T-cell prolymphocytic leukemia ( T-PLL ) , a rare form of mature T-cell leukemias , and ataxia telangiectasia clonal proliferation , a related condition occurring in patients suffering from ataxia telangiectasia , have been associated to translocations involving the 14q32.1 or Xq28 regions , where are located the TCL1 and MTCP1 putative oncogenes , respectively .

T-cell prolymphocytic leukemia ( T-PLL ) , a rare form of mature T-cell leukemias , and ataxia telangiectasia clonal proliferation , a related condition occurring in patients suffering from ataxia telangiectasia , have been associated to translocations involving the <dna>14q32.1</dna> or <dna>Xq28 regions</dna> , where are located the <dna>TCL1 and MTCP1 putative oncogenes</dna> , respectively .


The MTCP1 gene is involved in the t ( X ; 14 ) ( q28 ; q11 ) translocation associated with these T-cell proliferations .

The <dna>MTCP1 gene</dna> is involved in the <dna>t ( X ; 14 ) ( q28 ; q11 ) translocation</dna> associated with these T-cell proliferations .


Alternative splicing generates type A and B transcripts that potentially encode two entirely distinct proteins ; type A transcripts code for a small mitochondrial protein , p8MTCP1 , and type B transcripts , containing an additional open reading frame , may code for 107 amino-acid protein , p13MTCP1 .

Alternative splicing generates <rna>type A and B transcripts</rna> that potentially encode two entirely distinct proteins ; type <rna>A transcripts</rna> code for a small <protein>mitochondrial protein</protein> , <protein>p8MTCP1</protein> , and <rna>type B transcripts</rna> , containing an additional <dna>open reading frame</dna> , may code for <protein>107 amino-acid protein</protein> , <protein>p13MTCP1</protein> .


The recently cloned TCL1 gene , also involved in translocations and inversions associated with T-cell proliferations , codes for a 14-kD protein that displays significant homology with p13MTCP1 .

The recently cloned <dna>TCL1 gene</dna> , also involved in translocations and inversions associated with T-cell proliferations , codes for a <protein>14-kD protein</protein> that displays significant homology with <protein>p13MTCP1</protein> .


We have generated rabbit antisera against this putative p13MTCP1 protein and screened for expression of p13MTCP1 normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations using a sensitive Western blot assay .

We have generated rabbit antisera against this putative <protein>p13MTCP1 protein</protein> and screened for expression of <protein>p13MTCP1</protein> normal lymphoid tissues and 33 cases of <cell_type>immature and mature lymphoid T-cell proliferations</cell_type> using a sensitive Western blot assay .


We also investigated the MTCP1 locus configuration by Southern blot analysis .

We also investigated the <dna>MTCP1 locus</dna> configuration by Southern blot analysis .


The p13MTCP1 protein was detected in the three T-cell proliferations with MTCP1 rearrangements because of t ( X ; 14 ) translocations , but neither in normal resting and activated lymphocytes nor in the other T-cell leukemias .

The <protein>p13MTCP1 protein</protein> was detected in the three T-cell proliferations with <dna>MTCP1 rearrangements</dna> because of t ( X ; 14 ) translocations , but neither in normal resting and <cell_type>activated lymphocytes</cell_type> nor in the other <cell_type>T-cell</cell_type> leukemias .


Our data support the hypothesis that p13MTCP1 and p14TCL1 form a new protein family that plays a key role in the pathogenesis of T-PLL and related conditions .

Our data support the hypothesis that <protein>p13MTCP1</protein> and <protein>p14TCL1</protein> form a new <protein>protein family</protein> that plays a key role in the pathogenesis of T-PLL and related conditions .


Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation .

Preassociation of <protein>STAT1</protein> with <protein>STAT2</protein> and <protein>STAT3</protein> in separate <protein>signalling complexes</protein> prior to <protein>cytokine</protein> stimulation .


A variety of cytokines and growth factors act through an induction of gene expression mediated by a family of latent transcription factors called STAT ( signal transducers and activators of transcription ) proteins .

A variety of <protein>cytokines</protein> and <protein>growth factors</protein> act through an induction of gene expression mediated by a family of <protein>latent transcription factors</protein> called <protein>STAT ( signal transducers and activators of transcription ) proteins</protein> .


Ligand-induced tyrosine phosphorylation of the STATs promotes their homodimer and heterodimer formation and subsequent nuclear translocation .

Ligand-induced tyrosine phosphorylation of the <protein>STATs</protein> promotes their homodimer and heterodimer formation and subsequent nuclear translocation .


We demonstrate here that STAT protein heterocomplexes exist prior to cytokine treatment .

We demonstrate here that <protein>STAT protein heterocomplexes</protein> exist prior to <protein>cytokine</protein> treatment .


When unstimulated HeLa cells are ruptured in hypotonic buffer without salt or detergent , immunoadsorption of either STAT1 or STAT2 from the resulting cytosol yields coimmunoadsorption of the other STAT protein .

When <cell_line>unstimulated HeLa cells</cell_line> are ruptured in hypotonic buffer without salt or detergent , immunoadsorption of either <protein>STAT1</protein> or <protein>STAT2</protein> from the resulting cytosol yields coimmunoadsorption of the other <protein>STAT protein</protein> .


Similarly , STAT1 -STAT3 heterocomplexes are coimmunoadsorbed from hypotonic cytosol .

Similarly , <protein>STAT1</protein> <protein>-STAT3</protein> heterocomplexes are coimmunoadsorbed from hypotonic cytosol .


STAT1 and STAT2 or STAT1 and STAT3 translated in reticulocyte lysate spontaneously form heterocomplexes when the translation lysates are mixed at 0 degrees C .

<protein>STAT1</protein> and <protein>STAT2</protein> or <protein>STAT1</protein> and <protein>STAT3</protein> translated in reticulocyte lysate spontaneously form heterocomplexes when the translation lysates are mixed at 0 degrees C .


Our data suggest that interferon-alpha /beta-induced tyrosine phosphorylation increases the stability of a preexisting , latent , STAT1 - STAT2 signaling complex .

Our data suggest that <protein>interferon-alpha</protein> /beta-induced tyrosine phosphorylation increases the stability of a preexisting , latent , <protein>STAT1</protein> - <protein>STAT2 signaling complex</protein> .


Newly translated STAT1 binds in equilibrium fashion to STAT2 and STAT3 , but we show that STAT2 and STAT3 exist in separate heterocomplexes with STAT1 , consistent with a model in which STAT1 contains a common binding site for other STAT proteins .

Newly translated <protein>STAT1</protein> binds in equilibrium fashion to <protein>STAT2</protein> and <protein>STAT3</protein> , but we show that <protein>STAT2</protein> and <protein>STAT3</protein> exist in separate <protein>heterocomplexes</protein> with <protein>STAT1</protein> , consistent with a model in which <protein>STAT1</protein> contains a common binding site for other <protein>STAT proteins</protein> .


Interferon-gamma modulates the lipopolysaccharide-induced expression of AP-1 and NF-kappa B at the mRNA and protein level in human monocytes .

<protein>Interferon-gamma</protein> modulates the lipopolysaccharide-induced expression of <protein>AP-1</protein> and <protein>NF-kappa B</protein> at the mRNA and protein level in <cell_type>human monocytes</cell_type> .


Interferon-gamma ( IFN-gamma ) modulates the expression of several cytokines by human monocytes at the transcriptional level .

<protein>Interferon-gamma</protein> ( <protein>IFN-gamma</protein> ) modulates the expression of several <protein>cytokines</protein> by <cell_type>human monocytes</cell_type> at the transcriptional level .


In view of these findings , we analyzed the effects of IFN-gamma on the expression of different transcription factors in activated human monocytes .

In view of these findings , we analyzed the effects of <protein>IFN-gamma</protein> on the expression of different <protein>transcription factors</protein> in activated <cell_type>human monocytes</cell_type> .


Priming of human monocytes with IFN-gamma resulted in the down regulation of c-fos and c-jun mRNA in response to stimulation with lipopolysaccharide ( LPS ) compared to the effects of LPS alone .

Priming of <cell_type>human monocytes</cell_type> with <protein>IFN-gamma</protein> resulted in the down regulation of <rna>c-fos and c-jun mRNA</rna> in response to stimulation with lipopolysaccharide ( LPS ) compared to the effects of LPS alone .


Not only was this effect observed at the mRNA level , but activator protein-1 ( AP-1 ) DNA binding capacity was affected as well , A strong reduction was observed in the LPS-induced DNA-binding activity of AP-1 in the presence of IFN-gamma .

Not only was this effect observed at the mRNA level , but <protein>activator protein-1</protein> ( <protein>AP-1</protein> ) DNA binding capacity was affected as well , A strong reduction was observed in the LPS-induced DNA-binding activity of <protein>AP-1</protein> in the presence of <protein>IFN-gamma</protein> .


LPS-stimulated monocytes showed an increased expression of p105 mRNA , the precursor of the p50 subunit of the transcription factor nuclear factor-kappa B ( NF-kappa B ) , while no effect was noticed on the expression of p65 mRNA .

<cell_type>LPS-stimulated monocytes</cell_type> showed an increased expression of <rna>p105 mRNA</rna> , the precursor of the <protein>p50 subunit</protein> of the <protein>transcription factor nuclear factor-kappa B</protein> ( <protein>NF-kappa B</protein> ) , while no effect was noticed on the expression of <rna>p65 mRNA</rna> .


In contrast , IFN-gamma priming did not affect the expression of p105 transcripts but enhanced the expression of p65 mRNA ( two-fold ) .

In contrast , <protein>IFN-gamma</protein> priming did not affect the expression of <rna>p105 transcripts</rna> but enhanced the expression of <rna>p65 mRNA</rna> ( two-fold ) .


Priming with IFN-gamma followed by LPS stimulation resulted in a further increase in the expression of p65 mRNA .

Priming with <protein>IFN-gamma</protein> followed by LPS stimulation resulted in a further increase in the expression of <rna>p65 mRNA</rna> .


This was due to an increase in the half-life of p65 mRNA ( 75 vs 150 minutes ) .

This was due to an increase in the half-life of <rna>p65 mRNA</rna> ( 75 vs 150 minutes ) .


Electrophoretic mobility shift assays ( EMSAs ) demonstrated that unstimulated monocytes predominantly expressed p50 NF-kappa B .

Electrophoretic mobility shift assays ( EMSAs ) demonstrated that unstimulated monocytes predominantly expressed <protein>p50</protein> <protein>NF-kappa B</protein> .


Stimulation with LPS or IFN-gamma resulted in the expression of p50 and p65 subunits , while the combination of IFN-gamma plus LPS caused a further increase in the expression of NF-kappa B .

Stimulation with LPS or <protein>IFN-gamma</protein> resulted in the expression of <protein>p50</protein> and <protein>p65 subunits</protein> , while the combination of <protein>IFN-gamma</protein> plus LPS caused a further increase in the expression of <protein>NF-kappa B</protein> .


With Western blotting , it was shown that nuclear extracts from monocytes contained p50 and p65 protein in response to LPS and IFN-gamma stimulation .

With Western blotting , it was shown that nuclear extracts from <cell_type>monocytes</cell_type> contained <protein>p50</protein> and <protein>p65 protein</protein> in response to LPS and <protein>IFN-gamma</protein> stimulation .


However , the combined stimulation did not result in enhanced p50 and p65 protein expression .

However , the combined stimulation did not result in enhanced <protein>p50</protein> and <protein>p65 protein</protein> expression .


The effects of IFN-gamma on the transcription factors were specific , since no change was observed in the expression of NF-IL-6 or I kappa B alpha , the inhibitor of NF-kappa B .

The effects of <protein>IFN-gamma</protein> on the <protein>transcription factors</protein> were specific , since no change was observed in the expression of <protein>NF-IL-6</protein> or <protein>I kappa B alpha</protein> , the inhibitor of <protein>NF-kappa B</protein> .


We conclude that the effects of IFN-gamma on the expression of the transcription factors AP-1 and NF-kappa B may be important for the modulatory effects of IFN-gamma on the cytokine expression in activated human monocytes .

We conclude that the effects of <protein>IFN-gamma</protein> on the expression of the <protein>transcription factors</protein> <protein>AP-1</protein> and <protein>NF-kappa B</protein> may be important for the modulatory effects of <protein>IFN-gamma</protein> on the <protein>cytokine</protein> expression in activated <cell_type>human monocytes</cell_type> .


HIV-1 tat induces the expression of a new hematopoietic cell-specific transcription factor and downregulates MIP-1 alpha gene expression in activated T-cells .

<protein>HIV-1 tat</protein> induces the expression of a new <protein>hematopoietic cell-specific transcription factor</protein> and downregulates <dna>MIP-1 alpha gene</dna> expression in <cell_type>activated T-cells</cell_type> .


MIP-1 alpha is a secreted chemokine which can inhibit hematopoietic stem cells and modulate inflammatory responses .

<protein>MIP-1 alpha</protein> is a secreted <protein>chemokine</protein> which can inhibit <cell_type>hematopoietic stem cells</cell_type> and modulate inflammatory responses .


It is also an inhibitor of HIV replication in CD8+ T-cells .

It is also an inhibitor of HIV replication in <cell_type>CD8+ T-cells</cell_type> .


The expression of MIP-1 alpha is induced during cellular activation of CD4+ T-cells and monocytes .

The expression of <protein>MIP-1 alpha</protein> is induced during cellular activation of <cell_type>CD4+ T-cells</cell_type> and <cell_type>monocytes</cell_type> .


It is also expressed in transformed B-cells .

It is also expressed in <cell_line>transformed B-cells</cell_line> .


We have previously identified a new transcription factor family ( the MNP family ) whose expression is crucial for the induction of MIP-1 alpha transcription during cellular activation and in transformed B cells .

We have previously identified a new <protein>transcription factor family</protein> ( the <protein>MNP family</protein> ) whose expression is crucial for the induction of <protein>MIP-1 alpha</protein> transcription during cellular activation and in <cell_line>transformed B cells</cell_line> .


Monocytes and transformed B-cells normally express MNP-1 strongly and MNP-2 weakly , while T-cells strongly express only MNP-2 .

Monocytes and <cell_line>transformed B-cells</cell_line> normally express <protein>MNP-1</protein> strongly and <protein>MNP-2</protein> weakly , while T-cells strongly express only <protein>MNP-2</protein> .


Recently , we reported that HIV-1 tat downregulates MIP-1 alpha expression in Jurkat T-cells .

Recently , we reported that <protein>HIV-1 tat</protein> downregulates <protein>MIP-1 alpha</protein> expression in <cell_line>Jurkat T-cells</cell_line> .


In this report we show induction of MNP-1 in Jurkat T-cells expressing HIV-1 tat .

In this report we show induction of <protein>MNP-1</protein> in <cell_line>Jurkat T-cells</cell_line> expressing <protein>HIV-1 tat</protein> .


Expression of neither HTLV-1 tax in Jurkat T-cells nor EBV in B-cells had any effect on MNP-1 or MNP-2 expression , showing that the effect is specific for HIV-1 tat .

Expression of neither <protein>HTLV-1 tax</protein> in <cell_line>Jurkat T-cells</cell_line> nor EBV in <cell_type>B-cells</cell_type> had any effect on <protein>MNP-1</protein> or <protein>MNP-2</protein> expression , showing that the effect is specific for <protein>HIV-1 tat</protein> .


We propose that HIV-1 tat may inhibit MIP-1 alpha expression by inducing MNP-1 expression in T-cells , probably by either competing with MNP-2 for binding to the MIP-1 alpha promoter or by sequestering it into inactive forms .

We propose that <protein>HIV-1 tat</protein> may inhibit <protein>MIP-1 alpha</protein> expression by inducing <protein>MNP-1</protein> expression in <cell_type>T-cells</cell_type> , probably by either competing with <protein>MNP-2</protein> for binding to the <dna>MIP-1 alpha promoter</dna> or by sequestering it into inactive forms .


Differentiation of T-helper lymphocytes : selective regulation by members of the STAT family of transcription factors .

Differentiation of <cell_type>T-helper lymphocytes</cell_type> : selective regulation by members of the <protein>STAT family</protein> of <protein>transcription factors</protein> .


Interleukin-4 ( IL-4 ) and interleukin-12 ( IL-12 ) control the differentiation of T-helper cells .

<protein>Interleukin-4</protein> ( <protein>IL-4</protein> ) and <protein>interleukin-12</protein> ( <protein>IL-12</protein> ) control the differentiation of <cell_type>T-helper cells</cell_type> .


Here we summarize studies which investigate the mechanism by which these cytokines selectively reprogramme gene expression in T-lymphocytes .

Here we summarize studies which investigate the mechanism by which these <protein>cytokines</protein> selectively reprogramme gene expression in <cell_type>T-lymphocytes</cell_type> .


Cytokine stimulation leads to the phosphorylation of specific tyrosine residues within the intracellular domain of the corresponding cytokine receptor .

<protein>Cytokine</protein> stimulation leads to the phosphorylation of specific tyrosine residues within the <protein>intracellular domain</protein> of the corresponding <protein>cytokine receptor</protein> .


These phosphotyrosines serve as docking sites for latent , cytoplasmic transcription factors known as signal transducers and activators of transcription ( Stat ) proteins .

These phosphotyrosines serve as <protein>docking sites</protein> for latent , <protein>cytoplasmic transcription factors</protein> known as <protein>signal transducers and activators of transcription ( Stat ) proteins</protein> .


Receptor/Stat interaction is mediated by the src homology 2 ( SH2 ) domain of the corresponding Stat protein .

Receptor/Stat interaction is mediated by the <protein>src homology 2 ( SH2 ) domain</protein> of the corresponding <protein>Stat protein</protein> .


Although Stat binding to the intracellular domain of the cytokine receptor strongly depends on the phosphotyrosine residue , the recruitment of a specific Stat protein is dictated by amino acid residues C-terminal to the phosphotyrosine .

Although Stat binding to the <protein>intracellular domain</protein> of the <protein>cytokine receptor</protein> strongly depends on the phosphotyrosine residue , the recruitment of a specific <protein>Stat protein</protein> is dictated by amino acid residues C-terminal to the phosphotyrosine .


Specific docking sites within individual cytokine receptors have been identified for almost all Stat proteins .

Specific <protein>docking sites</protein> within individual <protein>cytokine receptors</protein> have been identified for almost all <protein>Stat proteins</protein> .


The direct coupling between cytokine receptor and transcription factor helps to explain how different cytokines elicit distinct patterns of gene expression .

The direct coupling between <protein>cytokine receptor</protein> and <protein>transcription factor</protein> helps to explain how different <protein>cytokines</protein> elicit distinct patterns of gene expression .


Role of EGR1 in regulation of stimulus-dependent CD44 transcription in B lymphocytes .

Role of <protein>EGR1</protein> in regulation of stimulus-dependent <protein>CD44</protein> transcription in B lymphocytes .


The immediate-early gene egr-1 encodes a transcription factor ( EGR1 ) that links B-cell antigen receptor ( BCR ) signals to downstream activation events through the regulation of previously unidentified target genes .

The <dna>immediate-early gene</dna> <dna>egr-1</dna> encodes a <protein>transcription factor</protein> ( <protein>EGR1</protein> ) that links <protein>B-cell antigen receptor</protein> ( <protein>BCR</protein> ) signals to downstream activation events through the regulation of previously unidentified <dna>target genes</dna> .


Here we identify the gene encoding the lymphocyte homing and migration protein CD44 as a target of EGR1 regulation in B cells .

Here we identify the gene encoding the <protein>lymphocyte homing and migration protein</protein> <protein>CD44</protein> as a target of <protein>EGR1</protein> regulation in <cell_type>B cells</cell_type> .


BCR -induced increases in CD44 mRNA expression and transcription levels are shown to occur in EGR1-expressing but not in nonexpressing subclones of the B-cell line WEHI-231 .

<protein>BCR</protein> -induced increases in <rna>CD44 mRNA</rna> expression and transcription levels are shown to occur in <cell_line>EGR1-expressing but not in nonexpressing subclones</cell_line> of the <cell_line>B-cell line</cell_line> <cell_line>WEHI-231</cell_line> .


Kinetics of egr-1 transcription and the appearance of nuclear EGR1 protein precede CD44 induction and occur within 30 min after stimulation in the EGR1-expressing subclone .

Kinetics of <dna>egr-1</dna> transcription and the appearance of nuclear <protein>EGR1 protein</protein> precede <protein>CD44</protein> induction and occur within 30 min after stimulation in the <cell_line>EGR1-expressing subclone</cell_line> .


A single EGR1 binding motif is demonstrated at bp -301 of the human CD44 promoter .

A single <protein>EGR1</protein> binding motif is demonstrated at bp -301 of the <dna>human CD44 promoter</dna> .


Cotransfection of a CD44 promoter-chloramphenicol acetyltransferase reporter construct with an egr-1 expression vector resulted in a 6.5- to 8.5-fold induction of transcriptional activity relative to an empty expression vector .

Cotransfection of a <dna>CD44 promoter-chloramphenicol acetyltransferase reporter construct</dna> with an <dna>egr-1 expression vector</dna> resulted in a 6.5- to 8.5-fold induction of transcriptional activity relative to an <dna>empty expression vector</dna> .


The EGR1 binding motif was shown to be necessary for stimulus-induced expression of a CD44 promoter-chloramphenicol acetyltransferase reporter construct in nontransformed B lymphocytes and was required for transactivation by an EGR1 expression vector in a B-cell line .

The <dna>EGR1 binding motif</dna> was shown to be necessary for stimulus-induced expression of a <protein>CD44</protein> <dna>promoter-chloramphenicol acetyltransferase reporter construct</dna> in <cell_type>nontransformed B lymphocytes</cell_type> and was required for transactivation by an <dna>EGR1 expression vector</dna> in a <cell_line>B-cell line</cell_line> .


These studies identify EGR1 as an intermediary linking BCR -derived signals to the induction of CD44 .

These studies identify <protein>EGR1</protein> as an intermediary linking <protein>BCR</protein> -derived signals to the induction of <protein>CD44</protein> .


The relevance of these molecular events to BCR signal transduction and antigen-stimulated B-cell-mediated immune responses is discussed .

The relevance of these molecular events to <protein>BCR</protein> signal transduction and antigen-stimulated B-cell-mediated immune responses is discussed .


Involvement of intracellular Ca2+ in oxidant-induced NF-kappa B activation .

Involvement of intracellular Ca2+ in oxidant-induced <protein>NF-kappa B</protein> activation .


In human Jurkat T cells and its subclone Wurzburg cells oxidant challenge elevated [ Ca2+ ] i by mobilizing Ca2+ from intracellular stores .

In <cell_line>human Jurkat T cells</cell_line> and its subclone <cell_line>Wurzburg cells</cell_line> oxidant challenge elevated [ Ca2+ ] i by mobilizing Ca2+ from intracellular stores .


In Jurkat cells this effect was rapid and transient , but in Wurzburg cells the response was slow and sustained .

In <cell_line>Jurkat cells</cell_line> this effect was rapid and transient , but in <cell_line>Wurzburg cells</cell_line> the response was slow and sustained .


H2O2-induced NF-kappaB activation in Wurzburg cells was not influenced by the presence of extracellular EGTA but was totally inhibited in cells that were loaded with esterified EGTA .

H2O2-induced <protein>NF-kappaB</protein> activation in <cell_line>Wurzburg cells</cell_line> was not influenced by the presence of extracellular EGTA but was totally inhibited in cells that were loaded with esterified EGTA .


In Jurkat cells that are not sensitive to H2O2-induced NF-kappaB activation , H2O2 potentiated NF-kappaB activation in the presence of sustained high [ Ca2+ ] i following thapsigargin treatment .

In <cell_line>Jurkat cells</cell_line> that are not sensitive to H2O2-induced <protein>NF-kappaB</protein> activation , H2O2 potentiated <protein>NF-kappaB</protein> activation in the presence of sustained high [ Ca2+ ] i following thapsigargin treatment .


NF-kappaB regulatory effect of alpha-lipoate and N-acetylcysteine appeared to be , at least in part , due to their ability to stabilize elevation of [ Ca2+ ] i following oxidant challenge .

<protein>NF-kappaB</protein> regulatory effect of alpha-lipoate and N-acetylcysteine appeared to be , at least in part , due to their ability to stabilize elevation of [ Ca2+ ] i following oxidant challenge .


Results of this study indicate that a sustained elevated [ Ca2+ ] i is a significant factor in oxidant-induced NF-kappaB activation .

Results of this study indicate that a sustained elevated [ Ca2+ ] i is a significant factor in oxidant-induced <protein>NF-kappaB</protein> activation .


Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins .

Transactivation of the <dna>interleukin-1alpha promoter</dna> by <protein>human T-cell leukemia virus type I and type II Tax proteins</protein> .


Human T-cell leukemia virus type I ( HTLV-I ) -infected T-cell lines constitutively produce high levels of interleukin-1alpha ( IL-1alpha ) .

<cell_line>Human T-cell leukemia virus type I ( HTLV-I ) -infected T-cell lines</cell_line> constitutively produce high levels of <protein>interleukin-1alpha</protein> ( <protein>IL-1alpha</protein> ) .


To analyze the mechanisms that lead to the expression of IL-1alpha in HTLV-I-infected cell lines , we studied regulatory regions of the human IL-1alpha promoter involved in activation of the IL-1alpha gene .

To analyze the mechanisms that lead to the expression of <protein>IL-1alpha</protein> in <cell_line>HTLV-I-infected cell lines</cell_line> , we studied regulatory regions of the human <dna>IL-1alpha promoter</dna> involved in activation of the <dna>IL-1alpha gene</dna> .


IL-1alpha promoter constructs drive transcription of the chloramphenicol acetyltransferase ( CAT ) reporter gene in HTLV-I-positive MT-2 cells , which constitutively produce IL-1alpha .

<dna>IL-1alpha promoter constructs</dna> drive transcription of the <dna>chloramphenicol acetyltransferase ( CAT ) reporter gene</dna> in <cell_line>HTLV-I-positive MT-2 cells</cell_line> , which constitutively produce <protein>IL-1alpha</protein> .


In a cotransfection assay , the Tax protein of both HTLV-I and HTLV-II specifically activated transcription from the IL-1alpha promoter in an uninfected Jurkat cell line .

In a cotransfection assay , the <protein>Tax protein</protein> of both HTLV-I and HTLV-II specifically activated transcription from the <dna>IL-1alpha promoter</dna> in an <cell_line>uninfected Jurkat cell line</cell_line> .


A mutant Tax protein deficient in transactivation of genes by the nuclear factor ( NF ) -kappaB pathway was unable to induce transcriptional activity of IL-1alpha promoter-CAT constructs , but was rescued by exogenous provision of p65/p50 NF-kappaB .

A mutant <protein>Tax protein</protein> deficient in transactivation of genes by the <protein>nuclear factor ( NF ) -kappaB</protein> pathway was unable to induce transcriptional activity of <dna>IL-1alpha promoter-CAT constructs</dna> , but was rescued by exogenous provision of <protein>p65/p50</protein> <protein>NF-kappaB</protein> .


We found that two IL-1alpha kappaB-like sites ( positions -1 , 065 to -1 , 056 and +646 to +655 ) specifically formed a complex with NF-kappaB -containing nuclear extract from MT-2 cells and that NF-kappaB bound with higher affinity to the 3 ' NF-kappaB binding site than to the 5 ' NF-kappaB site .

We found that two <dna>IL-1alpha kappaB-like sites</dna> ( positions <dna>-1 , 065 to -1 , 056</dna> and <dna>+646 to +655</dna> ) specifically formed a complex with <protein>NF-kappaB</protein> -containing nuclear extract from <cell_line>MT-2 cells</cell_line> and that <protein>NF-kappaB</protein> bound with higher affinity to the <dna>3 ' NF-kappaB binding site</dna> than to the <dna>5 ' NF-kappaB site</dna> .


Moreover , deletion of either 5 ' or 3 ' NF-kappaB sites reduced IL-1alpha promoter activity in MT-2 cells and transactivation of the IL-1alpha promoter by exogenous NF-kappaB and Tax in Jurkat cells .

Moreover , deletion of either <dna>5 ' or 3 ' NF-kappaB sites</dna> reduced <dna>IL-1alpha promoter</dna> activity in <cell_line>MT-2 cells</cell_line> and transactivation of the <dna>IL-1alpha promoter</dna> by exogenous <protein>NF-kappaB</protein> and <protein>Tax</protein> in <cell_line>Jurkat cells</cell_line> .


These data suggest a general role for Tax induction of IL-1alpha gene transcription by the NF-kappaB pathway .

These data suggest a general role for <protein>Tax</protein> induction of <dna>IL-1alpha gene</dna> transcription by the <protein>NF-kappaB</protein> pathway .


Expression of IL-1alpha by HTLV-I productively infected cells may be important in the hypercalcemia , osteolytic bone lesions , neutrophilia , elevation of C-reactive protein , and fever frequently seen in patients with HTLV-I-induced adult T-cell leukemia/lymphoma .

Expression of <protein>IL-1alpha</protein> by HTLV-I productively <cell_type>infected cells</cell_type> may be important in the hypercalcemia , osteolytic bone lesions , neutrophilia , elevation of <protein>C-reactive protein</protein> , and fever frequently seen in patients with HTLV-I-induced adult T-cell leukemia/lymphoma .


The myeloid-cell-specific c-fes promoter is regulated by Sp1 , PU.1 , and a novel transcription factor .

The <dna>myeloid-cell-specific c-fes promoter</dna> is regulated by <protein>Sp1</protein> , <protein>PU.1</protein> , and a novel <protein>transcription factor</protein> .


The protein product of the c-fps/fes ( c-fes ) proto-oncogene has been implicated in the normal development of myeloid cells ( macrophages and neutrophils ) .

The protein product of the <dna>c-fps/fes ( c-fes ) proto-oncogene</dna> has been implicated in the normal development of <cell_type>myeloid cells</cell_type> ( <cell_type>macrophages</cell_type> and <cell_type>neutrophils</cell_type> ) .


mRNA for c-fes has been detected exclusively in myeloid cells and vascular endothelial cells in adult mammals .

mRNA for c-fes has been detected exclusively in <cell_type>myeloid cells</cell_type> and <cell_type>vascular endothelial cells</cell_type> in adult mammals .


Although a 13-kilobase-pair ( kb ) human c-fes transgene exhibits high levels of expression in mice , the sequences that confer myeloid-cell-specific expression of the human c-fes gene have not been defined .

Although a <dna>13-kilobase-pair ( kb ) human c-fes transgene</dna> exhibits high levels of expression in mice , the sequences that confer myeloid-cell-specific expression of the <dna>human c-fes gene</dna> have not been defined .


Transient-transfection experiments demonstrated that plasmids containing 446 bp of c-fes 5'-flanking sequences linked to a luciferase reporter gene were active exclusively in myeloid cells .

Transient-transfection experiments demonstrated that <dna>plasmids</dna> containing 446 bp of <dna>c-fes 5'-flanking sequences</dna> linked to a luciferase reporter gene were active exclusively in <cell_type>myeloid cells</cell_type> .


No other DNA element within the 13-kb human c-fes locus contained positive cis-acting elements , with the exception of a weakly active region within the 3'-flanking sequences .

No other DNA element within the <dna>13-kb human c-fes locus</dna> contained <dna>positive cis-acting elements</dna> , with the exception of a weakly active region within the <dna>3'-flanking sequences</dna> .


DNase I footprinting assays revealed four distinct sites that bind myeloid nuclear proteins ( -408 to -386 , -293 to -254 , -76 to -65 , and -34 to +3 ) .

DNase I footprinting assays revealed four distinct sites that bind <protein>myeloid nuclear proteins</protein> ( <dna>-408 to -386</dna> , <dna>-293 to -254</dna> , <dna>-76 to -65</dna> , and <dna>-34 to +3</dna> ) .


However , the first two footprints resided in sequences that were largely dispensable for transient activity .


Plasmids containing 151 bp of 5'-flanking sequences confer myeloid-cell-specific gene expression .

Plasmids containing <dna>151 bp</dna> of <dna>5'-flanking sequences</dna> confer myeloid-cell-specific gene expression .


Electrophoretic mobility shift analyses demonstrated that the 151-bp region contains nuclear protein binding sites for Sp1 , PU.1 , and/or Elf-1 , and a novel factor .

Electrophoretic mobility shift analyses demonstrated that the <dna>151-bp region</dna> contains <dna>nuclear protein binding sites</dna> for <protein>Sp1</protein> , <protein>PU.1</protein> , and/or <protein>Elf-1</protein> , and a <protein>novel factor</protein> .


This unidentified factor binds immediately 3 ' of the PU.1/Elf-1 sites and appears to be myeloid cell specific .

This unidentified factor binds immediately 3 ' of the <dna>PU.1/Elf-1 sites</dna> and appears to be myeloid cell specific .


Mutation of the PU.1 /Elf-1 site or the 3 ' site ( FP4-3 ' ) within the context of the c-fes promoter resulted in substantially reduced activity in transient transfections .

Mutation of the <protein>PU.1</protein> <protein>/Elf-1</protein> site or the <dna>3 ' site</dna> ( <dna>FP4-3 '</dna> ) within the context of the <dna>c-fes promoter</dna> resulted in substantially reduced activity in transient transfections .


Furthermore , transient-cotransfection assay demonstrated that PU.1 ( and not Elf-1 ) can transactivate the c-fes promoter in nonmyeloid cell lines .

Furthermore , transient-cotransfection assay demonstrated that <protein>PU.1</protein> ( and not <protein>Elf-1</protein> ) can transactivate the <dna>c-fes promoter</dna> in <cell_line>nonmyeloid cell lines</cell_line> .


We conclude that the human c-fes gene contains a strong myeloid-cell-specific promoter that is regulated by Sp1 , PU.1 , and a novel transcription factor .

We conclude that the <dna>human c-fes gene</dna> contains a strong <dna>myeloid-cell-specific promoter</dna> that is regulated by <protein>Sp1</protein> , <protein>PU.1</protein> , and a novel <protein>transcription factor</protein> .


IL-10 inhibits nuclear factor-kappa B/Rel nuclear activity in CD3-stimulated human peripheral T lymphocytes .

<protein>IL-10</protein> inhibits <protein>nuclear factor-kappa B/Rel</protein> nuclear activity in <cell_line>CD3-stimulated human peripheral T lymphocytes</cell_line> .


IL-10 markedly reduces nuclear factor ( NF ) -kappa B/Rel nuclear activity induced in PBMC by stimulation with the anti-CD3 mAb OKT3 .

<protein>IL-10</protein> markedly reduces nuclear factor <protein>( NF ) -kappa B/Rel</protein> nuclear activity induced in <cell_type>PBMC</cell_type> by stimulation with the <protein>anti-CD3 mAb</protein> <protein>OKT3</protein> .


The inhibition is exerted specifically on the NF-kappa B/Rel activation induced by mAb OKT3 , and not that produced by PMA .

The inhibition is exerted specifically on the <protein>NF-kappa B/Rel</protein> activation induced by <protein>mAb OKT3</protein> , and not that produced by PMA .


As judged by supershifting the DNA-protein complexes with Abs recognizing specific components of the NF-kappa B/Rel protein family , the p50/p65 ( Rel A ) heterodimeric form of NF-kappa B is primarily affected .

As judged by supershifting the <protein>DNA-protein complexes</protein> with <protein>Abs</protein> recognizing specific components of the <protein>NF-kappa B/Rel protein family</protein> , the <protein>p50/p65</protein> ( <protein>Rel A</protein> ) heterodimeric form of <protein>NF-kappa B</protein> is primarily affected .


The maximal effect is observed at the IL-10 concentration of 20 U/ml .

The maximal effect is observed at the <protein>IL-10</protein> concentration of 20 U/ml .


IL-10 inhibitory activity is exerted on T lymphocytes and is mediated by monocytes .

<protein>IL-10</protein> inhibitory activity is exerted on <cell_type>T lymphocytes</cell_type> and is mediated by <cell_type>monocytes</cell_type> .


Indeed , monocytes pretreated with IL-10 are able so inhibit NF-kappa B nuclear activity in purified T lymphocytes stimulated with OKT3 .

Indeed , <cell_type>monocytes</cell_type> pretreated with <protein>IL-10</protein> are able so inhibit <protein>NF-kappa B</protein> nuclear activity in purified <cell_type>T lymphocytes</cell_type> stimulated with <protein>OKT3</protein> .


Soluble factors do not appear to be involved in the mechanism of inhibition .


On the other hand , the up-regulation of CD80 Ag , found on monocytes obtained from PBMC incubated with OKT3 , is not detected after addition of IL-10 , and the anti-CD28 mAb CLB-CD28/1 restores the NF-kappa B/Rel nuclear activity in IL-10-inhibited lymphocytes .

On the other hand , the up-regulation of <protein>CD80 Ag</protein> , found on <cell_type>monocytes</cell_type> obtained from <cell_type>PBMC</cell_type> incubated with <protein>OKT3</protein> , is not detected after addition of <protein>IL-10</protein> , and the <protein>anti-CD28 mAb</protein> <protein>CLB-CD28/1</protein> restores the <protein>NF-kappa B/Rel</protein> nuclear activity in <cell_line>IL-10-inhibited lymphocytes</cell_line> .


Therefore , the NF-kappa B/Rel inhibition might be ascribed to a lack of cooperation between accessory cells and T lymphocytes , resulting from down-regulation of a costimulatory molecule , such as CD80 , produced by IL-10 on activated monocytes .

Therefore , the <protein>NF-kappa B/Rel</protein> inhibition might be ascribed to a lack of cooperation between accessory cells and <cell_type>T lymphocytes</cell_type> , resulting from down-regulation of a costimulatory molecule , such as <protein>CD80</protein> , produced by <protein>IL-10</protein> on activated <cell_type>monocytes</cell_type> .


Our results demonstrate that IL-10 can inhibit the induction of NF-kappa B/Rel nuclear activity in CD3-stimulated T lymphocytes .

Our results demonstrate that <protein>IL-10</protein> can inhibit the induction of <protein>NF-kappa B/Rel</protein> nuclear activity in <cell_line>CD3-stimulated T lymphocytes</cell_line> .


Since inappropriate activation of kappa B-driven genes has a physiopathologic role in a number of diseases , such as HIV infection , our findings support the possibility of using this cytokine to suppress an undesirable activation of these transcription factors .

Since inappropriate activation of <dna>kappa B-driven genes</dna> has a physiopathologic role in a number of diseases , such as HIV infection , our findings support the possibility of using this cytokine to suppress an undesirable activation of these <protein>transcription factors</protein> .


Expression of A-myb , but not c-myb and B-myb , is restricted to Burkitt 's lymphoma , sIg+ B-acute lymphoblastic leukemia , and a subset of chronic lymphocytic leukemias .

Expression of <dna>A-myb</dna> , but not <dna>c-myb</dna> and <dna>B-myb</dna> , is restricted to Burkitt 's lymphoma , sIg+ B-acute lymphoblastic leukemia , and a subset of chronic lymphocytic leukemias .


The A-myb gene encodes a transcription factor that is related both functionally and structurally to the v-myb oncogene .

The <dna>A-myb gene</dna> encodes a <protein>transcription factor</protein> that is related both functionally and structurally to the <dna>v-myb oncogene</dna> .


Following our observations that A-myb is expressed in a restricted subset of normal mature human B lymphocytes , with the phenotype CD38+ , CD39- , slgM- , we have now investigated the pattern of A-myb expression in neoplastic B cells representating the whole spectrum of B-cell differentiation and compared it to that of c-myb and B-myb .

Following our observations that <dna>A-myb</dna> is expressed in a restricted subset of normal <cell_type>mature human B lymphocytes</cell_type> , with the phenotype CD38+ , CD39- , slgM- , we have now investigated the pattern of <dna>A-myb</dna> expression in neoplastic <cell_type>B cells</cell_type> representating the whole spectrum of B-cell differentiation and compared it to that of <dna>c-myb</dna> and <dna>B-myb</dna> .


In a panel of 32 B-cell lines , A-myb was very strongly expressed in most Burkitt 's lymphoma ( BL ) cell lines , but weak or negative in 2 pre-B acute lymphoblastic leukemia ( ALL ) , 4 non-Hodgkin 's lymphoma ( NHL ) , 6 Epstein-Barr virus-immortalized lymphoblastoid cell lines , and 6 myeloma lines .

In a panel of 32 <cell_line>B-cell lines</cell_line> , <dna>A-myb</dna> was very strongly expressed in most Burkitt 's lymphoma ( BL ) cell lines , but weak or negative in 2 pre-B acute lymphoblastic leukemia ( ALL ) , 4 non-Hodgkin 's lymphoma ( NHL ) , 6 <cell_line>Epstein-Barr virus-immortalized lymphoblastoid cell lines</cell_line> , and 6 <cell_line>myeloma lines</cell_line> .


Protein expression paralleled that of the RNA .


We have also investigated A-myb expression in 49 fresh cases of B leukemias .

We have also investigated <dna>A-myb</dna> expression in 49 fresh cases of B leukemias .


Among 24 ALL , 6 were of the null and 11 of the common type and all these were negative for A-myb expression ; on the other hand , all 7 B-ALL cases ( slg+ ) , as well as one fresh BL case with bone marrow infiltration , expressed A-myb .

Among 24 ALL , 6 were of the null and 11 of the common type and all these were negative for <protein>A-myb</protein> expression ; on the other hand , all 7 B-ALL cases ( slg+ ) , as well as one fresh BL case with bone marrow infiltration , expressed <dna>A-myb</dna> .


A-myb was undetectable in 4 prolymphocytic leukemias ( PLL ) but was strongly expressed in 5/20 ( 25 % ) of chronic lymphocytic leukemia ( CLL ) samples .

<dna>A-myb</dna> was undetectable in 4 prolymphocytic leukemias ( PLL ) but was strongly expressed in 5/20 ( 25 % ) of chronic lymphocytic leukemia ( CLL ) samples .


In the latter A-myb did not correlate with phenotype or clinical stage .

In the latter <dna>A-myb</dna> did not correlate with phenotype or clinical stage .


Finally , we have studied the progression of one case of CLL into Richter 's syndrome and have found that the Richter 's cells expressed about 25-fold less A-myb RNA than the CLL cells from the same patient. The pattern of c-myb and B-myb was clearly distinct from that of A-myb .

Finally , we have studied the progression of one case of CLL into Richter 's syndrome and have found that the <cell_line>Richter 's cells</cell_line> expressed about 25-fold less <rna>A-myb RNA</rna> than the <cell_line>CLL cells</cell_line> from the same patient. The pattern of <dna>c-myb</dna> and <dna>B-myb</dna> was clearly distinct from that of <dna>A-myb</dna> .


C-myb and B-myb were expressed in all neoplastic groups , except in CLL cells .

C-myb and <dna>B-myb</dna> were expressed in all neoplastic groups , except in <cell_line>CLL cells</cell_line> .


Thus , A-myb expression , unlike that of c-myb and B-myb , is restricted to a subset of B-cell neoplasias ( in particular BL and slg+B-ALL ) representative of a specific stage of B-cell differentiation .

Thus , <dna>A-myb</dna> expression , unlike that of <dna>c-myb</dna> and <dna>B-myb</dna> , is restricted to a subset of B-cell neoplasias ( in particular BL and slg+B-ALL ) representative of a specific stage of B-cell differentiation .


This expression may in part reflect expression of A-myb by the normal germinal center B cells that are the normal counterpart of these transformed B cells .

This expression may in part reflect expression of <dna>A-myb</dna> by the normal germinal center <cell_type>B cells</cell_type> that are the normal counterpart of these <cell_line>transformed B cells</cell_line> .


The data presented strongly support a role for this transcription factor in B-cell differentiation and perhaps in B-cell transformation in some neoplasias .

The data presented strongly support a role for this <protein>transcription factor</protein> in B-cell differentiation and perhaps in B-cell transformation in some neoplasias .


Granulocyte-macrophage colony-stimulating factor stimulates JAK2 signaling pathway and rapidly activates p93fes , STAT1 p91 , and STAT3 p92 in polymorphonuclear leukocytes .

<protein>Granulocyte-macrophage colony-stimulating factor</protein> stimulates <protein>JAK2</protein> signaling pathway and rapidly activates <protein>p93fes</protein> , <protein>STAT1 p91</protein> , and <protein>STAT3 p92</protein> in <cell_type>polymorphonuclear leukocytes</cell_type> .


Granulocyte-macrophage colony-stimulating factor ( GM-CSF ) , supports proliferation , differentiation , and functional activation of hemopoietic cells by its interaction with a heterodimeric receptor .

<protein>Granulocyte-macrophage colony-stimulating factor</protein> ( <protein>GM-CSF</protein> ) , supports proliferation , differentiation , and functional activation of hemopoietic cells by its interaction with a heterodimeric receptor .


Although GM-CSF receptor is devoid of tyrosine kinase enzymatic activity , GM-CSF-induced peripheral blood polymorphonuclear leukocytes ( PMN ) functional activation is mediated by the phosphorylation of a large number of intracellular signaling molecules .

Although <protein>GM-CSF</protein> receptor is devoid of <protein>tyrosine kinase</protein> enzymatic activity , <cell_line>GM-CSF-induced peripheral blood polymorphonuclear leukocytes</cell_line> ( <cell_type>PMN</cell_type> ) functional activation is mediated by the phosphorylation of a large number of <protein>intracellular signaling molecules</protein> .


We have previously shown that JAK2 becomes tyrosine-phosphorylated in response to GM-CSF in PMN .

We have previously shown that <protein>JAK2</protein> becomes tyrosine-phosphorylated in response to <protein>GM-CSF</protein> in <cell_type>PMN</cell_type> .


In the present study we demonstrate that also the signal transducers and activators of transcription ( STAT ) family members STAT1 p91 and STAT3 p92 and the product of the c-fps/fes protooncogene become tyrosine-phosphorylated upon GM-CSF stimulation and physically associated with both GM-CSF receptor beta common subunit and JAK2 .

In the present study we demonstrate that also the <protein>signal transducers and activators of transcription ( STAT ) family members</protein> <protein>STAT1 p91</protein> and <protein>STAT3 p92</protein> and the product of the <dna>c-fps/fes protooncogene</dna> become tyrosine-phosphorylated upon <protein>GM-CSF</protein> stimulation and physically associated with both <protein>GM-CSF</protein> receptor beta common subunit and <protein>JAK2</protein> .


Moreover GM-CSF was able to induce JAK2 and p93fes catalytic activity .

Moreover <protein>GM-CSF</protein> was able to induce <protein>JAK2</protein> and <protein>p93fes</protein> catalytic activity .


We also demonstrate that the association of the GM-CSF receptor beta common subunit with JAK2 is ligand-dependent .

We also demonstrate that the association of the <protein>GM-CSF receptor beta common subunit</protein> with <protein>JAK2</protein> is ligand-dependent .


Finally we demonstrate that GM-CSF induces a DNA-binding complex that contains both p91 and p92 .

Finally we demonstrate that <protein>GM-CSF</protein> induces a <protein>DNA-binding complex</protein> that contains both <protein>p91</protein> and <protein>p92</protein> .


These results identify a new signal transduction pathway activated by GM-CSF and provide a mechanism for rapid activation of gene expression in GM-CSF-stimulated PMN .

These results identify a new signal transduction pathway activated by <protein>GM-CSF</protein> and provide a mechanism for rapid activation of gene expression in <cell_type>GM-CSF-stimulated PMN</cell_type> .


Epstein-Barr virus nuclear antigen 2 ( EBNA2 ) -oestrogen receptor fusion proteins complement the EBNA2-deficient Epstein-Barr virus strain P3HR1 in transformation of primary B cells but suppress growth of human B cell lymphoma lines .

<protein>Epstein-Barr virus nuclear antigen 2 ( EBNA2 ) -oestrogen receptor fusion proteins</protein> complement the EBNA2-deficient Epstein-Barr virus strain P3HR1 in transformation of <cell_type>primary B cells</cell_type> but suppress growth of <cell_line>human B cell lymphoma lines</cell_line> .


To develop a transformation system with a conditional Epstein-Barr virus nuclear antigen 2 ( EBNA2 ) gene , we fused the hormone binding domain of the oestrogen receptor to the N or C terminus of EBNA2 .

To develop a transformation system with a conditional <dna>Epstein-Barr virus nuclear antigen 2 ( EBNA2 ) gene</dna> , we fused the <protein>hormone binding domain</protein> of the oestrogen receptor to the <protein>N or C terminus</protein> of <protein>EBNA2</protein> .


In promoter transactivation as well as primary B cell transformation assays these chimeric EBNA2 proteins are able to substitute for wild-type EBNA2 in the presence of oestrogen .

In promoter transactivation as well as primary B cell transformation assays these chimeric <protein>EBNA2</protein> proteins are able to substitute for <protein>wild-type EBNA2</protein> in the presence of oestrogen .


Here we provide evidence that this transformation is the result of double infection of a cell with two virions , the P3HR1 virus genome and a mini-EBV plasmid carrying the chimeric EBNA2 gene .

Here we provide evidence that this transformation is the result of double infection of a cell with two virions , the <dna>P3HR1 virus genome</dna> and a <dna>mini-EBV plasmid</dna> carrying the chimeric <dna>EBNA2 gene</dna> .


Unexpectedly , expression of the same EBNA2 -oestrogen receptor fusion protein in established human B cell lymphoma lines resulted in growth retardation or growth arrest upon the addition of oestrogen .

Unexpectedly , expression of the same <protein>EBNA2</protein> -oestrogen receptor fusion protein in <cell_line>established human B cell lymphoma lines</cell_line> resulted in growth retardation or growth arrest upon the addition of oestrogen .


By titrating the oestrogen concentration in these stably transfected cells , the growth retarding and the transactivating function of the chimeric proteins could not be dissociated .

By titrating the oestrogen concentration in these <cell_line>stably transfected cells</cell_line> , the growth retarding and the transactivating function of the <protein>chimeric proteins</protein> could not be dissociated .


We propose that growth inhibition of established B cell lymphoma lines is a novel function of EBNA2 which has not been detected in the absence of an inducible system .

We propose that growth inhibition of established <cell_line>B cell lymphoma lines</cell_line> is a novel function of <protein>EBNA2</protein> which has not been detected in the absence of an inducible system .


It remains open whether the growth retarding property of the EBNA2-oestrogen receptor fusion protein in B cell lymphoma lines is due to unphysiologically high expression of the chimeric protein or to interference with a cellular programme driving proliferation in these cell lines .

It remains open whether the growth retarding property of the <protein>EBNA2-oestrogen receptor fusion protein</protein> in <cell_line>B cell lymphoma lines</cell_line> is due to unphysiologically high expression of the <protein>chimeric protein</protein> or to interference with a cellular programme driving proliferation in these <cell_line>cell lines</cell_line> .


Tissue-specific activity of the gammac chain gene promoter depends upon an Ets binding site and is regulated by GA-binding protein .

Tissue-specific activity of the <dna>gammac chain gene promoter</dna> depends upon an <dna>Ets binding site</dna> and is regulated by <protein>GA-binding protein</protein> .


The gammac chain is a subunit of multiple cytokine receptors ( interleukin ( IL ) -2 , IL-4 , IL-7 , IL-9 , and IL-15 ) , the expression of which is restricted to hematopoietic lineages .

The <protein>gammac chain</protein> is a subunit of multiple <protein>cytokine receptors</protein> ( <protein>interleukin ( IL ) -2</protein> , <protein>IL-4</protein> , <protein>IL-7</protein> , <protein>IL-9</protein> , and <protein>IL-15</protein> ) , the expression of which is restricted to <cell_type>hematopoietic lineages</cell_type> .


A defect in gammac leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation .


In order to better characterize the human gammac promoter and define the minimal tissue-specific promoter region , progressive 5'-deletion constructs of a segment extending 1053 base pairs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoietic cell types .

In order to better characterize the <dna>human gammac promoter</dna> and define the <dna>minimal tissue-specific promoter region</dna> , progressive <dna>5'-deletion constructs</dna> of a segment extending <dna>1053 base pairs upstream</dna> of the <dna>major transcription start site</dna> were generated and tested for promoter activity in various <cell_type>hematopoietic and nonhematopoietic cell types</cell_type> .


The -1053/+34 construct allowed promoter activity only in cells of hematopoietic origin , and tissue specificity was conserved in all other constructs tested .

The <dna>-1053/+34 construct</dna> allowed promoter activity only in cells of <cell_type>hematopoietic origin</cell_type> , and tissue specificity was conserved in all other constructs tested .


The region downstream of -90 appeared critical for basal promoter activity .


It contains two potential Ets binding sites conserved in the murine gammac promoter gene , one of which was found essential for functional promoter activity as determined by mutational analysis .

It contains two potential <dna>Ets binding sites</dna> conserved in the <dna>murine gammac promoter gene</dna> , one of which was found essential for functional promoter activity as determined by mutational analysis .


The functional Ets binding site was found to bind Ets family proteins , principally GA-binding protein and Elf-1 and could be transactivated by GABPalpha and -beta synergistically .

The functional <dna>Ets binding site</dna> was found to bind <protein>Ets family proteins</protein> , principally <protein>GA-binding protein</protein> and <protein>Elf-1</protein> and could be transactivated by <protein>GABPalpha</protein> and <protein>-beta</protein> synergistically .


These results indicate that , as already reported for the IL2Rbeta promoter , GA-binding protein is an essential component of gammac basal promoter activity .

These results indicate that , as already reported for the <dna>IL2Rbeta promoter</dna> , <protein>GA-binding protein</protein> is an essential component of gammac basal promoter activity .


Although GABP expression is not restricted to the hematopoietic lineage , its interaction with other specific factors may contribute to the tissue-specific expression of the gammac gene .

Although <protein>GABP</protein> expression is not restricted to the <cell_type>hematopoietic lineage</cell_type> , its interaction with other <protein>specific factors</protein> may contribute to the tissue-specific expression of the <dna>gammac gene</dna> .


Detection of intracellular signal transduction molecules in PBMC from rhesus macaques and sooty mangabeys .

Detection of <protein>intracellular signal transduction molecules</protein> in <cell_type>PBMC</cell_type> from rhesus macaques and sooty mangabeys .


One of the manifestations of human HIV-1 and nonhuman primate SIV infection that lead to disease is reasoned to be secondary to generalized T-cell dysfunction .


The molecular mechanisms associated with the T-cell dysfunction remain to be elucidated .


To address this issue , we sought to utilize the nonhuman primate model to study intracellular signaling events in cells from disease-susceptible rhesus macaques and disease-resistant sooty mangabeys .


Because relatively little is known about these events in nonhuman primates , our laboratory defined optimal conditions , reagents , and assays for the study of signal transduction events in cells from nonhuman primates .


The protein phosphorylation patterns in the two monkeys exhibited quantitative , qualitative , and kinetic differences .


Antibodies to Stat6 detected a unique band in macaque cell lysates .

Antibodies to <protein>Stat6</protein> detected a unique band in macaque cell lysates .


This band is markedly decreased human cell lysates and never seen in mangabey cell lysates .


Detection of various other intracellular signaling proteins is also described .

Detection of various other <protein>intracellular signaling proteins</protein> is also described .


Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter : Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors .

Genetic characterization of transactivation of the <dna>human T-cell leukemia virus type 1 promoter</dna> : Binding of <protein>Tax</protein> to <dna>Tax-responsive element 1</dna> is mediated by the <protein>cyclic AMP-responsive members</protein> of the <protein>CREB/ATF family</protein> of transcription factors .


To achieve a better understanding of the mechanism of transactivation by Tax of human T-cell leukemia virus type 1 Tax-responsive element 1 ( TRE-1 ) , we developed a genetic approach with Saccharomyces cerevisiae .

To achieve a better understanding of the mechanism of transactivation by <protein>Tax</protein> of human T-cell leukemia virus type 1 <dna>Tax-responsive element 1</dna> ( <dna>TRE-1</dna> ) , we developed a genetic approach with Saccharomyces cerevisiae .


We constructed a yeast reporter strain containing the lacZ gene under the control of the CYC1 promoter associated with three copies of TRE-1 .

We constructed a yeast reporter strain containing the <dna>lacZ gene</dna> under the control of the <dna>CYC1 promoter</dna> associated with three copies of <dna>TRE-1</dna> .


Expression of either the cyclic AMP response element-binding protein ( CREB ) or CREB fused to the GAL4 activation domain ( GAD ) in this strain did not modify the expression of the reporter gene .

Expression of either the <protein>cyclic AMP response element-binding protein</protein> ( <protein>CREB</protein> ) or <protein>CREB</protein> fused to the <protein>GAL4 activation domain</protein> ( <protein>GAD</protein> ) in this strain did not modify the expression of the <dna>reporter gene</dna> .


Tax alone was also inactive .

<protein>Tax</protein> alone was also inactive .


However , expression of the reporter gene was induced by coexpression of Tax and CREB .

However , expression of the <dna>reporter gene</dna> was induced by coexpression of <protein>Tax</protein> and <protein>CREB</protein> .


This effect was stronger with the GAD-CREB fusion protein .

This effect was stronger with the <protein>GAD-CREB fusion protein</protein> .


Analysis of different CREB mutants with this genetic system indicated that the C-terminal 92 amino acid residues , which include the basic domain and the leucine zipper , are necessary and sufficient to mediate transactivation by Tax .

Analysis of different <protein>CREB mutants</protein> with this genetic system indicated that the <protein>C-terminal 92 amino acid residues</protein> , which include the <protein>basic domain</protein> and the <protein>leucine zipper</protein> , are necessary and sufficient to mediate transactivation by <protein>Tax</protein> .


To identify cellular proteins binding to TRE-1 in a Tax -dependent manner , this strain was also used to screen a library of human cDNAs fused to GAD .

To identify <protein>cellular proteins</protein> binding to <dna>TRE-1</dna> in a <protein>Tax</protein> -dependent manner , this strain was also used to screen a library of <dna>human cDNAs</dna> fused to <protein>GAD</protein> .


Of five positive clones isolated from 0.75 x 10 ( 6 ) yeast colonies , four were members of the CREB/activating transcription factor ( ATF ) family : CREB , two isoforms of the cyclic AMP-responsive element modulator ( CREM ) , and ATF-1 .

Of five positive clones isolated from 0.75 x 10 ( 6 ) yeast colonies , four were members of the <protein>CREB/activating transcription factor ( ATF ) family</protein> : <protein>CREB</protein> , <protein>two isoforms of the cyclic AMP-responsive element modulator</protein> ( <protein>CREM</protein> ) , and <protein>ATF-1</protein> .


Interestingly , these three proteins can be phosphorylated by protein kinase A and thus form a particular subgroup within the CREB/ATF family .

Interestingly , these three proteins can be phosphorylated by <protein>protein kinase A</protein> and thus form a particular subgroup within the <protein>CREB/ATF family</protein> .


Expression of ATF-2 in S. cerevisiae did not activate TRE-1 in the presence of Tax .

Expression of <protein>ATF-2</protein> in S. cerevisiae did not activate <dna>TRE-1</dna> in the presence of <protein>Tax</protein> .


This shows that in a eukaryotic nucleus , Tax specifically interacts with the basic domain-leucine zipper region of ATF-1 , CREB , and CREM .

This shows that in a eukaryotic nucleus , <protein>Tax</protein> specifically interacts with the <protein>basic domain-leucine zipper region</protein> of <protein>ATF-1</protein> , <protein>CREB</protein> , and <protein>CREM</protein> .


The fifth clone identified in this screening corresponded to the Ku autoantigen p70 subunit .

The fifth clone identified in this screening corresponded to the <protein>Ku autoantigen p70 subunit</protein> .


When fused to GAD , the C-terminal region of Ku was able to activate transcription via TRE-1 but this activation was not dependent on Tax .

When fused to <protein>GAD</protein> , the <protein>C-terminal region</protein> of <protein>Ku</protein> was able to activate transcription via <dna>TRE-1</dna> but this activation was not dependent on <protein>Tax</protein> .


A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p [ see comments ]

A <protein>mammalian histone deacetylase</protein> related to the <protein>yeast transcriptional regulator</protein> <protein>Rpd3p</protein> [ see comments ]


Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle .

Trapoxin is a microbially derived cyclotetrapeptide that inhibits <protein>histone</protein> deacetylation in vivo and causes mammalian cells to arrest in the cell cycle .


A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity .

A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with <protein>histone deacetylase</protein> activity .


Both proteins were identified by peptide microsequencing , and a complementary DNA encoding the histone deacetylase catalytic subunit ( HD1 ) was cloned from a human Jurkat T cell library .

Both proteins were identified by peptide microsequencing , and a <dna>complementary DNA</dna> encoding the <protein>histone deacetylase catalytic subunit</protein> ( <protein>HD1</protein> ) was cloned from a human Jurkat T cell library .


As the predicted protein is very similar to the yeast transcriptional regulator Rpd3p , these results support a role for histone deacetylase as a key regulator of eukaryotic transcription .

As the predicted protein is very similar to the <protein>yeast transcriptional regulator</protein> <protein>Rpd3p</protein> , these results support a role for <protein>histone deacetylase</protein> as a key regulator of eukaryotic transcription .


Coexpression of the interleukin-13 and interleukin-4 genes correlates with their physical linkage in the cytokine gene cluster on human chromosome 5q23-31 .

Coexpression of the <dna>interleukin-13 and interleukin-4 genes</dna> correlates with their physical linkage in the <dna>cytokine gene cluster</dna> on <dna>human chromosome 5q23-31</dna> .


Interleukin-13 ( IL-13 ) and IL-4 are cytokines produced by T cells that are encoded by the q23-31 region of human chromosome 5 .

<protein>Interleukin-13</protein> ( <protein>IL-13</protein> ) and <protein>IL-4</protein> are cytokines produced by T cells that are encoded by the q23-31 region of human chromosome 5 .


To investigate the regulation of IL-13 gene expression by T cells , we isolated and sequenced the human IL-13 gene , analyzed its 5'-flanking region for potential transcriptional activation elements , and examined its expression in nontransformed T-lineage cell populations .

To investigate the regulation of <dna>IL-13 gene</dna> expression by <cell_type>T cells</cell_type> , we isolated and sequenced the human <dna>IL-13 gene</dna> , analyzed its <dna>5'-flanking region</dna> for potential <dna>transcriptional activation elements</dna> , and examined its expression in <cell_line>nontransformed T-lineage cell populations</cell_line> .


The human IL-13 gene was located 12.5-kb upstream of the IL-4 gene and 2-kb downstream of a CpG island .

The <dna>human IL-13 gene</dna> was located <dna>12.5-kb upstream</dna> of the <dna>IL-4 gene</dna> and <dna>2-kb downstream</dna> of a <dna>CpG island</dna> .


The IL-13 gene 5 ' flank region included a segment with sequence homology to P elements of the IL-4 promoter involved in transcriptional activation in T cells .

The <dna>IL-13 gene 5 ' flank region</dna> included a segment with sequence homology to <dna>P elements</dna> of the <dna>IL-4 promoter</dna> involved in transcriptional activation in <cell_type>T cells</cell_type> .


Mutation of the IL-13 P element site significantly reduced IL-13 promoter activity in response to T-cell activation .

Mutation of the <dna>IL-13 P element site</dna> significantly reduced <protein>IL-13</protein> promoter activity in response to T-cell activation .


Oligonucleotides containing the IL-13 or IL-4 P element sites specifically bound the transcriptional activator protein , nuclear factor-activated T cells , preformed ( NF-ATp ) , when incubated with nuclear protein extracts from activated T cells .

Oligonucleotides containing the <protein>IL-13</protein> or <dna>IL-4 P element sites</dna> specifically bound the <protein>transcriptional activator protein</protein> , <protein>nuclear factor-activated T cells</protein> , preformed ( <protein>NF-ATp</protein> ) , when incubated with nuclear protein extracts from <cell_type>activated T cells</cell_type> .


Similar to IL-4 , IL-13 mRNA expression was highest in T-cell populations enriched for cells that had previously been primed in vivo or in vitro , indicating that priming increases the expression of the IL-13 and IL-4 genes in a coordinate manner .

Similar to <protein>IL-4</protein> , <rna>IL-13 mRNA</rna> expression was highest in <cell_line>T-cell populations</cell_line> enriched for cells that had previously been primed in vivo or in vitro , indicating that priming increases the expression of the <dna>IL-13 and IL-4 genes</dna> in a coordinate manner .


Because the primed T cells contain higher levels of nuclear NF-ATp , capable of binding to P elements of the IL-4 and IL-13 promoters , than do freshly-isolated T cells , the NF-AT-binding P elements are attractive candidates to mediate the coordinate expression of these two cytokine genes .

Because the <cell_line>primed T cells</cell_line> contain higher levels of <protein>nuclear NF-ATp</protein> , capable of binding to <dna>P elements</dna> of the <dna>IL-4 and IL-13 promoters</dna> , than do <cell_type>freshly-isolated T cells</cell_type> , the <dna>NF-AT-binding P elements</dna> are attractive candidates to mediate the coordinate expression of these two <dna>cytokine genes</dna> .


Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase .

Inhibition of <protein>alpha interferon</protein> but not <protein>gamma interferon</protein> signal transduction by phorbol esters is mediated by a <protein>tyrosine phosphatase</protein> .


Previous studies have indicated that the expression of viral oncoproteins , cell transformation , or phorbol ester treatment of cells can inhibit alpha/beta interferon ( IFN-alpha/beta ) -induced gene expression .


The mechanisms by which these promoters of cell growth exert their inhibitory effects vary , but in most instances they involve a disruption of the IFN-alpha/beta-induced transcription complex ISGF3 such that the DNA-binding component of this complex ( the 48-kDa ISGF3gamma protein ) does not bind to the interferon-stimulated response element ( ISRE ) .


In this report , we demonstrated that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3gamma .


Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the transcription factors Stat1alpha , Stat2 , and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-gamma activation of Stat1alpha .

Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the <protein>transcription factors</protein> <protein>Stat1alpha</protein> , <protein>Stat2</protein> , and <protein>Stat3</protein> and of the <protein>tyrosine kinase</protein> <protein>Tyk2</protein> but had no effect on <protein>IFN-gamma</protein> activation of <protein>Stat1alpha</protein> .


IFNalpha-stimulated tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor were unaffected by phorbol 12-myristate 13-acetate ( PMA ) .

IFNalpha-stimulated tyrosine phosphorylation of <protein>Jak1</protein> and the <protein>alpha subunit</protein> of the <protein>IFN-alpha receptor</protein> were unaffected by phorbol 12-myristate 13-acetate ( PMA ) .


Moreover , PMA caused the dephosphorylation of Tyk2 but not of Jak1 , which was activated by IFN .

Moreover , PMA caused the dephosphorylation of <protein>Tyk2</protein> but not of <protein>Jak1</protein> , which was activated by <protein>IFN</protein> .


Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation .

Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced <protein>Tyk2</protein> dephosphorylation .


These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but not Jak1 activity .

These observations suggest that PMA exerts its inhibitory effects by activation of a <protein>tyrosine phosphatase</protein> which selectively regulates <protein>Tyk2</protein> but not <protein>Jak1</protein> activity .


Transcriptional regulation of the interleukin-2 gene in normal human peripheral blood T cells .

Transcriptional regulation of the <dna>interleukin-2 gene</dna> in normal <cell_type>human peripheral blood T cells</cell_type> .


Convergence of costimulatory signals and differences from transformed T cells .

Convergence of costimulatory signals and differences from <cell_type>transformed T cells</cell_type> .


To study transcriptional regulation in normal human T cells , we have optimized conditions for transient transfection .

To study transcriptional regulation in <cell_type>normal human T cells</cell_type> , we have optimized conditions for transient transfection .


Interleukin-2 ( IL-2 ) promoter -reporter gene behavior closely parallels the endogenous gene in response to T cell receptor and costimulatory signals .

<dna>Interleukin-2 ( IL-2 ) promoter</dna> <dna>-reporter gene</dna> behavior closely parallels the <dna>endogenous gene</dna> in response to <protein>T cell receptor</protein> and costimulatory signals .


As assessed with mutagenized promoters , the most important IL-2 cis-regulatory elements in normal T cells are the proximal AP-1 site and the NF- kappaB site .

As assessed with <dna>mutagenized promoters</dna> , the most important <dna>IL-2 cis-regulatory elements</dna> in <cell_type>normal T cells</cell_type> are the <dna>proximal AP-1 site</dna> and the <dna>NF- kappaB site</dna> .


Both primary activation , with phytohemagglutinin or antibodies to CD3 , and costimulation , provided by pairs of CD2 antibodies or B7-positive ( B cells ) or B7-negative ( endothelial ) accessory cells , are mediated through the same cis-elements .

Both primary activation , with <protein>phytohemagglutinin</protein> or <protein>antibodies to CD3</protein> , and costimulation , provided by pairs of <protein>CD2 antibodies</protein> or <cell_type>B7-positive ( B cells )</cell_type> or <cell_type>B7-negative ( endothelial ) accessory cells ,</cell_type> are mediated through the same <dna>cis-elements</dna> .


Interestingly , the nuclear factor of activated T cell sites are much less important in normal T cells than in Jurkat T cells .

Interestingly , the <dna>nuclear factor of activated T cell sites</dna> are much less important in <cell_type>normal T cells</cell_type> than in <cell_line>Jurkat T cells</cell_line> .


We conclude that IL-2 transcriptional regulation differs in tumor cell lines compared with normal T cells and that different costimulatory signals converge on the same cis-elements in the IL-2 promoter .

We conclude that <protein>IL-2</protein> transcriptional regulation differs in <cell_line>tumor cell lines</cell_line> compared with <cell_type>normal T cells</cell_type> and that different costimulatory signals converge on the same <dna>cis-elements</dna> in the <dna>IL-2 promoter</dna> .


The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth inhibition of human CD34+ erythroid progenitor cells .

The <protein>RAR-RXR</protein> as well as the <protein>RXR-RXR</protein> pathway is involved in signaling growth inhibition of <cell_line>human CD34+ erythroid progenitor cells</cell_line> .


Previous studies have shown that retinoic acid ( RA ) , similar to tumor necrosis factor-alpha ( TNF-alpha ) , can act as a bifunctional regulator of the growth of bone marrow progenitors , in that it can stimulate granulocyte-macrophage colony-stimulating factor ( GM-CSF ) - or interleukin-3 ( IL-3 ) -induced GM colony formation , but potently inhibit G-CSF -induced growth .

Previous studies have shown that retinoic acid ( RA ) , similar to <protein>tumor necrosis factor-alpha</protein> ( <protein>TNF-alpha</protein> ) , can act as a bifunctional regulator of the growth of <cell_type>bone marrow progenitors</cell_type> , in that it can stimulate granulocyte-macrophage colony-stimulating factor ( GM-CSF ) - or interleukin-3 ( IL-3 ) -induced GM colony formation , but potently inhibit <protein>G-CSF</protein> -induced growth .


The present study , using highly enriched human CD34+ as well as Lin- murine bone marrow progenitor cells , demonstrates a potent inhibitory effect of 9-cis-RA on burst-forming unit-erythroid ( BFU-E ) colony formation regardless of the cytokine stimulating growth .

The present study , using highly enriched <protein>human CD34+</protein> as well as <cell_line>Lin- murine bone marrow progenitor cells</cell_line> , demonstrates a potent inhibitory effect of 9-cis-RA on burst-forming unit-erythroid ( BFU-E ) colony formation regardless of the <protein>cytokine</protein> stimulating growth .


Specifically , 9-cis-RA potently inhibited the growth of BFU-E response to erythropoietin ( Epo ) ( 100 % ) , stem cell factor ( SCF ) + Epo ( 92 % ) , IL-3 + Epo ( 97 % ) , IL-4 + Epo ( 88 % ) , and IL-9 + Epo ( 100 % ) .

Specifically , 9-cis-RA potently inhibited the growth of BFU-E response to <protein>erythropoietin</protein> ( <protein>Epo</protein> ) ( 100 % ) , <protein>stem cell factor</protein> ( <protein>SCF</protein> ) + <protein>Epo</protein> ( 92 % ) , <protein>IL-3</protein> + <protein>Epo</protein> ( 97 % ) , <protein>IL-4</protein> + <protein>Epo</protein> ( 88 % ) , and <protein>IL-9</protein> + <protein>Epo</protein> ( 100 % ) .


Erythroid colony growth was also inhibited when CD34+ progenitors were seeded at one cell per well , suggesting a direct action of RA .

Erythroid colony growth was also inhibited when <cell_type>CD34+ progenitors</cell_type> were seeded at one cell per well , suggesting a direct action of RA .


Using synthetic ligands to retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) that selectively bind and activate RAR-RXR or RXR-RXR dimers , respectively , we dissected the involvement of the two retinoid response pathways in the regulation of normal myeloid and erythroid progenitor cell growth .

Using synthetic ligands to <protein>retinoic acid receptors</protein> ( <protein>RARs</protein> ) and <protein>retinoid X receptors</protein> ( <protein>RXRs</protein> ) that selectively bind and activate <protein>RAR-RXR</protein> or <protein>RXR-RXR</protein> dimers , respectively , we dissected the involvement of the two retinoid response pathways in the regulation of normal myeloid and erythroid progenitor cell growth .


Transactivation studies showed that both the RAR ( Ro 13-7410 ) and RXR ( Ro 25-6603 and Ro 25-7386 ) ligands were highly selective at 100 nmol/L .

Transactivation studies showed that both the <protein>RAR</protein> ( Ro 13-7410 ) and <protein>RXR</protein> ( Ro 25-6603 and Ro 25-7386 ) ligands were highly selective at 100 nmol/L .


At this concentration , Ro 13-7410 potently inhibited G-CSF -stimulated myeloid as well as SCF + Epo -induced erythroid colony growth .

At this concentration , Ro 13-7410 potently inhibited <protein>G-CSF</protein> -stimulated myeloid as well as <protein>SCF</protein> + <protein>Epo</protein> -induced erythroid colony growth .


At the same concentration , Ro 25-6603 and Ro 25-7386 had little or no effect on G-CSF -induced colony formation , whereas they inhibited 75 % and 53 % , respectively , of SCF + Epo -stimulated BFU-E colony growth .

At the same concentration , Ro 25-6603 and Ro 25-7386 had little or no effect on <protein>G-CSF</protein> -induced colony formation , whereas they inhibited 75 % and 53 % , respectively , of <protein>SCF</protein> + <protein>Epo</protein> -stimulated BFU-E colony growth .


Thus , the RAR-RXR response pathway can signal growth inhibition of normal bone marrow myeloid and erythroid progenitor cells .

Thus , the <protein>RAR-RXR</protein> response pathway can signal growth inhibition of <cell_type>normal bone marrow myeloid and erythroid progenitor cells</cell_type> .


In addition , we demonstrate a unique involvement of the RXR-RXR pathway in mediating growth inhibition of erythroid but not myeloid progenitor cells .

In addition , we demonstrate a unique involvement of the <protein>RXR-RXR</protein> pathway in mediating growth inhibition of <cell_type>erythroid</cell_type> but not <cell_type>myeloid progenitor cells</cell_type> .


AM580 , a stable benzoic derivative of retinoic acid , has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells .

AM580 , a stable benzoic derivative of retinoic acid , has powerful and selective cyto-differentiating effects on <cell_line>acute promyelocytic leukemia cells</cell_line> .


All-trans retinoic acid ( ATRA ) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia ( APL ) .


Paradoxically , APL cells express PML-RAR , an aberrant form of the retinoic acid receptor type alpha ( RAR alpha ) derived from the leukemia-specific t ( 15 ; 17 ) chromosomal translocation .

Paradoxically , <cell_line>APL cells</cell_line> express <protein>PML-RAR</protein> , an aberrant form of the <protein>retinoic acid receptor type alpha</protein> ( <protein>RAR alpha</protein> ) derived from the <dna>leukemia-specific t ( 15 ; 17 ) chromosomal translocation</dna> .


We show here that AM580 , a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist , is a powerful inducer of granulocytic maturation in NB4 , an APL-derived cell line , and in freshly isolated APL blasts .

We show here that AM580 , a stable retinobenzoic derivative originally synthesized as a <protein>RAR alpha</protein> agonist , is a powerful inducer of granulocytic maturation in <cell_line>NB4</cell_line> , an <cell_line>APL-derived cell line</cell_line> , and in <cell_type>freshly isolated APL blasts</cell_type> .


After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor ( G-CSF ) , the compound induces granulocytic maturation , as assessed by determination of the levels of leukocyte alkaline phosphatase , CD11b , CD33 , and G-CSF receptor mRNA , at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects .

After treatment of <cell_line>APL cells</cell_line> with AM580 either alone or in combination with <protein>granulocyte colony-stimulating factor</protein> ( <protein>G-CSF</protein> ) , the compound induces granulocytic maturation , as assessed by determination of the levels of <rna>leukocyte alkaline phosphatase , CD11b , CD33 , and G-CSF receptor mRNA</rna> , at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects .


By contrast , AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease .

By contrast , AM580 is not effective as ATRA in modulating the expression of these <protein>differentiation markers</protein> in the <cell_line>HL-60 cell line</cell_line> and in <cell_type>freshly isolated granulocytes</cell_type> obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease .


In NB4 cells , two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580 , whereas RAR beta- or RAR gamma-specific ligands are totally ineffective .

In <cell_line>NB4 cells</cell_line> , two other synthetic nonselective RAR ligands are capable of inducing <protein>LAP</protein> as much as AM580 , whereas RAR beta- or RAR gamma-specific ligands are totally ineffective .


These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present .

These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which <protein>PML-RAR</protein> is present .


Binding experiments , using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha , show that AM580 has a lower affinity than ATRA for both receptors .

Binding experiments , using <cell_line>COS-7 cells</cell_line> transiently transfected with <protein>PML-RAR</protein> and the normal <protein>RAR alpha</protein> , show that AM580 has a lower affinity than ATRA for both receptors .


However , in the presence of PML-RAR , the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid , whereas , in the presence of RAR alpha , AM580 and ATRA have similar activity .

However , in the presence of <protein>PML-RAR</protein> , the synthetic retinoid is a much better transactivator of <dna>retinoic acid-responsive element-containing promoters</dna> than the natural retinoid , whereas , in the presence of <protein>RAR alpha</protein> , AM580 and ATRA have similar activity .


This may explain the strong cyto-differentiating potential of AM580 in PML-RAR-containing leukemic cells .

This may explain the strong cyto-differentiating potential of AM580 in <cell_type>PML-RAR-containing leukemic cells</cell_type> .


Inhibition of vitamin D receptor-retinoid X receptor-vitamin D response element complex formation by nuclear extracts of vitamin D-resistant New World primate cells .

Inhibition of <protein>vitamin D receptor-retinoid X receptor-vitamin D response element complex</protein> formation by nuclear extracts of <cell_type>vitamin D-resistant New World primate cells</cell_type> .


Most New World primate ( NWP ) genera evolved to require high circulating levels of steroid hormones and vitamin D .


We hypothesized that an intracellular vitamin D binding protein ( IDBP ) , present in both nuclear and cytoplasmic fractions of NWP cells , or another protein ( s ) may cause or contribute to the steroid hormone-resistant state in NWP by disruption of the receptor dimerization process and/or by interference of receptor complex binding to the consensus response elements present in the enhancer regions of steroid-responsive genes .

We hypothesized that an <protein>intracellular vitamin D binding protein</protein> ( <protein>IDBP</protein> ) , present in both nuclear and cytoplasmic fractions of <cell_line>NWP cells</cell_line> , or another protein ( s ) may cause or contribute to the steroid hormone-resistant state in <cell_line>NWP</cell_line> by disruption of the receptor dimerization process and/or by interference of <protein>receptor complex</protein> binding to the <dna>consensus response elements</dna> present in the <dna>enhancer regions</dna> of <dna>steroid-responsive genes</dna> .


We employed electromobility shift assay ( EMSA ) to screen for the presence of proteins capable of binding to the vitamin D response element ( VDRE ) .

We employed electromobility shift assay ( EMSA ) to screen for the presence of proteins capable of binding to the <dna>vitamin D response element</dna> ( <dna>VDRE</dna> ) .


Nuclear and post-nuclear extracts were prepared from two B-lymphoblastoid cell lines known to be representative of the vitamin D-resistant and wild type phenotypes , respectively .

Nuclear and post-nuclear extracts were prepared from two <cell_line>B-lymphoblastoid cell lines</cell_line> known to be representative of the <cell_line>vitamin D-resistant</cell_line> and <cell_line>wild type phenotypes</cell_line> , respectively .


The extracts were compared for their ability to retard the migration of radiolabeled double stranded oligomers representative of the VDREs of the human osteocalcin and the mouse osteopontin gene promoters .

The extracts were compared for their ability to retard the migration of radiolabeled double stranded oligomers representative of the <dna>VDREs</dna> of the <dna>human osteocalcin and the mouse osteopontin gene promoters</dna> .


A specific , retarded band containing VDR-RXR was identified when wild type cell but not when vitamin D-resistant cell nuclear extract was used in the binding reaction with either probe .

A specific , retarded band containing <protein>VDR-RXR</protein> was identified when wild type cell but not when vitamin D-resistant cell nuclear extract was used in the binding reaction with either probe .


In addition , vitamin D-resistant cell nuclear extract contained a protein ( s ) which was bound specifically to the VDRE and was capable of completely inhibiting VDR-RXR-VDRE complex formation ; these effects were not demonstrated with nuclear extract from the wild type cell line or with the post-nuclear extract of the vitamin D-resistant cell line .

In addition , vitamin D-resistant cell nuclear extract contained a protein ( s ) which was bound specifically to the <dna>VDRE</dna> and was capable of completely inhibiting <protein>VDR-RXR-VDRE complex</protein> formation ; these effects were not demonstrated with nuclear extract from the <cell_line>wild type cell line</cell_line> or with the post-nuclear extract of the <cell_line>vitamin D-resistant cell line</cell_line> .


We conclude that a VDRE-binding protein ( s ) , distinct from IDBP and present in nuclear extract of cells from a prototypical vitamin D-resistant NWP , is capable of inhibiting normal VDR-RXR heterodimer binding to the VDRE .

We conclude that a <protein>VDRE-binding protein</protein> ( s ) , distinct from <protein>IDBP</protein> and present in nuclear extract of cells from a <cell_line>prototypical vitamin D-resistant NWP</cell_line> , is capable of inhibiting normal <protein>VDR-RXR</protein> heterodimer binding to the <dna>VDRE</dna> .


BCL-6 expression during B-cell activation .

<protein>BCL-6</protein> expression during B-cell activation .


Translocations involving the BCL-6 gene are common in the diffuse large cell subtype of non-Hodgkin 's lymphoma .

Translocations involving the <dna>BCL-6 gene</dna> are common in the diffuse large cell subtype of non-Hodgkin 's lymphoma .


Invariably , the BCL-6 coding region is intact , but its 5 ' untranslated region is replaced with sequences from the translocation partner .

Invariably , the <protein>BCL-6</protein> coding region is intact , but its <dna>5 ' untranslated region</dna> is replaced with sequences from the <dna>translocation partner</dna> .


The present study shows that BCL-6 expression is regulated in lymphocytes during mitogenic stimulation .

The present study shows that <protein>BCL-6</protein> expression is regulated in <cell_type>lymphocytes</cell_type> during mitogenic stimulation .


Resting B and T lymphocytes contain high levels of BCL-6 mRNA .

<cell_type>Resting B and T lymphocytes</cell_type> contain high levels of <rna>BCL-6 mRNA</rna> .


Stimulation of mouse B cells with anti-IgM or IgD antibodies , bacterial lipopolysaccharide , phorbol 12-myristate 13-acetate plus ionomycin , or CD40 ligand led to a five-fold to 35-fold decrease in BCL-6 mRNA levels .

Stimulation of <cell_type>mouse B cells</cell_type> with <protein>anti-IgM or IgD antibodies</protein> , bacterial lipopolysaccharide , phorbol 12-myristate 13-acetate plus ionomycin , or <protein>CD40 ligand</protein> led to a five-fold to 35-fold decrease in <rna>BCL-6 mRNA</rna> levels .


Similar downregulation of BCL-6 mRNA was seen in human B cells stimulated with Staphylococcus aureus plus interleukin-2 or anti-IgM antibodies and in human T lymphocytes stimulated with phytohemagglutinin .

Similar downregulation of <rna>BCL-6 mRNA</rna> was seen in <cell_type>human B cells</cell_type> stimulated with Staphylococcus aureus plus <protein>interleukin-2</protein> or <protein>anti-IgM antibodies</protein> and in <cell_type>human T lymphocytes</cell_type> stimulated with <protein>phytohemagglutinin</protein> .


BCL-6 mRNA levels began to decrease 8 to 16 hours after stimulation , before cells entered S phase .

<rna>BCL-6 mRNA</rna> levels began to decrease 8 to 16 hours after stimulation , before cells entered S phase .


Although polyclonal activation of B cells in vitro invariably decreased BCL-6 MRNA expression , activated B cells from human germinal centers expressed BCL-6 mRNA at levels comparable to the levels in resting B cells .

Although polyclonal activation of <cell_type>B cells</cell_type> in vitro invariably decreased <protein>BCL-6</protein> MRNA expression , <cell_type>activated B cells</cell_type> from human germinal centers expressed BCL-6 mRNA at levels comparable to the levels in resting B cells .


Despite these similar mRNA levels , BCL-6 protein expression was threefold to 34-fold higher in germinal center B cells than in resting B cells , suggesting that BCL-6 protein levels are controlled by translational or posttranslational mechanisms .

Despite these similar mRNA levels , <protein>BCL-6</protein> protein expression was threefold to 34-fold higher in <cell_type>germinal center B cells</cell_type> than in <cell_type>resting B cells</cell_type> , suggesting that <protein>BCL-6</protein> protein levels are controlled by translational or posttranslational mechanisms .


These observations suggest that the germinal center reaction provides unique activation signals to B cells that allow for continued , high-level BCL-6 expression .

These observations suggest that the germinal center reaction provides unique activation signals to <cell_type>B cells</cell_type> that allow for continued , high-level <protein>BCL-6</protein> expression .


DNA-binding phosphoproteins induced after T cell activation : effects of cyclosporin A .

<protein>DNA-binding phosphoproteins</protein> induced after T cell activation : effects of cyclosporin A .


To define novel proteins involved in the early transcriptional response during the activation of human T lymphocytes , we used a high-resolution , two-dimensional gel electrophoresis system to identify nuclear , deoxyribonucleic acid ( DNA ) binding proteins exhibiting rapid changes in phosphorylation following cell stimulation .

To define <protein>novel proteins</protein> involved in the early transcriptional response during the activation of <cell_type>human T lymphocytes</cell_type> , we used a high-resolution , two-dimensional gel electrophoresis system to identify <protein>nuclear , deoxyribonucleic acid ( DNA ) binding proteins</protein> exhibiting rapid changes in phosphorylation following cell stimulation .


We identified 18 nuclear proteins whose phosphorylation level changed more than 5-fold upon activation .

We identified 18 <protein>nuclear proteins</protein> whose phosphorylation level changed more than 5-fold upon activation .


Of these , 11 were found to possess DNA-binding properties .


The 11 phosphoproteins with DNA-binding activity , along with 4 others , were analyzed further .

The 11 <protein>phosphoproteins</protein> with DNA-binding activity , along with 4 others , were analyzed further .


Phosphoamino acid analysis revealed several sets of proteins with different phosphorylated residues Kinetic analysis of the phosphorylation of the selected proteins was performed and revealed a complex group of transient and sustained responses to cell activation .


Finally , the activation-induced changes in one set of phosphoproteins were dramatically inhibited by cyclosporin A .

Finally , the activation-induced changes in one set of <protein>phosphoproteins</protein> were dramatically inhibited by cyclosporin A .


We suggest that these phosphoproteins may be directly involved in regulating the transcriptional response to cellular activation by external stimuli .

We suggest that these <protein>phosphoproteins</protein> may be directly involved in regulating the transcriptional response to cellular activation by external stimuli .


Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1 : a potential mechanism for constitutive induction of NF-kappaB .

Inactivation of <protein>IkappaBbeta</protein> by the <protein>tax protein</protein> of human T-cell leukemia virus type 1 : a potential mechanism for constitutive induction of <protein>NF-kappaB</protein> .


In resting T lymphocytes , the transcription factor NF-kappaB is sequestered in the cytoplasm via interactions with members of the I kappa B family of inhibitors , including IkappaBalpha and IkappaBbeta .

In <cell_type>resting T lymphocytes</cell_type> , the <protein>transcription factor</protein> <protein>NF-kappaB</protein> is sequestered in the cytoplasm via interactions with members of the <protein>I kappa B family</protein> of inhibitors , including <protein>IkappaBalpha</protein> and <protein>IkappaBbeta</protein> .


During normal T-cell activation , IkappaBalpha is rapidly phosphorylated , ubiquitinated , and degraded by the 26S proteasome , thus permitting the release of functional NF-kappaB .

During normal T-cell activation , <protein>IkappaBalpha</protein> is rapidly phosphorylated , ubiquitinated , and degraded by the <protein>26S proteasome</protein> , thus permitting the release of functional <protein>NF-kappaB</protein> .


In contrast to its transient pattern of nuclear induction during an immune response , NF-kappaB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type I ( HTLV-1 ) .

In contrast to its transient pattern of nuclear induction during an immune response , <protein>NF-kappaB</protein> is constitutively activated in cells expressing the <protein>Tax transforming protein</protein> of human T-cell leukemia virus type I ( HTLV-1 ) .


Recent studies indicate that HTLV-1 Tax targets IkappaBalpha to the ubiquitin-proteasome pathway .

Recent studies indicate that HTLV-1 <protein>Tax</protein> targets <protein>IkappaBalpha</protein> to the ubiquitin-proteasome pathway .


However , it remains unclear how this viral protein induces a persistent rather than transient NF-kappaB response .

However , it remains unclear how this <protein>viral protein</protein> induces a persistent rather than transient <protein>NF-kappaB</protein> response .


In this report , we provide evidence that in addition to acting on IkappaBalpha , Tax stimulates the turnover Of IkappaBbeta via a related targeting mechanism .

In this report , we provide evidence that in addition to acting on <protein>IkappaBalpha</protein> , <protein>Tax</protein> stimulates the turnover Of <protein>IkappaBbeta</protein> via a related targeting mechanism .


Like IkappaBalpha , Tax -mediated breakdown of IkappaBbeta in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation Of IkappaBbeta at two serine residues present within its N-terminal region .

Like <protein>IkappaBalpha</protein> , <protein>Tax</protein> -mediated breakdown of <protein>IkappaBbeta</protein> in <cell_line>transfected T lymphocytes</cell_line> is blocked either by cell-permeable proteasome inhibitors or by mutation Of <protein>IkappaBbeta</protein> at two serine residues present within its <protein>N-terminal region</protein> .