This atrophy induction does not involve apoptotic mechanisms in thymocytes affected by the bcl-2 proto-oncogene .

This atrophy induction does not involve apoptotic mechanisms in <cell_type>thymocytes</cell_type> affected by the <dna>bcl-2 proto-oncogene</dna> .


TCDD mediates atrophy induction through its specific receptor ( the AhR ) and not through effects on the estrogen receptor .

TCDD mediates atrophy induction through its specific receptor ( the <protein>AhR</protein> ) and not through effects on the estrogen receptor .


Both TCDD and estradiol induce extrathymic T-cell differentiation in the liver .


These extrathymic T-cell populations include cells expressing elevated levels of V beta T-cell receptors that are normally deleted in thymic development .

These <cell_type>extrathymic T-cell populations</cell_type> include cells expressing elevated levels of <protein>V beta T-cell receptors</protein> that are normally deleted in thymic development .


Identification of Bcd , a novel proto-oncogene expressed in B-cells .

Identification of <dna>Bcd</dna> , a novel <dna>proto-oncogene</dna> expressed in <cell_type>B-cells</cell_type> .


A novel B-cell derived ( Bcd ) oncogene has been isolated from the peripheral blood lymphocytes of one B-cell chronic lymphocytic leukemia ( B-CLL ) patient using DNA transfer and a mouse tumorigenicity assay .

A <cell_type>novel B-cell</cell_type> derived ( <dna>Bcd</dna> ) <dna>oncogene</dna> has been isolated from the peripheral blood lymphocytes of one B-cell chronic lymphocytic leukemia ( B-CLL ) patient using DNA transfer and a mouse tumorigenicity assay .


The Bcd proto-oncogene was activated by a truncation in the 5 ' UTR .

The <dna>Bcd</dna> <dna>proto-oncogene</dna> was activated by a truncation in the <dna>5 ' UTR</dna> .


It predicts for two open reading frames ( ORFs ) .

It predicts for two <dna>open reading frames</dna> ( <dna>ORFs</dna> ) .


ORF1 consists of 240 bp that would encode 80 amino acids , while the major ORF2 consists of 648 bp capable of coding for 216 amino acids .

<dna>ORF1</dna> consists of 240 bp that would encode 80 amino acids , while the <dna>major ORF2</dna> consists of 648 bp capable of coding for 216 amino acids .


Predicted peptide sequence of ORF2 contained a zinc finger domain which showed significant homology to GC box binding proteins BTEB2 and SP1 .

<protein>Predicted peptide sequence</protein> of <dna>ORF2</dna> contained a <protein>zinc finger domain</protein> which showed significant homology to <protein>GC box binding proteins</protein> <protein>BTEB2</protein> and <protein>SP1</protein> .


Transfection of an expression vector containing ORF2 but not full length cDNA was able to transform NIH3T3 cells and induce tumors in nude mice .

Transfection of an <dna>expression vector</dna> containing <dna>ORF2</dna> but not <dna>full length cDNA</dna> was able to transform <cell_line>NIH3T3 cells</cell_line> and induce tumors in nude mice .


Bcd mRNA transcripts of < or = 2.6 kb were selectively expressed in PBL and testis of healthy individuals .

<rna>Bcd mRNA transcripts</rna> of < or = 2.6 kb were selectively expressed in <cell_line>PBL</cell_line> and testis of healthy individuals .


Within the PBL , Bcd gene expression was restricted to CD19+ B-cells and absent from CD14+ monocytes and T-cells .

Within the <cell_type>PBL</cell_type> , <dna>Bcd</dna> gene expression was restricted to <cell_type>CD19+ B-cells</cell_type> and absent from <cell_type>CD14+ monocytes</cell_type> and <cell_type>T-cells</cell_type> .


Bcd transcripts were detected in all normal PBL samples tested but not in several malignant human B-cell lines and not in 50 % of B-cells from B-CLL patients .

<dna>Bcd</dna> transcripts were detected in all normal <cell_type>PBL</cell_type> samples tested but not in several <cell_line>malignant human B-cell lines</cell_line> and not in 50 % of <cell_type>B-cells</cell_type> from B-CLL patients .


However , stimulation of B-cells from B-CLL patients under conditions which induced differentiation into plasma cells was associated with induction of Bcd gene expression .

However , stimulation of <cell_type>B-cells</cell_type> from B-CLL patients under conditions which induced differentiation into <cell_type>plasma cells</cell_type> was associated with induction of <dna>Bcd</dna> gene expression .


The Bcd gene may therefore play an important role in B-cell growth and development .

The <dna>Bcd gene</dna> may therefore play an important role in B-cell growth and development .


A novel SP-1 site in the human interleukin-1 beta promoter confers preferential transcriptional activity in keratinocytes .

A <dna>novel SP-1 site</dna> in the <dna>human interleukin-1 beta promoter</dna> confers preferential transcriptional activity in <cell_type>keratinocytes</cell_type> .


To investigate the mechanisms of transcriptional activation of interleukin-1beta ( IL-1beta ) in non-monocytic cells , we constructed a series of reporter plasmids with the bacterial chloramphenicol acetyltransferase gene linked to various parts of the human IL-1beta promoter and performed transient transfection experiments .

To investigate the mechanisms of transcriptional activation of <protein>interleukin-1beta</protein> ( <protein>IL-1beta</protein> ) in non-monocytic cells , we constructed a series of reporter plasmids with the bacterial chloramphenicol acetyltransferase gene linked to various parts of the <dna>human IL-1beta promoter</dna> and performed transient transfection experiments .


We identified a promoter segment that activates transcription most efficiently in keratinocytes .

We identified a promoter segment that activates transcription most efficiently in <cell_type>keratinocytes</cell_type> .


Electrophoretic mobility shift assays ( EMSA ) with a 43-mer oligonucleotide derived from the functionally identified cis-acting element revealed specific complexes .

Electrophoretic mobility shift assays ( EMSA ) with a <dna>43-mer oligonucleotide</dna> derived from the functionally identified <dna>cis-acting element</dna> revealed specific complexes .


By competition analysis with transcription factor consensus sequence oligonucleotides and by immunosupershift , transcription factor SP-1 or a closely related protein was shown to bind to this regulatory element .

By competition analysis with <dna>transcription factor consensus sequence oligonucleotides</dna> and by immunosupershift , <protein>transcription factor SP-1</protein> or a closely related protein was shown to bind to this <dna>regulatory element</dna> .


The closest match to the known SP-1 consensus sequence within the respective region is a TCCCCTCCCCT motif .

The closest match to the known <dna>SP-1 consensus sequence</dna> within the respective region is a <dna>TCCCCTCCCCT motif</dna> .


Mutation of this motif almost completely , and specifically , abolished the binding of two low-mobility complexes and led to a 95 % decrease of constitutive transcriptional activation of a reporter construct IL-1beta ( -170/+108 ) .

Mutation of this motif almost completely , and specifically , abolished the binding of two <protein>low-mobility complexes</protein> and led to a 95 % decrease of constitutive transcriptional activation of a reporter construct <protein>IL-1beta</protein> ( -170/+108 ) .


Likewise , activation of this reporter construct by tumor necrosis factor-alpha depended on the SP-1 site .

Likewise , activation of this reporter construct by <protein>tumor necrosis factor-alpha</protein> depended on the <dna>SP-1 site</dna> .


These observations suggest that a so-far-unrecognized SP-1 site in the human IL-1beta promoter may participate in the transcriptional regulation of this gene in keratinocytes .

These observations suggest that a so-far-unrecognized <dna>SP-1 site</dna> in the <dna>human IL-1beta promoter</dna> may participate in the transcriptional regulation of this gene in <cell_type>keratinocytes</cell_type> .


Expression of Egr-1 correlates with the transformed phenotype and the type of viral latency in EBV genome positive lymphoid cell lines .

Expression of <protein>Egr-1</protein> correlates with the transformed phenotype and the type of viral latency in <cell_line>EBV genome positive lymphoid cell lines</cell_line> .


In this paper we have investigated the role of Egr-1 in B cell growth regulation by examining the gene expression in a panel of B cell lines , including both EBV genome negative and EBV carrying cell lines .

In this paper we have investigated the role of <protein>Egr-1</protein> in B cell growth regulation by examining the gene expression in a panel of <cell_line>B cell lines</cell_line> , including both <dna>EBV genome</dna> negative and <cell_line>EBV carrying cell lines</cell_line> .


Egr-1 expression correlates with the cellular phenotype and the specific pattern of viral latency established within the individual cell lines .

<protein>Egr-1</protein> expression correlates with the cellular phenotype and the specific pattern of viral latency established within the <cell_line>individual cell lines</cell_line> .


Thus , constitutive activation of Egr-1 gene is invariably associated with unrestricted expression of viral latent genes in all group III EBV genome carrying cell lines .

Thus , constitutive activation of <protein>Egr-1</protein> gene is invariably associated with unrestricted expression of viral latent genes in all <cell_line>group III EBV genome carrying cell lines</cell_line> .


In contrast , Egr-1 expression is abrogated in group I Burkitt tumor cells , irrespective of the EBV genome carrying status .

In contrast , <protein>Egr-1</protein> expression is abrogated in <cell_line>group I Burkitt tumor cells</cell_line> , irrespective of the <dna>EBV genome</dna> carrying status .


Activated viral gene expression associated with phenotypic conversion of group I cell lines in to group II or III restores the Egr-1 gene expression .

Activated viral gene expression associated with phenotypic conversion of <cell_line>group I cell lines</cell_line> in to <cell_line>group II</cell_line> or <cell_line>III</cell_line> restores the <dna>Egr-1 gene</dna> expression .


Several forms of EGR-1 protein are found within the different groups of cell lines , and the binding activity to DNA consensus sequences was investigated .

Several forms of <protein>EGR-1 protein</protein> are found within the different groups of cell lines , and the binding activity to <dna>DNA consensus sequences</dna> was investigated .


Finally , time course analysis of Egr-1 expression during the early steps of EBV infection in vitro demonstrated that Egr-1 is upregulated within minutes from the initial interaction with the B lymphocyte .

Finally , time course analysis of <protein>Egr-1</protein> expression during the early steps of EBV infection in vitro demonstrated that <protein>Egr-1</protein> is upregulated within minutes from the initial interaction with the <cell_type>B lymphocyte</cell_type> .


Expression of erythroid-specific genes in megakaryoblastic disorders .

Expression of <dna>erythroid-specific genes</dna> in megakaryoblastic disorders .


Currently available data indicate that erythroid and megakaryocytic differentiation pathways are closely related to each other , and there may exist progenitor cells common to those two lineages may exist .

Currently available data indicate that erythroid and megakaryocytic differentiation pathways are closely related to each other , and there may exist <cell_type>progenitor cells</cell_type> common to those two lineages may exist .


Acute megakaryoblastic leukemia ( AML-M7 ) and transient myeloproliferative disorder in Down 's syndrome ( TMD ) are characterized by rapid growth of abnormal blast cells which express megakaryocytic markers .

Acute megakaryoblastic leukemia ( AML-M7 ) and transient myeloproliferative disorder in Down 's syndrome ( TMD ) are characterized by rapid growth of <cell_type>abnormal blast cells</cell_type> which express <protein>megakaryocytic markers</protein> .


These blast cells express lineage-specific transcription factors such as GATA-1 common to these lineages and frequently express erythroid-specific mRNAs such as gamma-globin and erythroid delta-aminolevulinate synthase ( ALAS-E ) , indicating that most of the blasts in M7 and TMD cases have erythroid and megakaryocytic phenotypes .

These <cell_type>blast cells</cell_type> express <protein>lineage-specific transcription factors</protein> such as <protein>GATA-1</protein> common to these lineages and frequently express <rna>erythroid-specific mRNAs</rna> such as <protein>gamma-globin</protein> and <protein>erythroid delta-aminolevulinate synthase</protein> ( <protein>ALAS-E</protein> ) , indicating that most of the blasts in M7 and TMD cases have erythroid and megakaryocytic phenotypes .


These results suggest that blasts in M7 and TMD may correspond to progenitors of both erythroid and megakaryocytic lineages .

These results suggest that <cell_type>blasts</cell_type> in M7 and TMD may correspond to <cell_type>progenitors</cell_type> of both <cell_type>erythroid and megakaryocytic lineages</cell_type> .


Stat3 recruitment by two distinct ligand-induced , tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain .

<protein>Stat3</protein> recruitment by two distinct <protein>ligand-induced , tyrosine-phosphorylated docking sites</protein> in the <protein>interleukin-10 receptor intracellular domain</protein> .


Recent work has shown that IL-10 induces activation of the JAK -STAT signaling pathway .

Recent work has shown that <protein>IL-10</protein> induces activation of the <protein>JAK</protein> <protein>-STAT</protein> signaling pathway .


To define the mechanism underlying signal transducer and activator of transcription ( STAT ) protein recruitment to the interleukin 10 ( IL-10 ) receptor , the STAT proteins activated by IL-10 in different cell populations were first defined using electrophoretic mobility shift assays .

To define the mechanism underlying <protein>signal transducer and activator of transcription ( STAT ) protein</protein> recruitment to the <protein>interleukin 10 ( IL-10 ) receptor</protein> , the <protein>STAT proteins</protein> activated by <protein>IL-10</protein> in different cell populations were first defined using electrophoretic mobility shift assays .


In all cells tested , IL-10 activated Stat1 and Stat3 and induced the formation of three distinct DNA binding complexes that contained different combinations of these two transcription factors .

In all cells tested , <protein>IL-10</protein> activated <protein>Stat1</protein> and <protein>Stat3</protein> and induced the formation of three distinct <protein>DNA binding complexes</protein> that contained different combinations of these two <protein>transcription factors</protein> .


IL-10 also activated Stat5 in Ba/F3 cells that stably expressed the murine IL-10 receptor .

<protein>IL-10</protein> also activated <protein>Stat5</protein> in <cell_line>Ba/F3 cells</cell_line> that stably expressed the murine <protein>IL-10 receptor</protein> .


Using a structure-function mutagenesis approach , two tyrosine residues ( Tyr427 and Tyr477 ) in the intracellular domain of the murine IL-10 receptor were found to be redundantly required for receptor function and for activation of Stat3 but not for Stat1 or Stat5 .

Using a structure-function mutagenesis approach , two tyrosine residues ( Tyr427 and Tyr477 ) in the <protein>intracellular domain</protein> of the murine <protein>IL-10</protein> receptor were found to be redundantly required for receptor function and for activation of <protein>Stat3</protein> but not for <protein>Stat1</protein> or <protein>Stat5</protein> .


Twelve amino acid peptides encompassing either of these two tyrosine residues in phosphorylated form coprecipitated Stat3 but not Stat1 and blocked IL-10 -induced Stat3 phosphorylation in a cell-free system .

Twelve amino acid peptides encompassing either of these two tyrosine residues in <protein>phosphorylated form</protein> coprecipitated <protein>Stat3</protein> but not <protein>Stat1</protein> and blocked <protein>IL-10</protein> -induced <protein>Stat3</protein> phosphorylation in a cell-free system .


In contrast , tyrosine-phosphorylated peptides containing Tyr374 or Tyr396 did not interact with Stat3 or block Stat3 activation .

In contrast , tyrosine-phosphorylated peptides containing Tyr374 or Tyr396 did not interact with <protein>Stat3</protein> or block <protein>Stat3</protein> activation .


These data demonstrate that Stat3 but not Stat1 or Stat5 is directly recruited to the ligand-activated IL-10 receptor by binding to specific but redundant receptor intracellular domain sequences containing phosphotyrosine .

These data demonstrate that <protein>Stat3</protein> but not <protein>Stat1</protein> or <protein>Stat5</protein> is directly recruited to the <protein>ligand-activated IL-10 receptor</protein> by binding to specific but redundant <protein>receptor intracellular domain sequences</protein> containing phosphotyrosine .


This study thus supports the concept that utilization of distinct STAT proteins by different cytokine receptors is dependent on the expression of particular ligand-activatable , tyrosine-containing STAT docking sites in receptor intracellular domains .

This study thus supports the concept that utilization of distinct <protein>STAT proteins</protein> by different <protein>cytokine receptors</protein> is dependent on the expression of particular ligand-activatable , <protein>tyrosine-containing STAT docking sites</protein> in <protein>receptor intracellular domains</protein> .


Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF .

Silencing of human fetal <protein>globin</protein> expression is impaired in the absence of the <protein>adult beta-globin gene activator protein</protein> <protein>EKLF</protein> .


Globin genes are subject to tissue-specific and developmental stage-specific regulation .

<dna>Globin genes</dna> are subject to tissue-specific and developmental stage-specific regulation .


A switch from human fetal ( gamma ) -to adult ( beta ) -globin expression occurs within erythroid precursor cells of the adult lineage .

A switch from <protein>human fetal ( gamma )</protein> -to <protein>adult ( beta ) -globin</protein> expression occurs within <cell_type>erythroid precursor cells</cell_type> of the <cell_type>adult lineage</cell_type> .


Previously we and others showed by targeted gene disruption that the zinc finger gene , erythroid Kruppel-like factor ( EKLF ) , is required for expression of the beta-globin gene in mice , presumably through interaction with a high-affinity binding site in the proximal promoter .

Previously we and others showed by targeted gene disruption that the <dna>zinc finger gene</dna> , <protein>erythroid Kruppel-like factor</protein> ( <protein>EKLF</protein> ) , is required for expression of the <dna>beta-globin gene</dna> in mice , presumably through interaction with a <dna>high-affinity binding site</dna> in the <dna>proximal promoter</dna> .


To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes ( +/- ) with mice harboring a human beta-globin yeast artificial chromosome transgene .

To examine the role of <protein>EKLF</protein> in the developmental regulation of the <dna>human gamma-globin gene</dna> we interbred <protein>EKLF heterozygotes</protein> ( +/- ) with mice harboring a <dna>human beta-globin yeast artificial chromosome transgene</dna> .


We find that in the absence of EKLF , while human beta-globin expression is dramatically reduced , gamma-globin transcripts are elevated approximately 5-fold .

We find that in the absence of <protein>EKLF</protein> , while <protein>human beta-globin</protein> expression is dramatically reduced , <rna>gamma-globin transcripts</rna> are elevated approximately 5-fold .


Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch .

Impaired silencing of <protein>gamma-globin</protein> expression identifies <protein>EKLF</protein> as the first <protein>transcription factor</protein> participating quantitatively in the <protein>gamma-globin</protein> to <protein>beta-globin</protein> switch .


Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene .

Our findings are compatible with a competitive model of switching in which <protein>EKLF</protein> mediates an adult stage-specific interaction between the <dna>beta-globin gene promoter</dna> and the <dna>locus control region</dna> that excludes the <dna>gamma-globin gene</dna> .


Stimulation of human peripheral blood mononuclear cells by zinc and related cations .

Stimulation of <cell_type>human peripheral blood mononuclear cells</cell_type> by zinc and related cations .


Zinc is an important trace element for immune function .


Here , we show that zinc addition in a serum- and lipopolysaccharide-free cell culture system leads to significantly enhanced levels of interleukin 1 beta ( IL-1 beta ) and tumour necrosis factor alpha ( TNF-alpha ) and to expression of the corresponding mRNA in human peripheral blood mononuclear cells ( PBMC ) .

Here , we show that zinc addition in a serum- and lipopolysaccharide-free cell culture system leads to significantly enhanced levels of <protein>interleukin 1 beta</protein> ( <protein>IL-1 beta</protein> ) and <protein>tumour necrosis factor alpha</protein> ( <protein>TNF-alpha</protein> ) and to expression of the corresponding <rna>mRNA</rna> in <cell_type>human peripheral blood mononuclear cells</cell_type> ( <cell_type>PBMC</cell_type> ) .


Structurally related divalent cations like cobalt , nickel , and mercury also partially increase monokine secretion but to a much lower and thus insignificant extent .


They fail to induce mRNA of TNF-alpha after 3 h of culture .

They fail to induce <rna>mRNA</rna> of <protein>TNF-alpha</protein> after 3 h of culture .


Therefore , monokine induction is a zinc-specific effect influenced by the physicochemical properties of the ion .


Confirmation of the unique significance of zinc for immune function provides a better understanding of the mechanisms of specific zinc-mediated immune modulation .


E3 , a hematopoietic-specific transcript directly regulated by the retinoic acid receptor alpha .

<protein>E3</protein> , a <protein>hematopoietic-specific transcript</protein> directly regulated by the <protein>retinoic acid receptor alpha</protein> .


Retinoic acid ( RA ) -induced maturation mediated by the retinoic acid receptor alpha ( RAR alpha ) has been implicated in myeloid development .

Retinoic acid ( RA ) -induced maturation mediated by the <protein>retinoic acid receptor alpha</protein> ( <protein>RAR alpha</protein> ) has been implicated in myeloid development .


We have used differential hybridization analysis of a cDNA library constructed from the murine RA-inducible MPRO promyelocyte cell line to identify immediate-early genes induced by RA during granulocytic differentiation .

We have used differential hybridization analysis of a <dna>cDNA library</dna> constructed from the murine <cell_line>RA-inducible MPRO promyelocyte cell line</cell_line> to identify <dna>immediate-early genes</dna> induced by RA during granulocytic differentiation .


E3 , one of nine sequences identified , was upregulated in an immediate-early manner , with transcript levels peaking after 60 minutes exposure to RA .

<protein>E3</protein> , one of nine sequences identified , was upregulated in an immediate-early manner , with transcript levels peaking after 60 minutes exposure to RA .


E3 transcripts were RA-inducible in HL60 cells , but not in an RA-resistant subclone , HL60R , that harbors a mutated RAR alpha gene .

<protein>E3 transcripts</protein> were RA-inducible in <cell_line>HL60 cells</cell_line> , but not in an <cell_line>RA-resistant subclone</cell_line> , <cell_line>HL60R</cell_line> , that harbors a mutated <dna>RAR alpha gene</dna> .


However , when HL60R cells were transduced with a functional copy of the RAR alpha gene , RA induced a 10-fold increase in E3 mRNA levels .

However , when <cell_line>HL60R cells</cell_line> were transduced with a functional copy of the <dna>RAR alpha gene</dna> , RA induced a 10-fold increase in <protein>E3</protein> mRNA levels .


E3 transcripts are present in the myeloid , B-lymphoid , and erythroid lineages , absent in nonhematopoietic cells , and encode a highly hydrophobic , potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in myeloid cells .

<protein>E3 transcripts</protein> are present in the <cell_type>myeloid , B-lymphoid , and erythroid lineages</cell_type> , absent in <cell_type>nonhematopoietic cells</cell_type> , and encode a highly hydrophobic , potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in <cell_type>myeloid cells</cell_type> .


The murine E3 promoter harbors a single bipartite retinoic acid response element which in transient transfection assays conferred RA sensitivity .

The murine <dna>E3 promoter</dna> harbors a single <dna>bipartite retinoic acid response element</dna> which in transient transfection assays conferred RA sensitivity .


These results indicate that E3 is a hematopoietic-specific gene that is an immediate target for the activated RAR alpha during myelopoiesis .

These results indicate that <protein>E3</protein> is a <dna>hematopoietic-specific gene</dna> that is an immediate target for the activated <protein>RAR alpha</protein> during myelopoiesis .


Multifactor cis-dominant negative regulation of IL-2 gene expression in anergized T cells .

Multifactor cis-dominant negative regulation of <dna>IL-2 gene</dna> expression in <cell_type>anergized T cells</cell_type> .


The molecular mechanism underlying IL-2 transcriptional blockade in anergic T cell clones is not fully understood .

The molecular mechanism underlying <protein>IL-2</protein> transcriptional blockade in <cell_line>anergic T cell clones</cell_line> is not fully understood .


To examine whether an active negative regulatory process occurs , we created a reporter construct containing as an enhancer four copies of the NF-AT site and one copy of the octamer site ( 4X NF-AT-Oct ) .

To examine whether an active negative regulatory process occurs , we created a <dna>reporter construct</dna> containing as an <dna>enhancer</dna> four copies of the <dna>NF-AT site</dna> and one copy of the <dna>octamer site</dna> ( <dna>4X NF-AT-Oct</dna> ) .


This construct was only slightly reduced ( 1.3-fold ) in its expression when stimulated under anergic conditions , while a whole mouse IL-2 enhancer construct showed a reduction of 4.3-fold .

This construct was only slightly reduced ( 1.3-fold ) in its expression when stimulated under anergic conditions , while a whole mouse <dna>IL-2 enhancer construct</dna> showed a reduction of 4.3-fold .


Addition of the -176 to -96 sequence to the 4X NF-AT-Oct construct did not impart the ability to be affected by anergy , but addition of the -236 to -96 sequence did , demonstrating that anergy is an active inhibitory process and that more than the presence of the -150 AP-1 binding site ( -152 to -147 ) is required to mediate the effect .

Addition of the <dna>-176 to -96 sequence</dna> to the <dna>4X NF-AT-Oct construct</dna> did not impart the ability to be affected by anergy , but addition of the <dna>-236 to -96 sequence</dna> did , demonstrating that anergy is an active inhibitory process and that more than the presence of the <dna>-150 AP-1 binding site</dna> ( <dna>-152 to -147</dna> ) is required to mediate the effect .


Mutational studies of the -236 to -96 sequence indicated that the presence of both the -130 AP-1-like site ( -187 to -181 ) and the -150 proximal AP-1 site were necessary to observe anergy .

Mutational studies of the <dna>-236 to -96 sequence</dna> indicated that the presence of both the <dna>-130 AP-1-like site</dna> ( <dna>-187 to -181</dna> ) and the <dna>-150 proximal AP-1 site</dna> were necessary to observe anergy .


Because the -180 site is not required for trans-activation , it was possible to confirm by mutation in the normal mouse IL-2 enhancer that this site is absolutely essential for anergy induction .

Because the <dna>-180 site</dna> is not required for trans-activation , it was possible to confirm by mutation in the normal <dna>mouse IL-2 enhancer</dna> that this site is absolutely essential for anergy induction .


The simplest model to explain these results is that anergy is mediated by a complex of multiple transcription factors that exert a cis-acting dominant negative regulatory effect on the trans-activation of the IL-2 gene .

The simplest model to explain these results is that anergy is mediated by a complex of multiple <protein>transcription factors</protein> that exert a cis-acting dominant negative regulatory effect on the trans-activation of the <dna>IL-2 gene</dna> .


Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings .

Severe combined immunodeficiency due to defective binding of the <protein>nuclear factor of activated T cells</protein> in <cell_type>T lymphocytes</cell_type> of two male siblings .


Peripheral blood lymphocytes ( PBL ) and alloreactive T cell lines of two male infants born to consanguinous parents and presenting with severe combined immunodeficiency ( SCID ) showed a pronounced deficiency in T cell activation .

<cell_type>Peripheral blood lymphocytes</cell_type> ( <cell_type>PBL</cell_type> ) and <cell_line>alloreactive T cell lines</cell_line> of two male infants born to consanguinous parents and presenting with severe combined immunodeficiency ( SCID ) showed a pronounced deficiency in T cell activation .


Although phenotypically normal , the proliferative response of the childrens ' T cells was strongly reduced but could be improved by the addition of interleukin-2 ( IL-2 ) .

Although phenotypically normal , the proliferative response of the childrens ' <cell_type>T cells</cell_type> was strongly reduced but could be improved by the addition of <protein>interleukin-2</protein> ( <protein>IL-2</protein> ) .


Furthermore both childrens ' T cells were unable to produce the cytokines IL-2 , interferon-gamma ( IFN-gamma ) , IL-4 and tumor necrosis factor-alpha ( TNF-alpha ) .

Furthermore both childrens ' <cell_type>T cells</cell_type> were unable to produce the <protein>cytokines</protein> <protein>IL-2</protein> , <protein>interferon-gamma</protein> ( <protein>IFN-gamma</protein> ) , <protein>IL-4</protein> and <protein>tumor necrosis factor-alpha</protein> ( <protein>TNF-alpha</protein> ) .


This multiple cytokine production deficiency could not be restored by IL-2 or co-stimulatory signals provided by antigen-presenting cells ( APC ) .

This multiple <protein>cytokine</protein> production deficiency could not be restored by <protein>IL-2</protein> or co-stimulatory signals provided by <cell_type>antigen-presenting cells</cell_type> ( <cell_type>APC</cell_type> ) .


Moreover , mRNA for IL-2 and IFN-gamma could not be detected .

Moreover , <rna>mRNA</rna> for <protein>IL-2</protein> and <protein>IFN-gamma</protein> could not be detected .


In contrast , expression of the activation-dependent cell surface markers CD25 and CD69 was within normal limits .

In contrast , expression of the <protein>activation-dependent cell surface markers</protein> <protein>CD25</protein> and <protein>CD69</protein> was within normal limits .


To determine whether the functional defect of the patients ' T cells was due to the absence or abnormal binding of transcription factors involved in cytokine gene expression , electrophoretic mobility shift assays were used to examine the DNA binding of AP-1 , Oct , CREB , SP1 , NF-kappa B and the nuclear factor of activated T cells ( NF-AT ) to their respective response elements in the promoter of the IL-2 gene .

To determine whether the functional defect of the patients ' <cell_type>T cells</cell_type> was due to the absence or abnormal binding of <protein>transcription factors</protein> involved in <dna>cytokine gene</dna> expression , electrophoretic mobility shift assays were used to examine the DNA binding of <protein>AP-1</protein> , <protein>Oct</protein> , <protein>CREB</protein> , <protein>SP1</protein> , <protein>NF-kappa B</protein> and the <protein>nuclear factor of activated T cells</protein> ( <protein>NF-AT</protein> ) to their respective <dna>response elements</dna> in the <dna>promoter</dna> of the <dna>IL-2 gene</dna> .


Whereas AP-1 , NF-kappa B , Oct , CREB and SP1 displayed normal binding activities in nuclear extracts , the binding of NF-AT to its IL-2 promoter response element was barely detectable both before and after T cell stimulation .

Whereas <protein>AP-1</protein> , NF-kappa B , <protein>Oct</protein> , <protein>CREB</protein> and <protein>SP1</protein> displayed normal binding activities in nuclear extracts , the binding of <protein>NF-AT</protein> to its <protein>IL-2</protein> promoter response element was barely detectable both before and after T cell stimulation .


Our results strongly suggest that this NF-AT /DNA binding defect is responsible for the multiple cytokine deficiency and the SCID phenotype observed in the two infant brothers .

Our results strongly suggest that this <protein>NF-AT</protein> /DNA binding defect is responsible for the multiple <protein>cytokine</protein> deficiency and the SCID phenotype observed in the two infant brothers .


oriP is essential for EBNA gene promoter activity in Epstein-Barr virus-immortalized lymphoblastoid cell lines .

<dna>oriP</dna> is essential for <dna>EBNA gene</dna> promoter activity in <cell_line>Epstein-Barr virus-immortalized lymphoblastoid cell lines</cell_line> .


During Epstein-Barr virus latent infection of B lymphocytes in vitro , six viral nuclear antigens ( EBNAs ) are expressed from one of two promoters , Cp or Wp , whose activities are mutually exclusive .

During Epstein-Barr virus latent infection of <cell_type>B lymphocytes</cell_type> in vitro , six <protein>viral nuclear antigens</protein> ( <protein>EBNAs</protein> ) are expressed from one of two <dna>promoters</dna> , <dna>Cp</dna> or <dna>Wp</dna> , whose activities are mutually exclusive .


Upon infection , Wp is initially active , followed by a switch to Cp for the duration of latency .

Upon infection , <dna>Wp</dna> is initially active , followed by a switch to <dna>Cp</dna> for the duration of latency .


In this study , the region upstream of Cp was analyzed for the presence of cis elements involved in regulating the activities of the EBNA gene promoters in established in vitro immortalized lymphoblastoid cell lines ( LCLs ) .

In this study , the region upstream of <dna>Cp</dna> was analyzed for the presence of cis elements involved in regulating the activities of the <dna>EBNA gene promoters</dna> in established <cell_line>in vitro immortalized lymphoblastoid cell lines</cell_line> ( <cell_line>LCLs</cell_line> ) .


It was determined that oriP , the origin for episomal maintenance during latency , is essential for efficient transcription initiation from either Cp or Wp in LCLs , as well as in some Burkitt 's lymphoma cell lines .

It was determined that <dna>oriP</dna> , the origin for episomal maintenance during latency , is essential for efficient transcription initiation from either <dna>Cp</dna> or <dna>Wp</dna> in <cell_line>LCLs</cell_line> , as well as in some <cell_line>Burkitt 's lymphoma cell lines</cell_line> .


Deletion of the EBNA2-dependent enhancer located upstream of Cp resulted in a ca. two- to fivefold reduction in Cp activity in the LCLs assayed .

Deletion of the <dna>EBNA2-dependent enhancer</dna> located upstream of <dna>Cp</dna> resulted in a ca. two- to fivefold reduction in <dna>Cp</dna> activity in the <cell_line>LCLs</cell_line> assayed .


More extensive deletion of sequences upstream of Cp , including the EBNA2-dependent enhancer , resulted in nearly complete loss of Cp activity .

More extensive deletion of sequences upstream of <dna>Cp</dna> , including the <dna>EBNA2-dependent enhancer</dna> , resulted in nearly complete loss of <dna>Cp</dna> activity .


This loss of activity was shown to correlate with deletion of two CCAAT boxes , a proximal CCAAT box located at bp -61 to -65 and a distal CCAAT box located at bp -253 to -257 , upstream of Cp .

This loss of activity was shown to correlate with deletion of two <dna>CCAAT boxes</dna> , a <dna>proximal CCAAT box</dna> located at <dna>bp -61 to -65</dna> and a distal <dna>CCAAT box</dna> located at bp <dna>-253 to -257</dna> , upstream of <dna>Cp</dna> .


Site-directed mutagenesis of these cis elements demonstrated that Cp activity is highly dependent on the presence of a properly positioned CCAAT box , with the dependence on the distal CCAAT box apparent only when the proximal CCAAT box was deleted or mutated .

Site-directed mutagenesis of these <dna>cis elements</dna> demonstrated that <dna>Cp</dna> activity is highly dependent on the presence of a properly positioned <dna>CCAAT box</dna> , with the dependence on the <dna>distal CCAAT box</dna> apparent only when the <dna>proximal CCAAT box</dna> was deleted or mutated .


Deletion of the glucocorticoid response elements located at ca. bp -850 upstream of Cp did not result in a significant loss in activity .

Deletion of the glucocorticoid response elements located at <dna>ca. bp -850</dna> upstream of <dna>Cp</dna> did not result in a significant loss in activity .


In general , deletions which diminished Cp activity resulted in induction of Wp activity , consistent with suppression of Wp activity by transcriptional interference from Cp .

In general , deletions which diminished <dna>Cp</dna> activity resulted in induction of <dna>Wp</dna> activity , consistent with suppression of <dna>Wp</dna> activity by transcriptional interference from <dna>Cp</dna> .


The identification of oriP and the EBNA2-dependent enhancer as the major positive cis elements involved in regulating Cp activity in LCL suggests that EBNA gene transcription is largely autoregulated by EBNA 1 and EBNA 2 .

The identification of <dna>oriP</dna> and the <dna>EBNA2-dependent enhancer</dna> as the major positive <dna>cis elements</dna> involved in regulating <dna>Cp</dna> activity in <cell_line>LCL</cell_line> suggests that <dna>EBNA gene</dna> transcription is largely autoregulated by <protein>EBNA 1</protein> and <protein>EBNA 2</protein> .


Protein-tyrosine kinase activation is required for lipopolysaccharide induction of interleukin 1beta and NFkappaB activation , but not NFkappaB nuclear translocation .

Protein-tyrosine kinase activation is required for lipopolysaccharide induction of <protein>interleukin 1beta</protein> and <protein>NFkappaB</protein> activation , but not <protein>NFkappaB</protein> nuclear translocation .


In human monocytes , interleukin 1beta protein production and steady state mRNA levels are increased in response to lipopolysaccharide , predominantly as a result of increased transcription of the interleukin 1beta gene .

In <cell_type>human monocytes</cell_type> , <protein>interleukin 1beta</protein> protein production and steady state mRNA levels are increased in response to lipopolysaccharide , predominantly as a result of increased transcription of the <protein>interleukin 1beta</protein> gene .


Expression of interleukin 1beta and other cytokines , such as interleukin 6 and tumor necrosis factor alpha , has been shown to be dependent on the activation of the transcription factor , NFkappaB .

Expression of <protein>interleukin 1beta</protein> and other <protein>cytokines</protein> , such as <protein>interleukin 6</protein> and <protein>tumor necrosis factor alpha</protein> , has been shown to be dependent on the activation of the <protein>transcription factor</protein> , <protein>NFkappaB</protein> .


Since recent studies have shown that lipopolysaccharide-induced tyrosine kinase activation is not required for NFkappaB nuclear translocation , we sought to determine whether NFkappaB translocated in the absence of tyrosine kinase activity was active in stimulating transcription .

Since recent studies have shown that lipopolysaccharide-induced <protein>tyrosine kinase</protein> activation is not required for <protein>NFkappaB</protein> nuclear translocation , we sought to determine whether <protein>NFkappaB</protein> translocated in the absence of <protein>tyrosine kinase</protein> activity was active in stimulating transcription .


We have found that , in the human pro-monocytic cell line , THP-1 , the lipopolysaccharide-induced expression of interleukin 1beta is dependent on tyrosine kinase activation .

We have found that , in the human <cell_line>pro-monocytic cell line</cell_line> , <cell_line>THP-1</cell_line> , the lipopolysaccharide-induced expression of <protein>interleukin 1beta</protein> is dependent on <protein>tyrosine kinase</protein> activation .


Tyrosine kinases are not required for lipopolysaccharide-mediated nuclear translocation of NFkappaB .

Tyrosine kinases are not required for lipopolysaccharide-mediated nuclear translocation of <protein>NFkappaB</protein> .


However , in the absence of tyrosine kinase activity , the ability of NFkappaB to stimulate transcription is impaired .

However , in the absence of <protein>tyrosine kinase</protein> activity , the ability of <protein>NFkappaB</protein> to stimulate transcription is impaired .


This inhibition of transcription is specific for NFkappaB ; in the absence of tyrosine kinase activity , AP-1 -dependent transcription is enhanced .

This inhibition of transcription is specific for <protein>NFkappaB</protein> ; in the absence of <protein>tyrosine kinase</protein> activity , <protein>AP-1</protein> -dependent transcription is enhanced .


These results suggest that , while lipopolysaccharide-induced expression of inflammatory mediators requires tyrosine kinase activity , tyrosine kinase activity is not obligatory for lipopolysaccharide signal transduction .

These results suggest that , while lipopolysaccharide-induced expression of <protein>inflammatory mediators</protein> requires <protein>tyrosine kinase</protein> activity , <protein>tyrosine kinase</protein> activity is not obligatory for lipopolysaccharide signal transduction .


Chronic human immunodeficiency virus type 1 infection of myeloid cells disrupts the autoregulatory control of the NF-kappaB/Rel pathway via enhanced IkappaBalpha degradation .

Chronic human immunodeficiency virus type 1 infection of <cell_type>myeloid cells</cell_type> disrupts the autoregulatory control of the <protein>NF-kappaB/Rel</protein> pathway via enhanced <protein>IkappaBalpha</protein> degradation .


Productive human immunodeficiency virus type 1 ( HIV-1 ) infection causes sustained NF-kappaB DNA-binding activity in chronically infected monocytic cells .

Productive human immunodeficiency virus type 1 ( HIV-1 ) infection causes sustained <protein>NF-kappaB</protein> DNA-binding activity in chronically infected monocytic cells .


A direct temporal correlation exists between HIV infection and the appearance of NF-kappaB DNA-binding activity in myelomonoblastic PLB-985 cells .

A direct temporal correlation exists between HIV infection and the appearance of <protein>NF-kappaB</protein> DNA-binding activity in <cell_line>myelomonoblastic PLB-985 cells</cell_line> .


To examine the molecular basis of constitutive NF-kappaB DNA-binding activity in HIV1 -infected cells , we analyzed the phosphorylation and turnover of IkappaBalpha protein , the activity of the double-stranded RNA-dependent protein kinase ( PKR ) and the intracellular levels of NF-kappaB subunits in the PLB-985 and U937 myeloid cell models .

To examine the molecular basis of constitutive <protein>NF-kappaB</protein> DNA-binding activity in <cell_type>HIV1 -infected cells</cell_type> , we analyzed the phosphorylation and turnover of <protein>IkappaBalpha</protein> protein , the activity of the <protein>double-stranded RNA-dependent protein kinase</protein> ( <protein>PKR</protein> ) and the intracellular levels of <protein>NF-kappaB subunits</protein> in the <cell_line>PLB-985</cell_line> and <cell_line>U937 myeloid cell models</cell_line> .


HIV-1 infection resulted in constitutive , low-level expression of type 1 interferon ( IFN ) at the mRNA level .

HIV-1 infection resulted in constitutive , low-level expression of <protein>type 1 interferon</protein> ( <protein>IFN</protein> ) at the mRNA level .


Constitutive PKR activity was also detected in HIV-1-infected cells as a result of low-level IFN production , since the addition of anti-IFN-alpha/beta antibody to the cells decreased PKR expression .

Constitutive <protein>PKR</protein> activity was also detected in <cell_line>HIV-1-infected cells</cell_line> as a result of low-level <protein>IFN</protein> production , since the addition of <protein>anti-IFN-alpha/beta antibody</protein> to the cells decreased <protein>PKR</protein> expression .


Furthermore , the analysis of IkappaBalpha turnover demonstrated an increased degradation of IkappaBalpha in HIV-1-infected cells that may account for the constitutive DNA binding activity .

Furthermore , the analysis of <protein>IkappaBalpha</protein> turnover demonstrated an increased degradation of <protein>IkappaBalpha</protein> in <cell_line>HIV-1-infected cells</cell_line> that may account for the <dna>constitutive DNA</dna> binding activity .


A dramatic increase in the intracellular levels of NF-kappaB subunits c-Rel and NF-kappaB2 p100 and a moderate increase in NF-kappaB2 p52 and RelA ( p65 ) were detected in HIV-1-infected cells , whereas NF-kappaB1 p105/p50 levels were not altered relative to the levels in uninfected cells .

A dramatic increase in the intracellular levels of <protein>NF-kappaB</protein> subunits <protein>c-Rel</protein> and <protein>NF-kappaB2 p100</protein> and a moderate increase in <protein>NF-kappaB2 p52</protein> and <protein>RelA ( p65 )</protein> were detected in <cell_line>HIV-1-infected cells</cell_line> , whereas <protein>NF-kappaB1 p105/p50</protein> levels were not altered relative to the levels in <cell_type>uninfected cells</cell_type> .


We suggest that HIV-1 infection of myeloid cells induces IFN production and PKR activity , which in turn contribute to enhanced IkappaBalpha phosphorylation and subsequent degradation .

We suggest that HIV-1 infection of <cell_type>myeloid cells</cell_type> induces <protein>IFN</protein> production and <protein>PKR</protein> activity , which in turn contribute to enhanced <protein>IkappaBalpha</protein> phosphorylation and subsequent degradation .


Nuclear translocation of NF-kappaB subunits may ultimately increase the intracellular pool of NF-kappaB/IkappaBalpha by an autoregulatory mechanism .

Nuclear translocation of <protein>NF-kappaB subunits</protein> may ultimately increase the intracellular pool of <protein>NF-kappaB/IkappaBalpha</protein> by an autoregulatory mechanism .


Enhanced turnover of IkappaBalpha and the accumulation of NF-kappaB/Rel proteins may contribute to the chronically activated state of HIV-1-infected cells .

Enhanced turnover of <protein>IkappaBalpha</protein> and the accumulation of <protein>NF-kappaB/Rel proteins</protein> may contribute to the chronically activated state of <cell_line>HIV-1-infected cells</cell_line> .


The c-Jun delta-domain inhibits neuroendocrine promoter activity in a DNA sequence- and pituitary-specific manner .

The <protein>c-Jun delta-domain</protein> inhibits <dna>neuroendocrine promoter</dna> activity in a DNA sequence- and pituitary-specific manner .


The transcription and transformation activity of c-Jun is governed by a 27-amino acid regulatory motif , labeled the delta-domain , which is deleted in v-Jun .

The transcription and transformation activity of <protein>c-Jun</protein> is governed by a <protein>27-amino acid regulatory motif</protein> , labeled the <protein>delta-domain</protein> , which is deleted in <protein>v-Jun</protein> .


We have previously shown that c-Jun is a potent inhibitor of the rat prolactin ( rPRL ) promoter activity induced by either oncogenic Ras or phorbol esters .

We have previously shown that <protein>c-Jun</protein> is a potent inhibitor of the <dna>rat prolactin ( rPRL ) promoter</dna> activity induced by either <protein>oncogenic Ras</protein> or phorbol esters .


Here , we have characterized the structural and cell-specific requirements for this c-Jun inhibitory response , and we show that this c-Jun inhibitory response mapped to the rPRL footprint II repressor site , was pituitary-specific and required the c-Jun delta-domain .

Here , we have characterized the structural and cell-specific requirements for this <protein>c-Jun</protein> inhibitory response , and we show that this <protein>c-Jun</protein> inhibitory response mapped to the <dna>rPRL footprint II repressor site</dna> , was pituitary-specific and required the <protein>c-Jun delta-domain</protein> .


Moreover , alteration of any one of these features ( e.g. , cis-element , trans-factor , or cell-specific background ) switched c-Jun to a transcriptional activator of the rPRL promoter .

Moreover , alteration of any one of these features ( e.g. , <dna>cis-element</dna> , <dna>trans-factor</dna> , or cell-specific background ) switched <protein>c-Jun</protein> to a <protein>transcriptional activator</protein> of the <dna>rPRL promoter</dna> .


In HeLa nonpituitary cells , c-Jun alone activated the rPRL promoter via the most proximal GHF-1/Pit-1 binding site , footprint I , and synergized with GHF-1 .

In <cell_line>HeLa nonpituitary cells</cell_line> , <protein>c-Jun</protein> alone activated the <dna>rPRL promoter</dna> via the most proximal <dna>GHF-1/Pit-1 binding site</dna> , <dna>footprint I</dna> , and synergized with <protein>GHF-1</protein> .


Finally , recombinant GHF-1 interacted directly with c-Jun but not c-Fos proteins .

Finally , recombinant <protein>GHF-1</protein> interacted directly with <protein>c-Jun</protein> but not <protein>c-Fos proteins</protein> .


These data provide important fundamental insights into the molecular mechanisms by which the c-Jun delta-domain functions as a modulatory switch and further imply that the functional role of c-Jun is dictated by cell-specific influences and the delta-domain motif .

These data provide important fundamental insights into the molecular mechanisms by which the <protein>c-Jun delta-domain</protein> functions as a modulatory switch and further imply that the functional role of <protein>c-Jun</protein> is dictated by cell-specific influences and the <protein>delta-domain motif</protein> .


Retinoic acid activates interferon regulatory factor-1 gene expression in myeloid cells .

Retinoic acid activates <protein>interferon regulatory factor-1</protein> gene expression in <cell_type>myeloid cells</cell_type> .


All-trans-retinoic acid ( ATRA ) is the drug of choice in the treatment of acute promyelocytic leukemia ( APL ) .


ATRA induces both in vitro and in vivo differentiation of APL cells into mature granulocytes .

ATRA induces both in vitro and in vivo differentiation of <cell_line>APL cells</cell_line> into <cell_type>mature granulocytes</cell_type> .


However , the molecular mechanisms involved in ATRA-dependent growth inhibition and cellular differentiation are not presently understood .


The NB4 cell line , which is derived from the bone marrow of a patient with APL during relapse , can be used as a model system to study the growth and differentiation of APL cells .

The <cell_line>NB4 cell line</cell_line> , which is derived from the bone marrow of a patient with APL during relapse , can be used as a model system to study the growth and differentiation of <cell_line>APL cells</cell_line> .


Because interferon ( IFN ) regulatory factors ( IRF-1 and IRF-2 ) and other IFN-inducible gene products regulate cell growth , we analyzed the effects of ATRA on the expression of these genes .

Because <protein>interferon ( IFN ) regulatory factors</protein> ( <protein>IRF-1</protein> and <protein>IRF-2</protein> ) and other <protein>IFN-inducible gene products</protein> regulate cell growth , we analyzed the effects of ATRA on the expression of these genes .


We show that ATRA directly activates IRF-1 gene expression , followed by activation of IRF-2 and 2'-5 ' oligoadenylate synthetase ( OAS ) gene expression with slower kinetics .

We show that ATRA directly activates <dna>IRF-1 gene</dna> expression , followed by activation of <protein>IRF-2</protein> and <protein>2'-5 ' oligoadenylate synthetase</protein> ( OAS ) gene expression with slower kinetics .


In addition to NB4 cells , ATRA also activated IRF-1 gene expression in HL-60 , U937 , and THP-1 cells , which all respond to ATRA by growth inhibition .

In addition to NB4 cells , ATRA also activated <dna>IRF-1 gene</dna> expression in <cell_line>HL-60</cell_line> , <cell_line>U937</cell_line> , and <cell_line>THP-1 cells</cell_line> , which all respond to ATRA by growth inhibition .


A more than additive increase in IRF-1 gene expression was seen with ATRA and IFN-gamma in NB4 cells .

A more than additive increase in <dna>IRF-1 gene</dna> expression was seen with ATRA and <protein>IFN-gamma</protein> in <cell_line>NB4 cells</cell_line> .


ATRA did not activate nuclear factor kappa B or signal transducer and activator of transcription ( STAT ) activation pathways , suggesting that an alternate mechanism is involved in IRF-1 gene activation .

ATRA did not activate nuclear factor kappa B or signal transducer and activator of transcription ( STAT ) activation pathways , suggesting that an alternate mechanism is involved in <dna>IRF-1 gene</dna> activation .


The ATRA-induced expression of IRF-1 , an activator of transcription and repressor of transformation , may be one of the molecular mechanisms of ATRA-induced growth inhibition , and the basis for the synergistic actions of ATRA and IFNs in myeloid leukemia cells .

The ATRA-induced expression of <protein>IRF-1</protein> , an activator of transcription and repressor of transformation , may be one of the molecular mechanisms of ATRA-induced growth inhibition , and the basis for the synergistic actions of ATRA and <protein>IFNs</protein> in <cell_line>myeloid leukemia cells</cell_line> .


Recombinant NFAT1 ( NFATp ) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes .

Recombinant <protein>NFAT1</protein> ( NFATp ) is regulated by calcineurin in <cell_type>T cells</cell_type> and mediates transcription of several <dna>cytokine genes</dna> .


Transcription factors of the NFAT family play a key role in the transcription of cytokine genes and other genes during the immune response .

<protein>Transcription factors</protein> of the <protein>NFAT family</protein> play a key role in the transcription of <dna>cytokine genes</dna> and other genes during the immune response .


We have identified two new isoforms of the transcription factor NFAT1 ( previously termed NFATp ) that are the predominant isoforms expressed in murine and human T cells .

We have identified two new isoforms of the <protein>transcription factor</protein> <protein>NFAT1</protein> ( previously termed <protein>NFATp</protein> ) that are the predominant isoforms expressed in <cell_type>murine and human T cells</cell_type> .


When expressed in Jurkat T cells , recombinant NFAT1 is regulated , as expected , by the calmodulin-dependent phosphatase calcineurin , and its function is inhibited by the immunosuppressive agent cyclosporin A ( CsA ) .

When expressed in <cell_line>Jurkat T cells</cell_line> , recombinant <protein>NFAT1</protein> is regulated , as expected , by the <protein>calmodulin-dependent phosphatase</protein> <protein>calcineurin</protein> , and its function is inhibited by the immunosuppressive agent cyclosporin A ( CsA ) .


Transactivation by recombinant NFAT1 in Jurkat T cells requires dual stimulation with ionomycin and phorbol 12-myristate 13-acetate ; this activity is potentiated by coexpression of constitutively active calcineurin and is inhibited by CsA .

Transactivation by recombinant <protein>NFAT1</protein> in <cell_line>Jurkat T cells</cell_line> requires dual stimulation with ionomycin and phorbol 12-myristate 13-acetate ; this activity is potentiated by coexpression of constitutively active <protein>calcineurin</protein> and is inhibited by CsA .


Immunocytochemical analysis indicates that recombinant NFAT1 localizes in the cytoplasm of transiently transfected T cells and translocates into the nucleus in a CsA-sensitive manner following ionomycin stimulation .

Immunocytochemical analysis indicates that recombinant <protein>NFAT1</protein> localizes in the cytoplasm of <cell_type>transiently transfected T cells</cell_type> and translocates into the nucleus in a CsA-sensitive manner following ionomycin stimulation .


When expressed in COS cells , however , NFAT1 is capable of transactivation , but it is not regulated correctly : its subcellular localization and transcriptional function are not affected by stimulation of the COS cells with ionomycin and phorbol 12-myristate 13-acetate .

When expressed in <cell_line>COS cells</cell_line> , however , <protein>NFAT1</protein> is capable of transactivation , but it is not regulated correctly : its subcellular localization and transcriptional function are not affected by stimulation of the <cell_line>COS cells</cell_line> with ionomycin and phorbol 12-myristate 13-acetate .


Recombinant NFAT1 can mediate transcription of the interleukin-2 , interleukin-4 , tumor necrosis factor alpha , and granulocyte-macrophage colony-stimulating factor promoters in T cells , suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response .

Recombinant <protein>NFAT1</protein> can mediate transcription of the <protein>interleukin-2</protein> , interleukin-4 , <protein>tumor necrosis factor alpha</protein> , and <dna>granulocyte-macrophage colony-stimulating factor promoters</dna> in <cell_type>T cells</cell_type> , suggesting that <protein>NFAT1</protein> contributes to the CsA-sensitive transcription of these <dna>genes</dna> during the immune response .


Human TAFII 105 is a cell type-specific TFIID subunit related to hTAFII130 .

<protein>Human TAFII 105</protein> is a <protein>cell type-specific TFIID subunit</protein> related to <protein>hTAFII130</protein> .


We previously characterized Drosophila and human TAF subunits that make up the core TFIID complex found in all cells .

We previously characterized <protein>Drosophila and human TAF subunits</protein> that make up the core <protein>TFIID complex</protein> found in all cells .


Here , we report that differentiated B cells contain a novel substoichiometric TAF of 105 kDa not found associated with TFIID isolated from other cell types .

Here , we report that <cell_type>differentiated B cells</cell_type> contain a novel substoichiometric <protein>TAF</protein> of 105 kDa not found associated with <protein>TFIID</protein> isolated from other cell types .


The cDNA encoding hTAFII105 reveals a highly conserved C-terminal domain shared by hTAFII130 and oTAFII110 , while the N-terminal coactivator domain has diverged significantly .

The <dna>cDNA</dna> encoding <protein>hTAFII105</protein> reveals a highly conserved <protein>C-terminal domain</protein> shared by <protein>hTAFII130</protein> and <protein>oTAFII110</protein> , while the <protein>N-terminal coactivator domain</protein> has diverged significantly .


All cells tested express TAFII105 mRNA , but only B cells contain significant levels of protein associated with TFIID .

All cells tested express <rna>TAFII105 mRNA</rna> , but only <cell_type>B cells</cell_type> contain significant levels of protein associated with <protein>TFIID</protein> .


Transient overexpression of hTAFII105 selectively squelches the transcription of some genes in B cells .

Transient overexpression of <protein>hTAFII105</protein> selectively squelches the transcription of some genes in <cell_type>B cells</cell_type> .


These properties suggest that TAFII105 is a cell type-specific subunit of TFIID that may be responsible for mediating transcription by a subset of activators in B cells .

These properties suggest that <protein>TAFII105</protein> is a cell type-specific subunit of <protein>TFIID</protein> that may be responsible for mediating transcription by a subset of activators in <cell_type>B cells</cell_type> .


Interstitial deletion constitutes the major mechanism for loss of heterozygosity on chromosome 20q in polycythemia vera .

Interstitial deletion constitutes the major mechanism for loss of heterozygosity on <dna>chromosome 20q</dna> in polycythemia vera .


An acquired deletion of the long arm of chromosome 20 is a recurrent abnormality in myeloproliferative disorders , particularly polycythemia vera and myelodysplastic syndromes .

An acquired deletion of the long arm of <dna>chromosome 20</dna> is a recurrent abnormality in myeloproliferative disorders , particularly polycythemia vera and myelodysplastic syndromes .


The association of 20q deletions with myeloid `` stem cell '' disorders suggests that the deletions mark the site of one or more genes , loss or inactivation of which plays a role in the regulation of normal hematopoietic progenitors .

The association of <dna>20q deletions</dna> with myeloid `` stem cell '' disorders suggests that the deletions mark the site of one or more genes , loss or inactivation of which plays a role in the regulation of <cell_type>normal hematopoietic progenitors</cell_type> .


We have recently performed a detailed molecular analysis of 20q deletions in peripheral blood ( PB ) granulocytes and defined a commonly deleted region of 16 to 21 centimorgan ( cM ) .

We have recently performed a detailed molecular analysis of <dna>20q deletions</dna> in <cell_type>peripheral blood ( PB ) granulocytes</cell_type> and defined a <dna>commonly deleted region</dna> of 16 to 21 centimorgan ( cM ) .


To further reduce the size of the common deleted region we have searched for small deletions or mitotic recombination events , neither of which would be detected by conventional cytogenetics .


We have studied 48 patients with polycythemia vera and four patients with idiopathic myelofibrosis .


In each case , cytogenetic analysis had either failed or had shown no abnormalities of chromosome 20 .

In each case , cytogenetic analysis had either failed or had shown no abnormalities of <dna>chromosome 20</dna> .


Seventeen microsatellite markers that span the common deleted region were used to search for loss of heterozygosity in granulocyte DNA .

Seventeen <dna>microsatellite markers</dna> that span the common deleted region were used to search for loss of heterozygosity in <dna>granulocyte DNA</dna> .


No instance of microsatellite instability was observed in a total of 880 comparisons of granulocyte and T-cell DNA .

No instance of microsatellite instability was observed in a total of 880 comparisons of <dna>granulocyte and T-cell DNA</dna> .


Granulocyte DNA from four patients exhibited allele loss on 20q .

Granulocyte DNA from four patients exhibited allele loss on <dna>20q</dna> .


In each case the allele loss was caused by an interstitial deletion because heterozygosity at distal markers was retained and because quantitative Southern blotting demonstrated hemizygosity .

In each case the allele loss was caused by an interstitial deletion because heterozygosity at <dna>distal markers</dna> was retained and because quantitative Southern blotting demonstrated hemizygosity .


Loss of heterozygosity in PB granulocytes would be masked by the presence of significant numbers of normal granulocytes not derived from the malignant clone .

Loss of heterozygosity in <cell_type>PB granulocytes</cell_type> would be masked by the presence of significant numbers of <cell_type>normal granulocytes</cell_type> not derived from the <cell_line>malignant clone</cell_line> .


Therefore , the human androgen receptor assay ( HUMARA ) was used to determine granulocyte clonality .

Therefore , the <protein>human androgen receptor</protein> assay ( HUMARA ) was used to determine granulocyte clonality .


In 21 of 27 informative female patients the majority of the granulocytes were clonally derived .

In 21 of 27 informative female patients the majority of the <cell_type>granulocytes</cell_type> were clonally derived .


In 5 patients the granulocytes appeared polyclonal and in 1 patient unilateral X inactivation was observed in both granulocytes and T cells .

In 5 patients the <cell_type>granulocytes</cell_type> appeared polyclonal and in 1 patient unilateral X inactivation was observed in both <cell_type>granulocytes</cell_type> and <cell_type>T cells</cell_type> .


These results show that , in the vast majority of patients presented here , the failure to detect loss of heterozygosity can not be attributed to the presence of normal polyclonal granulocytes .

These results show that , in the vast majority of patients presented here , the failure to detect loss of heterozygosity can not be attributed to the presence of <cell_line>normal polyclonal granulocytes</cell_line> .


Our results therefore show that allele loss on chromosome 20q in polycythemia vera does not commonly involve mitotic recombination or chromosome loss and that microsatellite instability is a rare event in this disorder .

Our results therefore show that allele loss on <dna>chromosome 20q</dna> in polycythemia vera does not commonly involve mitotic recombination or <dna>chromosome</dna> loss and that microsatellite instability is a rare event in this disorder .


Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein .

<protein>Interleukin-6</protein> promotes multiple myeloma cell growth via phosphorylation of <protein>retinoblastoma protein</protein> .


Interleukin-6 ( IL-6 ) mediates autocrine and paracrine growth of multiple myeloma ( MM ) cells and inhibits tumor cell apoptosis .

<protein>Interleukin-6</protein> ( <protein>IL-6</protein> ) mediates autocrine and paracrine growth of <cell_line>multiple myeloma ( MM ) cells</cell_line> and inhibits tumor cell apoptosis .


Abnormalities of retinoblastoma protein ( pRB ) and mutations of RB gene have been reported in up to 70 % of MM patients and 80 % of MM-derived cell lines .

Abnormalities of <protein>retinoblastoma protein</protein> ( <protein>pRB</protein> ) and mutations of RB gene have been reported in up to 70 % of MM patients and 80 % of <cell_line>MM-derived cell lines</cell_line> .


Because dephosphorylated ( activated ) pRB blocks transition from G1 to S phase of the cell cycle whereas phosphorylated ( inactivated ) pRB releases this growth arrest , we characterized the role of pRB in IL-6 -mediated MM cell growth .

Because <protein>dephosphorylated ( activated ) pRB</protein> blocks transition from G1 to S phase of the cell cycle whereas <protein>phosphorylated ( inactivated ) pRB</protein> releases this growth arrest , we characterized the role of <protein>pRB</protein> in <protein>IL-6</protein> -mediated MM cell growth .


Both phosphorylated and dephosphorylated pRB were expressed in all serum-starved MM patient cells and MM-derived cell lines , but pRB was predominantly in its phosphorylated form .

Both phosphorylated and dephosphorylated <protein>pRB</protein> were expressed in all serum-starved MM patient cells and <cell_line>MM-derived cell lines</cell_line> , but <protein>pRB</protein> was predominantly in its phosphorylated form .


In MM cells that proliferated in response to IL-6 , exogenous IL-6 downregulated dephosphorylated pRB and decreased dephosphorylated pRB-E2F complexes .

In <cell_line>MM cells</cell_line> that proliferated in response to <protein>IL-6</protein> , exogenous <protein>IL-6</protein> downregulated <protein>dephosphorylated pRB</protein> and decreased dephosphorylated <protein>pRB-E2F complexes</protein> .


Importantly , culture of MM cells with RB antisense , but not RB sense , oligonucleotide ( ODN ) triggered IL-6 secretion and proliferation in MM cells ; however , proliferation was only partially inhibited by neutralizing anti-IL-6 monoclonal antibody ( MoAb ) .

Importantly , culture of <cell_line>MM cells</cell_line> with RB antisense , but not RB sense , oligonucleotide ( ODN ) triggered <protein>IL-6</protein> secretion and proliferation in <cell_line>MM cells</cell_line> ; however , proliferation was only partially inhibited by neutralizing <protein>anti-IL-6 monoclonal antibody</protein> ( <protein>MoAb</protein> ) .


In contrast to MM cells , normal splenic B cells express dephosphorylated pRB .

In contrast to <cell_line>MM cells</cell_line> , normal <cell_type>splenic B cells</cell_type> express <protein>dephosphorylated pRB</protein> .


Although CD40 ligand ( CD40L ) triggers a shift from dephosphorylated to phosphorylated pRB and proliferation of B cells , the addition of exogenous IL-6 to CD40L -treated B cells does not alter either pRB or proliferation , as observed in MM cells .

Although <protein>CD40 ligand</protein> ( <protein>CD40L</protein> ) triggers a shift from dephosphorylated to phosphorylated <protein>pRB</protein> and proliferation of <cell_type>B cells</cell_type> , the addition of exogenous <protein>IL-6</protein> to <protein>CD40L</protein> -treated <cell_type>B cells</cell_type> does not alter either <protein>pRB</protein> or proliferation , as observed in <cell_line>MM cells</cell_line> .


These results suggest that phosphorylated pRB is constitutively expressed in MM cells and that IL-6 further shifts pRB from its dephosphorylated to its phosphorylated form , thereby promoting MM cell growth via two mechanisms ; by decreasing the amount of E2F bound by dephosphorylated pRB due to reduced dephosphorylated pRB , thereby releasing growth arrest ; and by upregulating IL-6 secretion by MM cells and related IL-6 -mediated autocrine tumor cell growth .

These results suggest that <protein>phosphorylated pRB</protein> is constitutively expressed in <cell_line>MM cells</cell_line> and that <protein>IL-6</protein> further shifts <protein>pRB</protein> from its dephosphorylated to its phosphorylated form , thereby promoting MM cell growth via two mechanisms ; by decreasing the amount of E2F bound by <protein>dephosphorylated pRB</protein> due to reduced <protein>dephosphorylated pRB</protein> , thereby releasing growth arrest ; and by upregulating <protein>IL-6</protein> secretion by <cell_line>MM cells</cell_line> and related <protein>IL-6</protein> -mediated autocrine tumor cell growth .


Soluble factors secreted by activated T-lymphocytes modulate the transcription of the immunosuppressive cytokine TGF-beta 2 in glial cells .

<protein>Soluble factors</protein> secreted by <cell_type>activated T-lymphocytes</cell_type> modulate the transcription of the <protein>immunosuppressive cytokine</protein> <protein>TGF-beta 2</protein> in <cell_type>glial cells</cell_type> .


Coordination of the immune response to injury or disease in the brain is postulated to involve bi-directional discourse between the immune system and the central nervous system .


This cross communication involves soluble mediators , including various growth factors , cytokines , and neuropeptides .

This cross communication involves soluble mediators , including various <protein>growth factors</protein> , <protein>cytokines</protein> , and neuropeptides .


In this report , we demonstrate that the supernatant from activated T-lymphocytes is able to induce the transcription of a potent cytokine , TGF-beta 2 in glial cells .

In this report , we demonstrate that the supernatant from <cell_type>activated T-lymphocytes</cell_type> is able to induce the transcription of a potent <protein>cytokine</protein> , <protein>TGF-beta 2</protein> in <cell_type>glial cells</cell_type> .


The activating stimulus invokes signaling mechanisms distinct from known kinase or protease pathways .


Activation of TGF-beta 2 transcription correlates with the loss of binding activity for an 80 kDA glial labile repressor protein , GLRP , to a responsive region within the TFG-beta 2 promoter .

Activation of <protein>TGF-beta 2</protein> transcription correlates with the loss of binding activity for an <protein>80 kDA glial labile repressor protein</protein> , <protein>GLRP</protein> , to a responsive region within the <dna>TFG-beta 2 promoter</dna> .


Although GLRP shares some characteristics with the inducible transcription factor AP-1 , it appears to be distinct from known AP-1 family members .

Although <protein>GLRP</protein> shares some characteristics with the inducible <protein>transcription factor</protein> <protein>AP-1</protein> , it appears to be distinct from known <protein>AP-1 family members</protein> .


These data along with previous observations demonstrating the potent immunosuppressive activity of TGF-beta 2 , support a model for a feedback mechanism between the activated T-lymphocytes and astrocytes via TGF-beta 2 to regulate the immune response .

These data along with previous observations demonstrating the potent immunosuppressive activity of <protein>TGF-beta 2</protein> , support a model for a feedback mechanism between the activated <cell_type>T-lymphocytes</cell_type> and <cell_type>astrocytes</cell_type> via <protein>TGF-beta 2</protein> to regulate the immune response .


Various modes of basic helix-loop-helix protein -mediated regulation of murine leukemia virus transcription in lymphoid cell lines .

Various modes of <protein>basic helix-loop-helix protein</protein> -mediated regulation of murine leukemia virus transcription in <cell_line>lymphoid cell lines</cell_line> .


The transcriptionally regulatory regions of the lymphomagenic Akv and SL3-3 murine leukemia retroviruses ( MLVs ) contain two types of E-box consensus motifs , CAGATG .

The <dna>transcriptionally regulatory regions</dna> of the lymphomagenic Akv and SL3-3 murine leukemia retroviruses ( MLVs ) contain two types of <dna>E-box consensus motifs</dna> , CAGATG .


One type , EA/S , is located in the upstream promoter region , and the other , E ( gre ) , is located in a tandem repeat with enhancer properties .

One type , <dna>EA/S</dna> , is located in the <dna>upstream promoter region</dna> , and the other , <dna>E ( gre )</dna> , is located in a <dna>tandem repeat</dna> with enhancer properties .


We have examined the requirements of the individual E-boxes in MLV transcriptional regulation .

We have examined the requirements of the individual <dna>E-boxes</dna> in MLV transcriptional regulation .


In lymphoid cell lines only , the E ( gre ) -binding protein complexes included ALF1 or HEB and E2A basic helix-loop-helix proteins .

In <cell_line>lymphoid cell lines</cell_line> only , the <protein>E ( gre ) -binding protein complexes</protein> included <protein>ALF1</protein> or <protein>HEB</protein> and <protein>E2A basic helix-loop-helix proteins</protein> .


Ectopic ALF1 and E2A proteins required intact E ( gre ) motifs for mediating transcriptional activation .

Ectopic <protein>ALF1</protein> and <protein>E2A proteins</protein> required intact <dna>E ( gre ) motifs</dna> for mediating transcriptional activation .


ALF1 transactivated transcription of Akv MLV through the two E ( gre ) motifs equally , whereas E2A protein required the promoter-proximal E ( gre ) motif .

<protein>ALF1</protein> transactivated transcription of Akv MLV through the two <dna>E ( gre ) motifs</dna> equally , whereas <protein>E2A protein</protein> required the promoter-proximal <dna>E ( gre )</dna> motif .


In T- and B-cell lines , the E ( gre ) motifs were of major importance for Akv MLV transcriptional activity , while the EA/S motif had some effect .

In <cell_line>T- and B-cell lines</cell_line> , the <dna>E ( gre ) motifs</dna> were of major importance for Akv MLV transcriptional activity , while the <dna>EA/S motif</dna> had some effect .


In contrast , neither E ( gre ) nor EA/S motifs contributed pronouncedly to Akv MLV transcription in NIH 3T3 cells lacking DNA-binding ALF1 or HEB and E2A proteins .

In contrast , neither <dna>E ( gre )</dna> nor <dna>EA/S motifs</dna> contributed pronouncedly to Akv MLV transcription in <cell_line>NIH 3T3 cells</cell_line> lacking DNA-binding <protein>ALF1</protein> or <protein>HEB</protein> and <protein>E2A proteins</protein> .


The Id1 protein was found to repress ALF1 activity in vitro and in vivo .

The Id1 protein was found to repress <protein>ALF1</protein> activity in vitro and in vivo .


Moreover , ectopic Id1 repressed E ( gre ) -directed but not EA/S -directed MLV transcription in lymphoid cell lines .

Moreover , <protein>ectopic Id1</protein> repressed <dna>E ( gre )</dna> -directed but not <dna>EA/S</dna> -directed MLV transcription in <cell_line>lymphoid cell lines</cell_line> .


In conclusion , E ( gre ) motifs and interacting basic helix-loop-helix proteins are important determinants for MLV transcriptional activity in lymphocytic cell lines .

In conclusion , <dna>E ( gre )</dna> motifs and interacting <protein>basic helix-loop-helix proteins</protein> are important determinants for MLV transcriptional activity in <cell_line>lymphocytic cell lines</cell_line> .


Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor .

Reversal of apoptosis by the leukaemia-associated <protein>E2A-HLF chimaeric transcription factor</protein> .


The E2A-HLF ( for hepatic leukaemia factor ) fusion gene , formed by action of the t ( 17 ; 19 ) ( q22 ; p13 ) chromosomal translocation , drives the leukaemic transformation of early B-cell precursors , but the mechanism of this activity remains unknown .

The <dna>E2A-HLF ( for hepatic leukaemia factor ) fusion gene</dna> , formed by action of the <dna>t ( 17 ; 19 ) ( q22 ; p13 )</dna> chromosomal translocation , drives the leukaemic transformation of early <cell_type>B-cell precursors</cell_type> , but the mechanism of this activity remains unknown .


Here we report that human leukaemia cells carrying the translocation t ( 17 ; 19 ) rapidly died by apoptosis when programmed to express a dominant-negative suppressor of the fusion protein E2A-HLF , indicating that the chimaeric oncoprotein probably affects cell survival rather than cell growth .

Here we report that <cell_type>human leukaemia cells</cell_type> carrying the translocation <dna>t ( 17 ; 19 )</dna> rapidly died by apoptosis when programmed to express a dominant-negative suppressor of the fusion protein <protein>E2A-HLF</protein> , indicating that the <protein>chimaeric oncoprotein</protein> probably affects cell survival rather than cell growth .


Moreover , when introduced into murine pro-B lymphocytes , the oncogenic E2A-HLF fusion protein reversed both interleukin-3-dependent and p53-mediated apoptosis .

Moreover , when introduced into <cell_line>murine pro-B lymphocytes</cell_line> , the <protein>oncogenic E2A-HLF fusion protein</protein> reversed both interleukin-3-dependent and p53-mediated apoptosis .


The close homology of the basic region/leucine zipper ( bZIP ) DNA-binding and dimerization domain of HLF to that of the CES-2 cell-death specification protein of Caenorhabditis elegans suggests a model of leukaemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell-death pathway .

The close homology of the <protein>basic region/leucine zipper</protein> ( <protein>bZIP</protein> ) DNA-binding and <protein>dimerization domain</protein> of <protein>HLF</protein> to that of the <protein>CES-2 cell-death specification protein</protein> of Caenorhabditis elegans suggests a model of leukaemogenesis in which <protein>E2A-HLF</protein> blocks an early step within an evolutionarily conserved cell-death pathway .


The role of early growth response gene 1 ( egr-1 ) in regulation of the immune response .

The role of <dna>early growth response gene 1</dna> ( <dna>egr-1</dna> ) in regulation of the immune response .


The induction of immediate early genes in cells of the immune system is critical to determining the ultimate outcome of exposure to antigen .

The induction of <dna>immediate early genes</dna> in cells of the immune system is critical to determining the ultimate outcome of exposure to antigen .


The importance of many of these genes relates to the role their transcription factor products play in dictating patterns of expression of downstream , function-related genes .

The importance of many of these genes relates to the role their <protein>transcription factor products</protein> play in dictating patterns of expression of downstream , <dna>function-related genes</dna> .


Evidence from several systems indicates that the immediate early gene , egr-1 may be of particular importance in the immune system .

Evidence from several systems indicates that the <dna>immediate early gene</dna> , <dna>egr-1</dna> may be of particular importance in the immune system .


Recently , the egr-1 promoter has been shown to be highly responsive to the diverse biochemical signals generated by antigen and cytokines in cells of the immune system .

Recently , the <dna>egr-1 promoter</dna> has been shown to be highly responsive to the diverse biochemical signals generated by antigen and <protein>cytokines</protein> in cells of the immune system .


Furthermore , an important role for egr-1 in determining the differentiation pathway of myeloid cell precursors has been recently elaborated .

Furthermore , an important role for <dna>egr-1</dna> in determining the differentiation pathway of <cell_type>myeloid cell precursors</cell_type> has been recently elaborated .


Finally , potential targets of regulation by the zinc-finger transcription factor encoded by egr-1 include the interleukin-2 , CD44 , ICAM-1 , and tumor necrosis factor genes .

Finally , potential targets of regulation by the <protein>zinc-finger transcription factor</protein> encoded by <dna>egr-1</dna> include the <dna>interleukin-2 , CD44 , ICAM-1 , and tumor necrosis factor genes</dna> .


The role of egr-1 in regulation of the immune response will be discussed in the context of these recent studies .

The role of <dna>egr-1</dna> in regulation of the immune response will be discussed in the context of these recent studies .


Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction .


Vaccination with synthetic peptides representing cytotoxic T lymphocyte ( CTL ) epitopes can lead to a protective CTL-mediated immunity against tumors or viruses .


We now report that vaccination with a CTL epitope derived from the human adenovirus type 5 E1A-region ( Ad5E1A234-243 ) , which can serve as a target for tumor-eradicating CTL , enhances rather than inhibits the growth of Ad5E1A-expressing tumors .

We now report that vaccination with a CTL epitope derived from the <dna>human adenovirus type 5 E1A-region</dna> ( <dna>Ad5E1A234-243</dna> ) , which can serve as a target for <cell_type>tumor-eradicating CTL</cell_type> , enhances rather than inhibits the growth of Ad5E1A-expressing tumors .


This adverse effect of peptide vaccination was rapidly evoked , required low doses of peptide ( 10 micrograms ) , and was achieved by a mode of peptide delivery that induces protective T-cell-mediated immunity in other models .


Ad5E1A -specific CTL activity could no longer be isolated from mice after injection of Ad5E1A-peptide , indicating that tolerization of Ad5E1A -specific CTL activity causes the enhanced tumor outgrowth .

<protein>Ad5E1A</protein> -specific CTL activity could no longer be isolated from mice after injection of Ad5E1A-peptide , indicating that tolerization of <protein>Ad5E1A</protein> -specific CTL activity causes the enhanced tumor outgrowth .


In contrast to peptide vaccination , immunization with adenovirus , expressing Ad5E1A , induced Ad5E1A -specific immunity and prevented the outgrowth of Ad5E1A -expressing tumors .

In contrast to peptide vaccination , immunization with adenovirus , expressing <protein>Ad5E1A</protein> , induced <protein>Ad5E1A</protein> -specific immunity and prevented the outgrowth of <protein>Ad5E1A</protein> -expressing tumors .


These results show that immunization with synthetic peptides can lead to the elimination of anti-tumor CTL responses .


These findings are important for the design of safe peptide-based vaccines against tumors , allogeneic organ transplants , and T-cell-mediated autoimmune diseases .


[ NGFI-B/nur77 family involved in T-cell apoptosis ]

[ <protein>NGFI-B/nur77 family</protein> involved in T-cell apoptosis ]


NGFI-B/nur77 is a member of the steroid receptor superfamily .

<protein>NGFI-B/nur77</protein> is a member of the <protein>steroid receptor superfamily</protein> .


NGFI-B/nur77 and its related genes constitute a family and the NGFI-B/nur77 family consists of three subtypes , named nur77 alpha , nur77 beta , nur77 gamma .

<protein>NGFI-B/nur77</protein> and its related genes constitute a family and the <protein>NGFI-B/nur77 family</protein> consists of three subtypes , named <protein>nur77 alpha</protein> , <protein>nur77 beta</protein> , <protein>nur77 gamma</protein> .


We cloned human nur77 beta cDNA , called TINUR .

We cloned human <dna>nur77 beta cDNA</dna> , called <dna>TINUR</dna> .


Although NGFI-B/nur77 is essential for TCR-mediated apoptosis in T-cell hybridomas , the reports on nur77 knock-out mice and nur77 dominant negative transgenic mice suggest that there is a functional redundancy among NGFI-B/nur77 family .

Although <protein>NGFI-B/nur77</protein> is essential for TCR-mediated apoptosis in <protein>T-cell hybridomas</protein> , the reports on nur77 knock-out mice and nur77 dominant negative transgenic mice suggest that there is a functional redundancy among <protein>NGFI-B/nur77 family</protein> .


NGFI-B/nur77 binds to the response element by monomer or heterodimer with retinoid X receptor ( RXR ) .

<protein>NGFI-B/nur77</protein> binds to the <dna>response element</dna> by monomer or heterodimer with <protein>retinoid X receptor</protein> ( <protein>RXR</protein> ) .


Assuming that 9-cis-retinoic acid ( 9-cis-RA ) inhibits TCR-mediated apoptosis , nur77 may cause apoptosis by monomer in the absence of 9-cis-RA and may inhibit apoptosis by heterodimer with RXR in the presence of 9-cis-RA .

Assuming that 9-cis-retinoic acid ( 9-cis-RA ) inhibits TCR-mediated apoptosis , <protein>nur77</protein> may cause apoptosis by monomer in the absence of 9-cis-RA and may inhibit apoptosis by heterodimer with <protein>RXR</protein> in the presence of 9-cis-RA .


Glucocorticoids and interferon-alpha in the acquired immunodeficiency syndrome .

Glucocorticoids and <protein>interferon-alpha</protein> in the acquired immunodeficiency syndrome .


Some patients with acquired immunodeficiency syndrome ( AIDS ) develop glucocorticoid resistance characterized by low receptor affinity ( Kd ) for glucocorticoids in mononuclear , cells and high values of ACTH and cortisol .

Some patients with acquired immunodeficiency syndrome ( AIDS ) develop glucocorticoid resistance characterized by low receptor affinity ( Kd ) for glucocorticoids in <cell_type>mononuclear</cell_type> , cells and high values of ACTH and cortisol .


As glucocorticoids regulate interferon-alpha ( IFN alpha ) production , we hypothesized that IFN alpha , a cytokine produced predominantly by monocytes in AIDS , should be increased in cortisol-resistant AIDS , attributing the lack of cortisol inhibition to IFN alpha production .

As glucocorticoids regulate <protein>interferon-alpha</protein> ( <protein>IFN alpha</protein> ) production , we hypothesized that <protein>IFN alpha</protein> , a <protein>cytokine</protein> produced predominantly by <cell_type>monocytes</cell_type> in AIDS , should be increased in cortisol-resistant AIDS , attributing the lack of cortisol inhibition to <protein>IFN alpha</protein> production .


Therefore , we examined glucocorticoid receptor characteristics on monocytes by [ 3H ] dexamethasone binding and measured IFN alpha , cortisol , and ACTH in AIDS patients with ( AIDS-GR ) or without glucocorticoid resistance ( AIDS-C ) and controls ( C ) .

Therefore , we examined <protein>glucocorticoid receptor</protein> characteristics on <cell_type>monocytes</cell_type> by [ 3H ] dexamethasone binding and measured <protein>IFN alpha</protein> , cortisol , and ACTH in AIDS patients with ( AIDS-GR ) or without glucocorticoid resistance ( AIDS-C ) and controls ( C ) .


Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/L that was higher than that in the AIDS-C group ( 2.9 +/- 0.8 nmol/L ) and normal subjects ( 2.0 +/- 0.8 nmol/L ; P < 0.01 ) .


IFN alpha levels were increased in the AIDS-GR group ( 17 +/- 6 vs .

<protein>IFN alpha</protein> levels were increased in the AIDS-GR group ( 17 +/- 6 vs .


4 +/- 1 U/mL in the AIDS-C group and 2 +/- 0.5 U/mL in the C group ; P < 0.01 ) .


Correlations were found between plasma IFN alpha and receptor Kd on monocytes of AIDS-GR ( r = 0.77 ) and between IFN alpha and plasma cortisol in the same group ( r = 0.74 ) .

Correlations were found between <protein>plasma IFN alpha</protein> and receptor Kd on <cell_type>monocytes</cell_type> of AIDS-GR ( r = 0.77 ) and between <protein>IFN alpha</protein> and plasma cortisol in the same group ( r = 0.74 ) .


The poly ( I ) -poly ( C ) -induced IFN alpha production by monocytes was inhibited by glucocorticoids in the C and AIDS-C groups ( approximately 80 % inhibition in both groups ) ; the effect was reversed by the receptor antagonist RU-38486 .

The <protein>poly ( I ) -poly ( C ) -induced IFN alpha</protein> production by <cell_type>monocytes</cell_type> was inhibited by glucocorticoids in the C and AIDS-C groups ( approximately 80 % inhibition in both groups ) ; the effect was reversed by the receptor antagonist RU-38486 .


By contrast , glucocorticoids failed to inhibit IFNalpha production from AIDS-GR monocytes ( approximately 20 % inhibition ) .

By contrast , glucocorticoids failed to inhibit <protein>IFNalpha</protein> production from <cell_type>AIDS-GR monocytes</cell_type> ( approximately 20 % inhibition ) .


In conclusion , elevated IFN alpha levels in AIDS-GR may be due to the lack of inhibitory effect of cortisol on IFN alpha production due to cortisol resistance in monocytes

In conclusion , elevated <protein>IFN alpha</protein> levels in AIDS-GR may be due to the lack of inhibitory effect of cortisol on <protein>IFN alpha</protein> production due to cortisol resistance in <cell_type>monocytes</cell_type>


JNK ( c-Jun NH2-terminal kinase ) is a target for antioxidants in T lymphocytes .

<protein>JNK</protein> ( <protein>c-Jun NH2-terminal kinase</protein> ) is a target for antioxidants in <cell_type>T lymphocytes</cell_type> .


AP-1 has been shown to behave as a redox-sensitive transcription factor that can be activated by both oxidant and antioxidant stimuli .

<protein>AP-1</protein> has been shown to behave as a <protein>redox-sensitive transcription factor</protein> that can be activated by both oxidant and antioxidant stimuli .


However , the mechanisms involved in the activation of AP-1 by antioxidants are largely unknown .

However , the mechanisms involved in the activation of <protein>AP-1</protein> by antioxidants are largely unknown .


In this study we show that the structurally unrelated antioxidant agents pyrrolidine dithiocarbamate ( PDTC ) , butylated hydroxyanisole , and Nacetylcysteine activated JNK ( c-Jun NH2-terminal kinase ) in Jurkat T cells .

In this study we show that the structurally unrelated antioxidant agents pyrrolidine dithiocarbamate ( PDTC ) , butylated hydroxyanisole , and Nacetylcysteine activated <protein>JNK</protein> ( <protein>c-Jun NH2-terminal kinase</protein> ) in <cell_line>Jurkat T cells</cell_line> .


This activation differed substantially from that mediated by phorbol 12-myristate 13-acetate ( PMA ) and Ca2+ ionophore or produced by costimulation with antibodies against the T cell receptor-CD3 complex and to CD28 .

This activation differed substantially from that mediated by phorbol 12-myristate 13-acetate ( PMA ) and Ca2+ ionophore or produced by costimulation with <protein>antibodies</protein> against the <protein>T cell receptor-CD3 complex</protein> and to <protein>CD28</protein> .


The activation of JNK by classical T cell stimuli was transient , whereas that mediated by PDTC and butylated hydroxyanisole ( but not N-acetylcysteine ) was sustained .

The activation of <protein>JNK</protein> by classical T cell stimuli was transient , whereas that mediated by PDTC and butylated hydroxyanisole ( but not N-acetylcysteine ) was sustained .


The kinetics of JNK activation correlated with the expression of c-jun which was transient after stimulation with PMA plus ionophore and prolonged in response to PDTC , which also transiently induced c-fos .

The kinetics of <protein>JNK</protein> activation correlated with the expression of <dna>c-jun</dna> which was transient after stimulation with PMA plus ionophore and prolonged in response to PDTC , which also transiently induced <dna>c-fos</dna> .


In addition , JNK activation by PMA plus ionophore was sensitive to inhibitors of signaling pathways involving Ca2+ , protein kinase C , and tyrosine phosphorylation , which failed to inhibit the activation mediated by PDTC .

In addition , <protein>JNK</protein> activation by PMA plus ionophore was sensitive to inhibitors of signaling pathways involving Ca2+ , <protein>protein kinase C</protein> , and tyrosine phosphorylation , which failed to inhibit the activation mediated by PDTC .


Transfection of trans-dominant negative expression vectors of ras and raf , together with AP-1-dependent reporter constructs , as well as Western blot analysis using anti-ERK ( extracellular signal-regulated kinase ) antibodies , indicated that the Ras/Raf/ERK pathway did not appear to mediate the effect of the antioxidant .

Transfection of <dna>trans-dominant negative expression vectors</dna> of <dna>ras</dna> and <dna>raf</dna> , together with <dna>AP-1-dependent reporter constructs</dna> , as well as Western blot analysis using <protein>anti-ERK ( extracellular signal-regulated kinase ) antibodies</protein> , indicated that the Ras/Raf/ERK pathway did not appear to mediate the effect of the antioxidant .


However , the combined treatment with PDTC and PMA , two agents that synergize on AP-1 activation , resulted in the persistent phosphorylation of ERK-2 .

However , the combined treatment with PDTC and PMA , two agents that synergize on <protein>AP-1</protein> activation , resulted in the persistent phosphorylation of <protein>ERK-2</protein> .


In conclusion , our results identify JNK as a target of antioxidant agents which can be regulated differentially under oxidant and antioxidant conditions .

In conclusion , our results identify <protein>JNK</protein> as a target of antioxidant agents which can be regulated differentially under oxidant and antioxidant conditions .


[ Molecular mechanisms of age-related lymphocyte dysfunction ]


Aging is classically accompanied by a dysregulation of the immunologic machinery .


As a consequence , the immune response developed in senescent organisms is usually inappropriate , often inefficient , sometimes aberrant , and potentially detrimental .


The age-associated immune dysfunction may be implicated to some degree in the extreme susceptibility of the elderly to infection and neoplasia and may even participate in various aspects of senescence .


The current understanding of the molecular mechanisms underlying immunosenescence is still fragmentary .


The most extensively studied phenomenon is the progressive decline in the proliferative capacities of T lymphocytes with aging .

The most extensively studied phenomenon is the progressive decline in the proliferative capacities of <cell_type>T lymphocytes</cell_type> with aging .


The loss of proliferative potential in response to antigenic challenge is a characteristic feature of immune senescence .


It is directly implicated in the emergence of the age-related immune deficiency .


The purpose of this review is to show how the accumulation of various biochemical lesions with advancing age leads to the failure of a critical cell function , namely the activation-induced lymphocyte proliferation .


The biochemical modifications responsible for the defect in transduction and execution of the proliferative signal are analyzed as a function of age .


The multiple alterations observed on the various biochemical pathways may appear as a consequence of a unique deleterious mechanism more fundamentally related to the process of senescence such as the inability to cope with oxidative stress .


Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis .

Induction of <protein>bcl-2</protein> expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis .


Engagement of surface immunoglobulin on mature B cells leads to rescue from apoptosis and to proliferation .


Levels of bcl-2 mRNA and protein increase with cross-linking of surface immunoglobulin .

Levels of <rna>bcl-2 mRNA</rna> and protein increase with cross-linking of <protein>surface immunoglobulin</protein> .


We have located the major positive regulatory region for control of bcl-2 expression in B cells in the 5'-flanking region .

We have located the major positive regulatory region for control of <protein>bcl-2</protein> expression in <cell_type>B cells</cell_type> in the <dna>5'-flanking region</dna> .


The positive region can be divided into an upstream and a downstream regulatory region .

The positive region can be divided into an <dna>upstream and a downstream regulatory region</dna> .


The downstream regulatory region contains a cyclic AMP-responsive element ( CRE ) .

The downstream regulatory region contains a <dna>cyclic AMP-responsive element</dna> ( <dna>CRE</dna> ) .


We show by antibody supershift experiments and UV cross-linking followed by denaturing polyacrylamide gel electrophoresis that both CREB and ATF family members bind to this region in vitro .


Mutations of the CRE site that result in loss of CREB binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays .

Mutations of the <dna>CRE site</dna> that result in loss of <protein>CREB</protein> binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays .