans-acting factor</protein> <protein>T cell-specific factor-1</protein> ( <protein>TCF-1</protein> ) .


Indeed , TCF-1 binds to two sites in the Ly-49a promoter and regulates its activity , suggesting that the Ly-49a gene is a direct TCF-1 target .

Indeed , <protein>TCF-1</protein> binds to two sites in the <dna>Ly-49a promoter</dna> and regulates its activity , suggesting that the <dna>Ly-49a gene</dna> is a direct <protein>TCF-1</protein> target .


TCF-1 deficiency resulted in the altered usage of additional Ly-49 receptors .

<protein>TCF-1</protein> deficiency resulted in the altered usage of additional <protein>Ly-49 receptors</protein> .


We show in this study , using TCF-1 beta ( 2 ) -microglobulin double-deficient mice , that these repertoire alterations are not due to Ly-49/MHC class I interactions .

We show in this study , using <protein>TCF-1 beta ( 2 ) -microglobulin</protein> double-deficient mice , that these repertoire alterations are not due to Ly-49/MHC class I interactions .


Our findings rather suggest a TCF-1 -dependent , cell autonomous effect on the acquisition of multiple Ly-49 receptors .

Our findings rather suggest a <protein>TCF-1</protein> -dependent , cell autonomous effect on the acquisition of multiple <protein>Ly-49 receptors</protein> .


Besides reduced receptor usage ( Ly-49A and D ) , we also observed no effect ( Ly-49C ) and significantly expanded ( Ly-49G and I ) receptor usage in the absence of TCF-1 .

Besides reduced receptor usage ( <protein>Ly-49A and D</protein> ) , we also observed no effect ( <protein>Ly-49C</protein> ) and significantly expanded ( <protein>Ly-49G and I</protein> ) receptor usage in the absence of <protein>TCF-1</protein> .


These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter .

These effects did not in all cases correlate with the presence of <dna>TCF binding sites</dna> in the respective <dna>proximal promoter</dna> .


Therefore , besides TCF-1 binding to the proximal promoter , Ly-49 acquisition may also be regulated by TCF-1 binding to more distant cis-acting elements and/or by regulating the expression of additional trans-acting factors .

Therefore , besides <protein>TCF-1</protein> binding to the <dna>proximal promoter</dna> , Ly-49 acquisition may also be regulated by <protein>TCF-1</protein> binding to more distant <dna>cis-acting elements</dna> and/or by regulating the expression of additional <dna>trans-acting factors</dna> .


Consistent with the observed differential , positive or negative role of TCF-1 for Ly-49 receptor acquisition , reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly-49 promoters .

Consistent with the observed differential , positive or negative role of <protein>TCF-1</protein> for <protein>Ly-49 receptor</protein> acquisition , reporter gene assays revealed the presence of an inducing as well as a repressing <dna>TCF site</dna> in certain proximal <dna>Ly-49 promoters</dna> .


These findings reveal an important role of TCF-1 for the formation of the NK cell receptor repertoire .

These findings reveal an important role of <protein>TCF-1</protein> for the formation of the <protein>NK cell receptor</protein> repertoire .


Ligation of CD11b and CD11c beta ( 2 ) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha ( MIP-1alpha ) and MIP-1beta production in primary human monocytes through a pathway dependent on nuclear factor-kappaB .

Ligation of <protein>CD11b</protein> and <protein>CD11c beta ( 2 )</protein> <protein>integrins</protein> by <protein>antibodies</protein> or <protein>soluble CD23</protein> induces <protein>macrophage inflammatory protein 1alpha</protein> ( <protein>MIP-1alpha</protein> ) and <protein>MIP-1beta</protein> production in <cell_type>primary human monocytes</cell_type> through a pathway dependent on <protein>nuclear factor-kappaB</protein> .


Chemokines and adhesion molecules such as integrins play a major part in the trafficking , extravasation , and recruitment of leukocytes to inflammatory sites .

<protein>Chemokines</protein> and <protein>adhesion molecules</protein> such as <protein>integrins</protein> play a major part in the trafficking , extravasation , and recruitment of <cell_type>leukocytes</cell_type> to inflammatory sites .


This study investigated the effects of beta ( 2 ) integrin engagement on chemokine production by freshly isolated human monocytes .

This study investigated the effects of beta ( 2 ) integrin engagement on chemokine production by <cell_type>freshly isolated human monocytes</cell_type> .


We found that ligation of CD11b or CD11c but not CD11a alpha chains of beta ( 2 ) integrins by antibodies or soluble CD23 ( sCD23 ) fusion proteins rapidly induced transcription and secretion of interleukin 8 , macrophage inflammatory protein ( MIP ) 1alpha , and MIP-1beta .

We found that ligation of <protein>CD11b</protein> or <protein>CD11c</protein> but not <protein>CD11a alpha chains</protein> of <protein>beta ( 2 ) integrins</protein> by <protein>antibodies</protein> or <protein>soluble CD23 ( sCD23 ) fusion proteins</protein> rapidly induced transcription and secretion of <protein>interleukin 8</protein> , <protein>macrophage inflammatory protein ( MIP ) 1alpha</protein> , and <protein>MIP-1beta</protein> .


Because the promoters of these chemokine genes contain kappaB binding sites , we assessed the possible role of nuclear factor-kappaB ( NF-kappaB ) in controlling induction of the genes through beta ( 2 ) integrin engagement .

Because the <dna>promoters</dna> of these <dna>chemokine genes</dna> contain <dna>kappaB binding sites</dna> , we assessed the possible role of <protein>nuclear factor-kappaB</protein> ( <protein>NF-kappaB</protein> ) in controlling induction of the genes through beta ( 2 ) integrin engagement .


Electrophoretic mobility shift assays showed that sCD23 or antibodies to CD11b or to CD11c up-regulated DNA-binding activity of NF-kappaB .

Electrophoretic mobility shift assays showed that <protein>sCD23</protein> or <protein>antibodies</protein> to <protein>CD11b</protein> or to <protein>CD11c</protein> up-regulated DNA-binding activity of <protein>NF-kappaB</protein> .


Activation of NF-kappaB was accompanied by degradation of its cytosolic inhibitor IkappaB-alpha .

Activation of <protein>NF-kappaB</protein> was accompanied by degradation of its <protein>cytosolic inhibitor IkappaB-alpha</protein> .


Blockade of depletion of IkappaB-alpha by proteasome inhibitors ( proteasome inhibitor I or acetyl-leucinyl-leucinyl-norleucinal ) led to concomitant inhibition of NF-kappaB DNA-binding activity and expression of MIP-1alpha and MIP-1beta messenger RNA induced by beta ( 2 ) integrin ligation .

Blockade of depletion of <protein>IkappaB-alpha</protein> by proteasome inhibitors ( proteasome inhibitor I or acetyl-leucinyl-leucinyl-norleucinal ) led to concomitant inhibition of NF-kappaB DNA-binding activity and expression of <rna>MIP-1alpha and MIP-1beta messenger RNA</rna> induced by beta ( 2 ) integrin ligation .


These results suggest that triggering of CD11b or CD11c beta ( 2 ) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF-kappaB and subsequent secretion of MIP-1alpha and MIP-1beta that may have an important role in recruitment of other inflammatory cells during initiation of an inflammatory response

These results suggest that triggering of <protein>CD11b</protein> or <protein>CD11c beta ( 2 )</protein> integrin on <cell_type>primary human monocytes</cell_type> provides activation signals leading to nuclear translocation of <protein>NF-kappaB</protein> and subsequent secretion of <protein>MIP-1alpha</protein> and <protein>MIP-1beta</protein> that may have an important role in recruitment of other <cell_type>inflammatory cells</cell_type> during initiation of an inflammatory response


Synergistic transcriptional activation of human Acyl-coenzyme A : cholesterol acyltransterase-1 gene by interferon-gamma and all-trans-retinoic acid THP-1 cells .

Synergistic transcriptional activation of <dna>human Acyl-coenzyme A : cholesterol acyltransterase-1 gene</dna> by <protein>interferon-gamma</protein> and all-trans-retinoic acid <cell_type>THP-1 cells</cell_type> .


Acyl-coenzyme A : cholesterol acyltransferase ( ACAT ) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation .

<protein>Acyl-coenzyme A : cholesterol acyltransferase</protein> ( <protein>ACAT</protein> ) is an <protein>intracellular enzyme</protein> involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation .


Human ACAT-1 gene contains two promoters ( P1 and P7 ) , each located in a different chromosome ( 1 and 7 ) ( Li , B. L. , Li , X. L. , Duan , Z. J. , Lee , O. , Lin , S. , Ma , Z. M. , Chang , C. C. , Yang , X. Y. , Park , J. P. , Mohandas , T. K. , Noll , W. , Chan , L. , and Chang , T. Y. ( 1999 ) J. Biol Chem. 274 , 11060-11071 ) .

<dna>Human ACAT-1 gene</dna> contains two <dna>promoters</dna> ( <dna>P1</dna> and <dna>P7</dna> ) , each located in a different <dna>chromosome ( 1 and 7 )</dna> ( Li , B. L. , Li , X. L. , Duan , Z. J. , Lee , O. , Lin , S. , Ma , Z. M. , Chang , C. C. , Yang , X. Y. , Park , J. P. , Mohandas , T. K. , Noll , W. , Chan , L. , and Chang , T. Y. ( 1999 ) J. Biol Chem. 274 , 11060-11071 ) .


Interferon-gamma ( IFN-gamma ) , a cytokine that exerts many pro-atherosclerotic effects in vivo , causes up-regulation of ACAT-1 mRNA in human blood monocyte-derived macrophages and macrophage-like cells but not in other cell types .

<protein>Interferon-gamma</protein> ( <protein>IFN-gamma</protein> ) , a <protein>cytokine</protein> that exerts many pro-atherosclerotic effects in vivo , causes up-regulation of <rna>ACAT-1 mRNA</rna> in <cell_type>human blood monocyte-derived macrophages</cell_type> and <cell_type>macrophage-like cells</cell_type> but not in other cell types .


To examine the molecular nature of this observation , we identified within the ACAT-1 P1 promoter a 159-base pair core region .

To examine the molecular nature of this observation , we identified within the <dna>ACAT-1 P1 promoter</dna> a <dna>159-base pair core region</dna> .