Conversely , classic HD ( CHD ) is heterogeneous because the tumor cells of a fraction of CHD display the BCL-6 ( - ) / syn-1 ( + ) phenotype of post-GC B-cells , whereas another fraction of CHD is constituted by a mixture of tumor cells reflecting the GC ( BCL-6 ( + ) / syn-1 ( - ) ) or post-GC ( BCL-6 ( - ) / syn-1 ( + ) ) phenotypes .

Conversely , classic HD ( CHD ) is heterogeneous because the <cell_type>tumor cells</cell_type> of a fraction of CHD display the <protein>BCL-6</protein> ( - ) / <protein>syn-1</protein> ( + ) phenotype of post-GC B-cells , whereas another fraction of CHD is constituted by a mixture of <cell_type>tumor cells</cell_type> reflecting the GC ( <protein>BCL-6</protein> ( + ) / <protein>syn-1</protein> ( - ) ) or post-GC ( <protein>BCL-6</protein> ( - ) / <protein>syn-1</protein> ( + ) ) phenotypes .


BCL-6 ( - ) /syn-1 ( + ) tumor cells of CHD are mostly found surrounded by T cells expressing CD40L , consistent with the observation that CD40 signaling downregulates BCL-6 expression .

<cell_line>BCL-6 ( - ) /syn-1 ( + ) tumor cells</cell_line> of CHD are mostly found surrounded by <cell_type>T cells</cell_type> expressing <protein>CD40L</protein> , consistent with the observation that <protein>CD40</protein> signaling downregulates <protein>BCL-6</protein> expression .


These data indicate that tumor cells of NLPHD uniformly display a GC B-cell phenotype , whereas the phenotype of tumor cells of CHD appears to be modulated by the surrounding cellular background , particularly CD40L+ reactive T cells .

These data indicate that <cell_type>tumor cells</cell_type> of NLPHD uniformly display a GC B-cell phenotype , whereas the phenotype of <cell_type>tumor cells</cell_type> of CHD appears to be modulated by the surrounding cellular background , particularly <cell_type>CD40L+ reactive T cells</cell_type> .


Molecular and cellular analysis of human immunodeficiency virus-induced apoptosis in lymphoblastoid T-cell-line-expressing wild-type and mutated CD4 receptors .

Molecular and cellular analysis of human immunodeficiency virus-induced apoptosis in <protein>lymphoblastoid T-cell-line-expressing wild-type and mutated CD4 receptors</protein> .


We have previously shown that the presence of the CD4 cytoplasmic tail is critical for human immunodeficiency virus ( HIV ) -induced apoptosis ( J.Corbeil , M.Tremblay , and D.D.Richman , J.Exp.Med.183 : 39-48 , 1996 ) .

We have previously shown that the presence of the <protein>CD4 cytoplasmic tail</protein> is critical for human immunodeficiency virus ( HIV ) -induced apoptosis ( J.Corbeil , M.Tremblay , and D.D.Richman , J.Exp.Med.183 : 39-48 , 1996 ) .


We have pursued our investigation of the role of the CD4 transduction pathway in HIV-induced apoptosis .

We have pursued our investigation of the role of the <protein>CD4</protein> transduction pathway in HIV-induced apoptosis .


To do this , wild-type and mutant forms of the CD4 cytoplasmic tail were stably expressed in the lymphoblastoid T-cell line A2.01 .

To do this , wild-type and mutant forms of the <protein>CD4 cytoplasmic tail</protein> were stably expressed in the <cell_line>lymphoblastoid T-cell line</cell_line> <cell_line>A2.01</cell_line> .


Apoptosis was prevented when CD4 truncated at residue 402 was expressed ; however , cells expressing mutated receptors that do not associate with p56 ( lck ) ( mutated at the dicysteine motif and truncated at residue 418 ) but which conserved proximal domains of the cytoplasmic tail underwent apoptosis like wild- type CD4 .

Apoptosis was prevented when <protein>CD4</protein> truncated at residue 402 was expressed ; however , cells expressing mutated receptors that do not associate with <protein>p56 ( lck )</protein> ( mutated at the <protein>dicysteine motif</protein> and truncated at residue 418 ) but which conserved proximal domains of the <protein>cytoplasmic tail</protein> underwent apoptosis like <protein>wild- type CD4</protein> .


The differences between wild-type and mutated receptors in the induction of apoptosis were not related to levels of p56 ( lck ) or NF- kappaB activation .

The differences between <protein>wild-type and mutated receptors</protein> in the induction of apoptosis were not related to levels of <protein>p56 ( lck )</protein> or <protein>NF- kappaB</protein> activation .


Initial signaling through the CD4 receptor played a major role in the sensitization of HIV-infected T cells to undergo apoptosis .

Initial signaling through the <protein>CD4 receptor</protein> played a major role in the sensitization of <cell_type>HIV-infected T cells</cell_type> to undergo apoptosis .


Incubation of HIV-infected cells with monoclonal antibody ( MAb ) 13B8-2 , which binds to CD4 in a region critical for dimerization of the receptor , prevented apoptosis without inhibiting HIV replication .

Incubation of <cell_type>HIV-infected cells</cell_type> with <protein>monoclonal antibody ( MAb ) 13B8-2</protein> , which binds to <protein>CD4</protein> in a region critical for dimerization of the receptor , prevented apoptosis without inhibiting HIV replication .


Moreover , the apoptotic process was not related to Fas -Fas ligand interaction ; however , an antagonistic anti-Fas MAb ( ZB-4 ) enhanced apoptosis in HIV-infected cells without inducing apoptosis in uninfected cells .

Moreover , the apoptotic process was not related to <protein>Fas</protein> <protein>-Fas ligand</protein> interaction ; however , an antagonistic anti-Fas MAb ( ZB-4 ) enhanced apoptosis in <cell_type>HIV-infected cells</cell_type> without inducing apoptosis in <cell_type>uninfected cells</cell_type> .


These observations demonstrate that CD4 signaling mediates HIV-induced apoptosis by a mechanism independent of Fas -Fas ligand interaction , does not require p56 ( lck ) signaling , and may involve a critical region for CD4 dimerization .

These observations demonstrate that <protein>CD4</protein> signaling mediates HIV-induced apoptosis by a mechanism independent of <protein>Fas</protein> <protein>-Fas ligand</protein> interaction , does not require <protein>p56 ( lck )</protein> signaling , and may involve a critical region for <protein>CD4</protein> dimerization .


p130 , p107 , and pRb are differentially regulated in proliferating cells and during cell cycle arrest by alpha-interferon .

<protein>p130</protein> , <protein>p107</protein> , and <protein>pRb</protein> are differentially regulated in <cell_type>proliferating cells</cell_type> and during cell cycle arrest by <protein>alpha-interferon</protein> .


We have determined how the phosphorylation of the retinoblastoma family ( pRb , p107 , and p130 ) is governed in individual cell cycle phases of Daudi B-cells during cell cycle exit triggered by alpha-interferon ( alpha-IFN ) .

We have determined how the phosphorylation of the <protein>retinoblastoma family</protein> ( <protein>pRb</protein> , <protein>p107</protein> , and <protein>p130</protein> ) is governed in individual cell cycle phases of <cell_line>Daudi B-cells</cell_line> during cell cycle exit triggered by <protein>alpha-interferon</protein> ( <protein>alpha-IFN</protein> ) .


alpha-IFN causes dephosphorylation of pRb and loss of p130 phosphorylated Form 3 .

<protein>alpha-IFN</protein> causes dephosphorylation of <protein>pRb</protein> and loss of <protein>p130 phosphorylated Form 3</protein> .


However , the change in p130 phosphorylation in response to alpha-IFN occurs before dephosphorylation of pRb is complete because loss of p130 Form 3 occurs throughout the cell cycle prior to complete arrest in G1 , whereas pRb is dephosphorylated only in G1 .

However , the change in <protein>p130</protein> phosphorylation in response to <protein>alpha-IFN</protein> occurs before dephosphorylation of <protein>pRb</protein> is complete because loss of <protein>p130 Form 3</protein> occurs throughout the cell cycle prior to complete arrest in G1 , whereas <protein>pRb</protein> is dephosphorylated only in G1 .


In contrast , p107 is dephosphorylated and is then depleted from cells as they exit the cell cycle .

In contrast , <protein>p107</protein> is dephosphorylated and is then depleted from cells as they exit the cell cycle .


p130 , predominantly in Form 1 , and hypophosphorylated pRb bind an E2F DNA binding site ; p130 complexes E2F-4 , whereas pRb binds both E2F-4 and E2F-1 .

<protein>p130</protein> , predominantly in Form 1 , and <protein>hypophosphorylated pRb</protein> bind an <dna>E2F DNA binding site</dna> ; <protein>p130</protein> complexes <protein>E2F-4</protein> , whereas <protein>pRb</protein> binds both E2F-4 and <protein>E2F-1</protein> .


The phosphorylated forms of E2F-4 that bind to the E2F DNA site are different from hyperphosphorylated E2F-4 , which predominates in primary hemopoietic cells in G0 .

The phosphorylated forms of <protein>E2F-4</protein> that bind to the <dna>E2F DNA site</dna> are different from hyperphosphorylated <protein>E2F-4</protein> , which predominates in <cell_type>primary hemopoietic cells</cell_type> in G0 .


We conclude that although cell cycle arrest induced by alpha-IFN may be mediated in part by formation of a complex containing p130 and E2F-4 , alpha-IFN does not induce hyperphosphorylation of E2F-4 , which characterizes primary hemopoietic cells in G0 .

We conclude that although cell cycle arrest induced by <protein>alpha-IFN</protein> may be mediated in part by formation of a complex containing <protein>p130</protein> and <protein>E2F-4</protein> , <protein>alpha-IFN</protein> does not induce hyperphosphorylation of <protein>E2F-4</protein> , which characterizes <cell_type>primary hemopoietic cells</cell_type> in G0 .


The transcription factors c-myb and C/EBP alpha regulate the monocytic/myeloic gene MRP14 .

The <protein>transcription factors</protein> <protein>c-myb</protein> and <protein>C/EBP alpha</protein> regulate the <dna>monocytic/myeloic gene</dna> <dna>MRP14</dna> .


The entry of microorganisms into the body induces inflammatory processes .


During this process a sequence of cellular , humoral , non-specific and specific actions are evoked to combat the infection .


Macrophages and granulocytes , which are developed from a common progenitor cell , are the cellular components of the specific and non-specific immunoreaction .

<cell_type>Macrophages</cell_type> and <cell_type>granulocytes</cell_type> , which are developed from a common progenitor cell , are the cellular components of the specific and non-specific immunoreaction .


MRP14 ( Macrophage migration inhibitory related protein ) and MRP8 , two S-100 proteins contained in high concentrations in these cells are obviously essential for adhesion and migration of monocytes and granulocytes .

<dna>MRP14</dna> ( <protein>Macrophage migration inhibitory related protein</protein> ) and <protein>MRP8</protein> , two <protein>S-100 proteins</protein> contained in high concentrations in these cells are obviously essential for adhesion and migration of <cell_type>monocytes</cell_type> and <cell_type>granulocytes</cell_type> .


To investigate the transcriptional regulation of these genes we cotransfected constructs expressing CAT under control of the MRP14 promoter and expression constructs of C/EBP alpha and v-myb , two transcription factors involved in myeloid/monocytic differentiation .

To investigate the transcriptional regulation of these genes we cotransfected constructs expressing <protein>CAT</protein> under control of the <dna>MRP14 promoter</dna> and expression constructs of <protein>C/EBP alpha</protein> and <protein>v-myb</protein> , two <protein>transcription factors</protein> involved in myeloid/monocytic differentiation .


Transfection with C/EBP alpha revealed a massive enhancement of the MRP14 promoter in both , HL 60 cells ( granulocytic differentiated ) and L132 fibroblasts .

Transfection with <protein>C/EBP alpha</protein> revealed a massive enhancement of the <dna>MRP14 promoter</dna> in both , <cell_type>HL 60 cells</cell_type> ( granulocytic differentiated ) and <cell_type>L132 fibroblasts</cell_type> .


In contrast , v-myb reduces MRP14 promoter activity .

In contrast , <protein>v-myb</protein> reduces <dna>MRP14 promoter</dna> activity .


Northern blot analysis of L132 cells transfected with the C/EBP alpha expression vector demonstrate that C/EBP alpha is sufficient to enhance MRP14 expression in the context of the whole genome .

Northern blot analysis of <cell_type>L132 cells</cell_type> transfected with the <protein>C/EBP alpha</protein> expression vector demonstrate that <protein>C/EBP alpha</protein> is sufficient to enhance <protein>MRP14</protein> expression in the context of the whole genome .


A CD28 -associated signaling pathway leading to cytokine gene transcription and T cell proliferation without TCR engagement .

A <protein>CD28</protein> -associated signaling pathway leading to <dna>cytokine gene</dna> transcription and T cell proliferation without <protein>TCR</protein> engagement .


Stimulation of resting human T cells with the CD28-specific mAb BW 828 induces proliferation and cytokine synthesis without further requirement for TCR coengagement .

Stimulation of <cell_type>resting human T cells</cell_type> with the <protein>CD28-specific mAb BW 828</protein> induces proliferation and <protein>cytokine</protein> synthesis without further requirement for <protein>TCR</protein> coengagement .


This observation prompted us to postulate that signal 2 ( costimulatory signal ) alone without signal 1 ( TCR signal ) can activate T cells .

This observation prompted us to postulate that signal 2 ( costimulatory signal ) alone without signal 1 ( <protein>TCR</protein> signal ) can activate <cell_type>T cells</cell_type> .


To test whether this putative function of CD28 is mediated via a particular signaling pathway , we compared early signaling events initiated in resting T cells by the stimulatory mAb BW 828 with signals triggered by the nonstimulating CD28 mAb 9.3 .

To test whether this putative function of <protein>CD28</protein> is mediated via a particular signaling pathway , we compared early signaling events initiated in resting <cell_type>T cells</cell_type> by the <protein>stimulatory mAb BW 828</protein> with signals triggered by the <protein>nonstimulating CD28 mAb 9.3</protein> .


Stimulation of T cells with BW 828 induced an increase in intracellular Ca2+ , but did not lead to detectable activation of the protein kinases p56 ( lck ) and c-Raf-1 .

Stimulation of <cell_type>T cells</cell_type> with <protein>BW 828</protein> induced an increase in intracellular Ca2+ , but did not lead to detectable activation of the <protein>protein kinases</protein> <protein>p56 ( lck )</protein> and <protein>c-Raf-1</protein> .


This pathway resulted in the induction of the transcription factors NF-kappa B , NF-AT , and proteins binding to the CD28 response element of the IL-2 promoter .

This pathway resulted in the induction of the <protein>transcription factors</protein> <protein>NF-kappa B</protein> , <protein>NF-AT</protein> , and proteins binding to the <protein>CD28</protein> response element of the <dna>IL-2 promoter</dna> .


On the other hand , stimulation of T cells with mAb 9.3 increased the level of intracellular Ca2+ and triggered the activation of p56 ( lck ) and c-Raf-1 , but was unable to induce the binding of transcription factors to the IL-2 promoter .

On the other hand , stimulation of <cell_type>T cells</cell_type> with <protein>mAb 9.3</protein> increased the level of intracellular Ca2+ and triggered the activation of <protein>p56 ( lck )</protein> and <protein>c-Raf-1</protein> , but was unable to induce the binding of <protein>transcription factors</protein> to the <dna>IL-2 promoter</dna> .


In contrast to the differential signaling of BW 828 and 9.3 in resting T cells , the two mAbs exhibited a similar pattern of early signaling events in activated T cells and Jurkat cells ( p56 ( lck ) activation , association of phosphatidylinositol 3-kinase with CD28 ) , indicating that the signaling capacity of CD28 changes with activation .

In contrast to the differential signaling of <protein>BW 828</protein> and <protein>9.3</protein> in resting T cells , the two mAbs exhibited a similar pattern of early signaling events in <cell_type>activated T cells</cell_type> and <cell_type>Jurkat cells</cell_type> ( <protein>p56 ( lck )</protein> activation , association of <protein>phosphatidylinositol 3-kinase</protein> with <protein>CD28</protein> ) , indicating that the signaling capacity of <protein>CD28</protein> changes with activation .


These data support the view that stimulation through CD28 can induce some effector functions in T cells and suggest that this capacity is associated with a particular pattern of early signaling events

These data support the view that stimulation through <protein>CD28</protein> can induce some effector functions in <cell_type>T cells</cell_type> and suggest that this capacity is associated with a particular pattern of early signaling events


Decreased IL-12 production and Th1 cell development by acetyl salicylic acid-mediated inhibition of NF-kappaB .

Decreased <protein>IL-12</protein> production and Th1 cell development by acetyl salicylic acid-mediated inhibition of <protein>NF-kappaB</protein> .


IL-12 is a 75-kDa heterodimeric cytokine composed of two covalently linked p35 and p40 chains .

<protein>IL-12</protein> is a <protein>75-kDa heterodimeric cytokine</protein> composed of two covalently linked <protein>p35 and p40 chains</protein> .


This pro-inflammatory cytokine plays a prominent role in the development of Th1 cell-mediated immune responses .

This <protein>pro-inflammatory cytokine</protein> plays a prominent role in the development of Th1 cell-mediated immune responses .


Th1 cell-mediated immune responses have been implicated in the pathogenesis of chronic inflammatory autoimmune diseases .


Thus , IL-12 appears to be a critical factor in the generation and maintenance of chronic inflammatory conditions .

Thus , <protein>IL-12</protein> appears to be a critical factor in the generation and maintenance of chronic inflammatory conditions .


In this study , we investigated the effects of a commonly prescribed anti-inflammatory drug , acetyl salicylic acid ( ASA ) , on IL-12 production and Th1 cell development .

In this study , we investigated the effects of a commonly prescribed anti-inflammatory drug , acetyl salicylic acid ( ASA ) , on <protein>IL-12</protein> production and Th1 cell development .


ASA was found to inhibit secretion of the IL-12 heterodimer as well as p40 monomer by human monocytic cells .

ASA was found to inhibit secretion of the <protein>IL-12 heterodimer</protein> as well as <protein>p40 monomer</protein> by <cell_type>human monocytic cells</cell_type> .


This was associated with the down-regulation of IL-12p40 mRNA expression .

This was associated with the down-regulation of <rna>IL-12p40 mRNA</rna> expression .


Analysis of the regulation of the p40 gene promoter revealed that ASA inhibited NF-kappaB activation and binding to the p40-kappaB site in the p40 promoter , leading to transcriptional repression of the p40 gene .

Analysis of the regulation of the <dna>p40 gene promoter</dna> revealed that ASA inhibited <protein>NF-kappaB</protein> activation and binding to the <dna>p40-kappaB site</dna> in the <dna>p40 promoter</dna> , leading to transcriptional repression of the <dna>p40 gene</dna> .


Addition of ASA to an in vitro T helper cell differentiation system , at concentrations compatible with plasma levels reached during anti-inflammatory therapy , resulted in reduced development of Th1 cells .

Addition of ASA to an in vitro T helper cell differentiation system , at concentrations compatible with plasma levels reached during anti-inflammatory therapy , resulted in reduced development of <cell_type>Th1 cells</cell_type> .


These results suggest that the inhibition of NF-kappaB activation by ASA leads to down-regulation of IL-12 production and inhibition of Th1 cell development .

These results suggest that the inhibition of <protein>NF-kappaB</protein> activation by ASA leads to down-regulation of <protein>IL-12</protein> production and inhibition of Th1 cell development .


Attenuation of HLA-DR expression by mononuclear phagocytes infected with Mycobacterium tuberculosis is related to intracellular sequestration of immature class II heterodimers .

Attenuation of <protein>HLA-DR</protein> expression by <cell_type>mononuclear phagocytes</cell_type> infected with Mycobacterium tuberculosis is related to intracellular sequestration of <protein>immature class II heterodimers</protein> .


MHC class II expression was examined in macrophages infected with Mycobacterium tuberculosis .

<protein>MHC class II</protein> expression was examined in <cell_type>macrophages</cell_type> infected with Mycobacterium tuberculosis .


IFN-gamma increased the surface expression of class II molecules in THP-1 cells and this was markedly reduced in cells infected with M. tuberculosis .

<protein>IFN-gamma</protein> increased the surface expression of <protein>class II molecules</protein> in <cell_line>THP-1 cells</cell_line> and this was markedly reduced in cells infected with M. tuberculosis .


Despite this effect , steady state levels of HLA-DRalpha , HLA-DRbeta , and invariant ( Ii ) chains were equivalent in control and infected cells .

Despite this effect , steady state levels of <protein>HLA-DRalpha</protein> , <protein>HLA-DRbeta</protein> , and <protein>invariant ( Ii ) chains</protein> were equivalent in <cell_type>control and infected cells</cell_type> .


Metabolic labeling combined with pulse-chase experiments and biochemical analysis showed that the majority of class II molecules in infected cells became resistant to endoglycosidase H , consistent with normal Golgi processing .

Metabolic labeling combined with pulse-chase experiments and biochemical analysis showed that the majority of <protein>class II molecules</protein> in infected cells became resistant to <protein>endoglycosidase H</protein> , consistent with normal Golgi processing .


However , results of intracellular staining and dual color confocal microscopy revealed a significant defect in transport of newly synthesized class II molecules through the endocytic compartment .

However , results of intracellular staining and dual color confocal microscopy revealed a significant defect in transport of newly synthesized <protein>class II molecules</protein> through the endocytic compartment .


Thus , compared with findings in control cells , class II molecules in infected cells colocalized to a minimal extent with a lysosomal-associated membrane protein-1 + endosomal compartment .

Thus , compared with findings in control cells , <protein>class II molecules</protein> in <cell_type>infected cells</cell_type> colocalized to a minimal extent with a <protein>lysosomal-associated membrane protein-1</protein> + endosomal compartment .


In addition , in contrast to control cells , class II molecules in infected cells failed to colocalize with endocytosed BSA under conditions where this marker is known to label late endosomes , lysosomes , and the MHC class II compartment .

In addition , in contrast to <cell_type>control cells</cell_type> , <protein>class II molecules</protein> in <cell_type>infected cells</cell_type> failed to colocalize with <protein>endocytosed BSA</protein> under conditions where this marker is known to label late endosomes , lysosomes , and the <protein>MHC class II</protein> compartment .


Consistent with defective transport along the endocytic pathway , the maturation of SDS-stable class II alphabeta dimers -- dependent upon removal of Ii chain and peptide loading of class II dimers in the MHC class II compartment -- was markedly impaired in M. tuberculosis -infected cells .

Consistent with defective transport along the endocytic pathway , the maturation of <protein>SDS-stable class II alphabeta dimers</protein> -- dependent upon removal of <protein>Ii chain</protein> and peptide loading of <protein>class II dimers</protein> in the <protein>MHC class II</protein> compartment -- was markedly impaired in M. tuberculosis <cell_type>-infected cells</cell_type> .


These findings indicate that defective transport and processing of class II molecules through the endosomal/lysosomal system is responsible for diminished cell surface expression of MHC class II molecules in cells infected with M. tuberculosis .

These findings indicate that defective transport and processing of <protein>class II molecules</protein> through the endosomal/lysosomal system is responsible for diminished cell surface expression of <protein>MHC class II molecules</protein> in cells infected with M. tuberculosis .


Identification of upstream regulatory elements that repress expression of adult beta-like globin genes in a primitive erythroid environment .

Identification of <dna>upstream regulatory elements</dna> that repress expression of <dna>adult beta-like globin genes</dna> in a primitive erythroid environment .


Our investigations have focused on localizing cis-elements responsible for the down regulation of the adult beta-like globin genes ( delta and beta ) in immature , or primitive erythroid tissues .

Our investigations have focused on localizing <dna>cis-elements</dna> responsible for the down regulation of the <dna>adult beta-like globin genes</dna> ( <dna>delta</dna> and <dna>beta</dna> ) in immature , or primitive erythroid tissues .


We studied their activity after transfection into K562 cells , an erythroleukemia cell line with an embryonic-fetal phenotype .

We studied their activity after transfection into <cell_line>K562 cells</cell_line> , an <cell_line>erythroleukemia cell line</cell_line> with an embryonic-fetal phenotype .


Analyzed DNA sequences included delta and beta 5 ' flanking regions extending from approximately -500 to +50bp ( promoter regions ) , truncated delta and beta 5 ' flanking regions extending from approximately -250 to +50 bp , and chimeric promoter constructions , which consisted of a distal delta or beta fragment fused to a proximal beta or delta sequence .

Analyzed <dna>DNA sequences</dna> included <dna>delta and beta 5 ' flanking regions</dna> extending from approximately <dna>-500 to +50bp</dna> ( <dna>promoter regions</dna> ) , truncated delta and <dna>beta 5 ' flanking regions</dna> extending from approximately <dna>-250 to +50 bp</dna> , and <dna>chimeric promoter constructions</dna> , which consisted of a distal <dna>delta or beta fragment</dna> fused to a <dna>proximal beta or delta sequence</dna> .


In CAT reporter constructions no appreciable level of CAT activity was supported by the beta globin promoter , and only low level activity by the delta promoter .

In <dna>CAT reporter constructions</dna> no appreciable level of <protein>CAT</protein> activity was supported by the <dna>beta globin promoter</dna> , and only low level activity by the <dna>delta promoter</dna> .


Truncation of the beta globin promoter led to a 2-3 fold increase in promoter activity .

Truncation of the <dna>beta globin promoter</dna> led to a 2-3 fold increase in promoter activity .


In contrast , deletion of the upstream portion of the delta promoter led to a 10 fold decrease in expression .

In contrast , deletion of the <dna>upstream portion</dna> of the <dna>delta promoter</dna> led to a 10 fold decrease in expression .


Coupling of the upstream beta globin sequence from approximately -500 to -250 bp to the truncated delta promoter fragment led to complete extinction of transcription activity , consistent with a negative regulatory effect of the beta globin gene upstream element ( s ) .

Coupling of the <dna>upstream beta globin sequence</dna> from approximately -500 to -250 bp to the truncated <dna>delta promoter</dna> fragment led to complete extinction of transcription activity , consistent with a negative regulatory effect of the <dna>beta globin gene upstream element</dna> ( s ) .


Fusion of the upstream portion of the delta promoter to the truncated beta globin promoter yielded a modest increase in promoter strength relative to the truncated beta gene promoter , indicating the presence of a positive transcriptional element ( s ) in the upstream delta globin regulatory region .

Fusion of the <dna>upstream portion</dna> of the <dna>delta promoter</dna> to the truncated <dna>beta globin promoter</dna> yielded a modest increase in promoter strength relative to the <dna>truncated beta gene promoter</dna> , indicating the presence of a <dna>positive transcriptional element</dna> ( s ) in the <dna>upstream delta globin regulatory region</dna> .


Site-directed mutagenesis of binding sites for the repressor proteins BP1 and BP2 in the upstream portion of the beta globin gene flanking region led to a 4-6 fold increase in promoter activity .

Site-directed mutagenesis of binding sites for the <protein>repressor proteins BP1 and BP2</protein> in the <dna>upstream portion</dna> of the <dna>beta globin gene flanking region</dna> led to a 4-6 fold increase in promoter activity .


DNase I footprinting of the upstream delta-globin region revealed protected sequences corresponding to consensus binding sites for GATA-1 and BP2 .

<protein>DNase I</protein> footprinting of the <dna>upstream delta-globin region</dna> revealed <dna>protected sequences</dna> corresponding to <dna>consensus binding sites</dna> for <protein>GATA-1</protein> and <protein>BP2</protein> .


These results confirm that sequences in the upstream promoter region of the adult beta globin gene contribute to its factor-mediated suppression early in development and then may modulate its expression at a later stage .

These results confirm that sequences in the <dna>upstream promoter region</dna> of the <dna>adult beta globin gene</dna> contribute to its factor-mediated suppression early in development and then may modulate its expression at a later stage .


Analysis of cytokine signaling in patients with extrinsic asthma and hyperimmunoglobulin E .

Analysis of <protein>cytokine</protein> signaling in patients with extrinsic asthma and hyperimmunoglobulin E .


BACKGROUND : Recent data suggest that the regulation of class switching to IgE by cytokines is mediated by STAT transcription factors .

BACKGROUND : Recent data suggest that the regulation of class switching to <protein>IgE</protein> by <protein>cytokines</protein> is mediated by <protein>STAT transcription factors</protein> .


The induction of IgE by IL-4 and IL-13 occurs through the activation of the intracellular signal-transducing protein Stat6 , whereas the inhibition of IgE class switching by interferon-y ( IFN-gamma ) occurs through the activation of Statl .

The induction of <protein>IgE</protein> by <protein>IL-4</protein> and <protein>IL-13</protein> occurs through the activation of the <protein>intracellular signal-transducing protein Stat6</protein> , whereas the inhibition of <protein>IgE</protein> class switching by <protein>interferon-y</protein> ( <protein>IFN-gamma</protein> ) occurs through the activation of <protein>Statl</protein> .


OBJECTIVE : We hypothesized that in extrinsic asthma or in cases of markedly elevated IgE ( ie , hyperimmunoglobulin E [ HIE ] ) increased levels of IgE may be associated with alterations in the cytokine levels or the activation of Stat6 .

OBJECTIVE : We hypothesized that in extrinsic asthma or in cases of markedly elevated <protein>IgE</protein> ( ie , hyperimmunoglobulin E [ HIE ] ) increased levels of <protein>IgE</protein> may be associated with alterations in the <protein>cytokine</protein> levels or the activation of <protein>Stat6</protein> .


METHODS : PBMCs and sera from 8 patients with extrinsic asthma ( mean IgE , 285+/-100 IU/mL ) , 3 patients with HIE ( mean IgE , 7050+/-1122 IU/mL ) , and 14 nonatopic control subjects ( mean IgE , 112+/-28 IU/mL ) were analyzed .

METHODS : <cell_type>PBMCs</cell_type> and sera from 8 patients with extrinsic asthma ( mean <protein>IgE</protein> , 285+/-100 IU/mL ) , 3 patients with HIE ( mean <protein>IgE</protein> , 7050+/-1122 IU/mL ) , and 14 nonatopic control subjects ( mean <protein>IgE</protein> , 112+/-28 IU/mL ) were analyzed .


RESULTS : The mean IL-4 level detected by ELISA was much greater in patients with HIE than control subjects ( 88.6+/-11.5 pg/mL vs 11.5+/-7.1 pg/mL , P = .005 ) , and increased IL-4 levels among patients with both asthma and HIE correlated with the increased IgE levels .

RESULTS : The mean <protein>IL-4</protein> level detected by ELISA was much greater in patients with HIE than control subjects ( 88.6+/-11.5 pg/mL vs 11.5+/-7.1 pg/mL , P = .005 ) , and increased <protein>IL-4</protein> levels among patients with both asthma and HIE correlated with the increased <protein>IgE</protein> levels .


In contrast , IL-13 levels were not elevated .

In contrast , <protein>IL-13</protein> levels were not elevated .


Levels of Stat6 protein present in PBMCs did not differ in the patients and control subjects .

Levels of <protein>Stat6</protein> protein present in <cell_type>PBMCs</cell_type> did not differ in the patients and control subjects .


Examination of Stat6 DNA-binding activity demonstrated no activation of IL-4 signaling in patients with either HIE or acute asthma .

Examination of <protein>Stat6</protein> DNA-binding activity demonstrated no activation of <protein>IL-4</protein> signaling in patients with either HIE or acute asthma .


Interestingly , evidence for the presence of B cells that have already switched to IgE was seen in PBMCs of several patients with asthma or HIE .

Interestingly , evidence for the presence of <cell_type>B cells</cell_type> that have already switched to <protein>IgE</protein> was seen in <cell_type>PBMCs</cell_type> of several patients with asthma or HIE .


CONCLUSION : These results indicate that ( 1 ) IgE production in asthma and HIE usually is associated with elevated levels of IL-4 , but not IL-13 , in the peripheral blood ; ( 2 ) the increased sera IL-4 levels in asthma and HIE are not sufficient to induce Stat6 activation in PBMCs ; and ( 3 ) evidence of switch recombination to epsilon may be detected in isolated cases of elevated IgE .

CONCLUSION : These results indicate that ( 1 ) <protein>IgE</protein> production in asthma and HIE usually is associated with elevated levels of <protein>IL-4</protein> , but not <protein>IL-13</protein> , in the peripheral blood ; ( 2 ) the increased sera <protein>IL-4</protein> levels in asthma and HIE are not sufficient to induce <protein>Stat6</protein> activation in <cell_type>PBMCs</cell_type> ; and ( 3 ) evidence of switch recombination to epsilon may be detected in isolated cases of elevated <protein>IgE</protein> .


This implies that high levels of IgE in these patients either results from B cells that have already undergone class switching , from Ig class switching that is localized to target tissues , or both .

This implies that high levels of <protein>IgE</protein> in these patients either results from <cell_type>B cells</cell_type> that have already undergone class switching , from Ig class switching that is localized to target tissues , or both .


Carboxyl-terminal 15-amino acid sequence of NFATx1 is possibly created by tissue-specific splicing and is essential for transactivation activity in T cells .

<protein>Carboxyl-terminal 15-amino acid sequence</protein> of <protein>NFATx1</protein> is possibly created by tissue-specific splicing and is essential for transactivation activity in <cell_type>T cells</cell_type> .


NFAT regulates transcription of a number of cytokine and other immunoregulatory genes .

<protein>NFAT</protein> regulates transcription of a number of cytokine and other <dna>immunoregulatory genes</dna> .


We have isolated NFATx , which is one of four members of the NFAT family of transcription factors and is preferentially expressed in the thymus and peripheral blood leukocytes , and an isoform of NFATx , NFATx1 .

We have isolated <protein>NFATx</protein> , which is one of four members of the <protein>NFAT family</protein> of <protein>transcription factors</protein> and is preferentially expressed in the thymus and <cell_type>peripheral blood leukocytes</cell_type> , and an isoform of <protein>NFATx</protein> , <protein>NFATx1</protein> .


Here we provide evidence showing that 15 amino acids in the carboxyl-terminal end of NFATx1 are required for its maximum transactivation activity in Jurkat T cells .

Here we provide evidence showing that 15 amino acids in the <protein>carboxyl-terminal end</protein> of <protein>NFATx1</protein> are required for its maximum transactivation activity in <cell_line>Jurkat T cells</cell_line> .


A fusion between these 15 amino acids and the GAL4 DNA binding domain was capable of transactivating reporters driven by the GAL4 DNA binding site .

A fusion between these 15 amino acids and the <protein>GAL4 DNA binding domain</protein> was capable of transactivating reporters driven by the <dna>GAL4 DNA binding site</dna> .


Interestingly , this 15-amino acid transactivation sequence is well conserved in NFAT family proteins , although the sequences contiguous to the carboxyl-terminal regions of the NFAT family are much less conserved .

Interestingly , this <protein>15-amino acid transactivation sequence</protein> is well conserved in <protein>NFAT family proteins</protein> , although the sequences contiguous to the <protein>carboxyl-terminal regions</protein> of the <protein>NFAT family</protein> are much less conserved .


We also report three additional isoforms of NFATx , designated NFATx2 , NFATx3 , and NFATx4 .

We also report three additional isoforms of <protein>NFATx</protein> , designated <protein>NFATx2</protein> , <protein>NFATx3</protein> , and <protein>NFATx4</protein> .


This transactivation sequence is altered by tissue-specific alternative splicing in newly isolated NFATx isoforms , resulting in lower transactivation activity in Jurkat T cells .

This transactivation sequence is altered by tissue-specific alternative splicing in newly isolated <protein>NFATx isoforms</protein> , resulting in lower transactivation activity in <cell_line>Jurkat T cells</cell_line> .


NFATx1 is expressed predominantly in the thymus and peripheral blood leukocyte , while the skeletal muscle expressed primarily NFATx2 .

<protein>NFATx1</protein> is expressed predominantly in the thymus and <cell_type>peripheral blood leukocyte</cell_type> , while the skeletal muscle expressed primarily <protein>NFATx2</protein> .


In Jurkat cells , transcription from the NFAT site of the IL-2 promoter is activated strongly by NFATx1 but only weakly by NFATx2 .

In <cell_line>Jurkat cells</cell_line> , transcription from the <dna>NFAT site</dna> of the <dna>IL-2 promoter</dna> is activated strongly by <protein>NFATx1</protein> but only weakly by <protein>NFATx2</protein> .


These data demonstrate that the 15-amino acid sequence of NFATx1 is a major transactivation sequence required for induction of genes by NFATx1 in T cells and possibly regulates NFAT activity through tissue-specific alternative splicing .

These data demonstrate that the <protein>15-amino acid sequence</protein> of <protein>NFATx1</protein> is a <protein>major transactivation sequence</protein> required for induction of genes by <protein>NFATx1</protein> in <cell_type>T cells</cell_type> and possibly regulates <protein>NFAT</protein> activity through tissue-specific alternative splicing .


Altered DNA-binding specificity mutants of EKLF and Sp1 show that EKLF is an activator of the beta-globin locus control region in vivo .

<protein>Altered DNA-binding specificity mutants</protein> of <protein>EKLF</protein> and Sp1 show that <protein>EKLF</protein> is an activator of the <dna>beta-globin locus control region</dna> in vivo .


The locus control region of the beta-globin cluster contains five DNase I hypersensitive sites ( 5'HS1-5 ) required for locus activation .

The <dna>locus control region</dna> of the <dna>beta-globin cluster</dna> contains five <dna>DNase I hypersensitive sites</dna> ( <dna>5'HS1-5</dna> ) required for locus activation .


5'HS3 contains six G-rich motifs that are essential for its activity .

<dna>5'HS3</dna> contains six G-rich motifs that are essential for its activity .


Members of a protein family , characterized by three zinc fingers highly homologous to those found in transcription factor Sp1 , interact with these motifs .

Members of a protein family , characterized by three <protein>zinc fingers</protein> highly homologous to those found in <protein>transcription factor Sp1</protein> , interact with these motifs .


Because point mutagenesis can not distinguish between family members , it is not known which protein activates 5'HS3 .

Because point mutagenesis can not distinguish between family members , it is not known which protein activates <dna>5'HS3</dna> .


We show that the function of such closely related proteins can be distinguished in vivo by matching point mutations in 5'HS3 with amino acid changes in the zinc fingers of Sp1 and EKLF .

We show that the function of such closely related proteins can be distinguished in vivo by matching point mutations in <dna>5'HS3</dna> with amino acid changes in the <protein>zinc fingers</protein> of <protein>Sp1</protein> and <protein>EKLF</protein> .


Testing their activity in transgenic mice shows that EKLF is a direct activator of 5'HS3 .

Testing their activity in transgenic mice shows that <protein>EKLF</protein> is a direct activator of <dna>5'HS3</dna> .


The Epstein-Barr virus Rta protein activates lytic cycle genes and can disrupt latency in B lymphocytes .

The <protein>Epstein-Barr virus Rta protein</protein> activates <dna>lytic cycle genes</dna> and can disrupt latency in <cell_type>B lymphocytes</cell_type> .


The transition of Epstein-Barr virus ( EBV ) from latency into the lytic cycle is associated with the expression of two immediate-early viral genes , BZLF1 and BRLF1 .

The transition of Epstein-Barr virus ( EBV ) from latency into the lytic cycle is associated with the expression of two <dna>immediate-early viral genes</dna> , <dna>BZLF1</dna> and <dna>BRLF1</dna> .


Overexpression of ZEBRA , the product of BZLF1 , is sufficient to disrupt latency in B lymphocytes and epithelial cells by stimulating expression of lytic cycle genes , including BRLF1 .

Overexpression of ZEBRA , the product of <dna>BZLF1</dna> , is sufficient to disrupt latency in <cell_type>B lymphocytes</cell_type> and <cell_type>epithelial cells</cell_type> by stimulating expression of <dna>lytic cycle genes</dna> , including <dna>BRLF1</dna> .


The BRLF1 product Rta functions as a transcriptional activator in both B lymphocytes and epithelial cells .

The <protein>BRLF1 product Rta</protein> functions as a transcriptional activator in both <cell_type>B lymphocytes</cell_type> and <cell_type>epithelial cells</cell_type> .


However , Rta has recently been reported to disrupt latency in an epithelial specific manner ( S. Zalani , E. Holley-Guthrie , and S. Kenney , Proc. Natl. Acad. Sci. USA 93 : 9194-9199 , 1996 ) .

However , <protein>Rta</protein> has recently been reported to disrupt latency in an epithelial specific manner ( S. Zalani , E. Holley-Guthrie , and S. Kenney , Proc. Natl. Acad. Sci. USA 93 : 9194-9199 , 1996 ) .


Here we demonstrate that expression of Rta is also sufficient for disruption of latency in a permissive B-cell line .

Here we demonstrate that expression of <protein>Rta</protein> is also sufficient for disruption of latency in a <cell_line>permissive B-cell line</cell_line> .


In HH514-16 cells , transfection of Rta leads to synthesis of ZEBRA , viral DNA replication , and late gene expression .

In <cell_line>HH514-16 cells</cell_line> , transfection of <protein>Rta</protein> leads to synthesis of <protein>ZEBRA</protein> , viral DNA replication , and late gene expression .


However , Rta by itself is less potent than ZEBRA in the ability to activate most early and late lytic cycle genes .

However , <protein>Rta</protein> by itself is less potent than <protein>ZEBRA</protein> in the ability to activate most early and late <dna>lytic cycle genes</dna> .


In light of previous work implicating ZEBRA in the activation of Rta , we suggest a cooperative model for EBV entry into the lytic cycle .

In light of previous work implicating <protein>ZEBRA</protein> in the activation of <protein>Rta</protein> , we suggest a cooperative model for EBV entry into the lytic cycle .


Expression of either BZLF1 or BRLF1 triggers expression of the other immediate-early factor , and together these activators act individually or in synergy on downstream targets to activate the viral lytic cycle .

Expression of either <dna>BZLF1</dna> or <dna>BRLF1</dna> triggers expression of the other <protein>immediate-early factor</protein> , and together these activators act individually or in synergy on <dna>downstream targets</dna> to activate the viral lytic cycle .


Transcription of a minimal promoter from the NF-IL6 gene is regulated by CREB/ATF and SP1 proteins in U937 promonocytic cells .

Transcription of a <dna>minimal promoter</dna> from the <dna>NF-IL6 gene</dna> is regulated by <protein>CREB/ATF</protein> and <protein>SP1 proteins</protein> in <cell_line>U937 promonocytic cells</cell_line> .


NF-IL6 is an important transcriptional regulator of genes induced in activated monocytes/macrophages , and NF-IL6 is the only CCAAT/enhancer-binding protein ( C/EBP ) family member whose steady-state mRNA levels increase upon activation of monocytes ( 1 ) .

<protein>NF-IL6</protein> is an important transcriptional regulator of genes induced in <cell_type>activated monocytes/macrophages</cell_type> , and <protein>NF-IL6</protein> is the only <protein>CCAAT/enhancer-binding protein ( C/EBP ) family</protein> member whose steady-state mRNA levels increase upon activation of <cell_type>monocytes</cell_type> ( 1 ) .


We show that increased transcription of the NF-IL6 gene is responsible , at least in part , for induction of NF-IL6 mRNA following activation of U937 promonocytic cells .

We show that increased transcription of the <dna>NF-IL6 gene</dna> is responsible , at least in part , for induction of <rna>NF-IL6 mRNA</rna> following activation of <cell_line>U937 promonocytic cells</cell_line> .


We have identified a 104-bp minimal promoter region of the NF-IL6 gene that is sufficient for basal and activation-dependent induction of transcription in U937 cells .

We have identified a <dna>104-bp minimal promoter region</dna> of the <dna>NF-IL6 gene</dna> that is sufficient for basal and activation-dependent induction of transcription in <cell_line>U937 cells</cell_line> .


This region contains binding sites for the cAMP response element-binding protein/activation transcription factor ( CREB/ATF ) and Sp1 families of transcription factors .

This region contains binding sites for the <protein>cAMP response element-binding protein/activation transcription factor</protein> ( <protein>CREB/ATF</protein> ) and <protein>Sp1</protein> families of <protein>transcription factors</protein> .


Each site is functionally important and contributes independently to transcription of the NF-IL6 gene in U937 cells .

Each site is functionally important and contributes independently to transcription of the <dna>NF-IL6 gene</dna> in <cell_line>U937 cells</cell_line> .


CIITA B-cell-specific promoter suppression in MHC class II-silenced cell hybrids .

<protein>CIITA</protein> <dna>B-cell-specific promoter</dna> suppression in <cell_line>MHC class II-silenced cell hybrids</cell_line> .


In this study , various sets of somatic cell hybrids , generated by the fusion of epithelial cell lines with B-lymphoblastoid cell lines , were analyzed for the expression of major histocompatibility complex ( MHC ) class II antigens .

In this study , various sets of <cell_line>somatic cell hybrids</cell_line> , generated by the fusion of <cell_line>epithelial cell lines</cell_line> with <cell_line>B-lymphoblastoid cell lines</cell_line> , were analyzed for the expression of <protein>major histocompatibility complex ( MHC ) class II antigens</protein> .


We first demonstrate , in human and mouse intraspecies hybrids , the coordinate suppression of MHC class II , Ii ( invariant chain ) and HLA-DM gene transcription , and the release of the silencing by the addition of interferon gamma .

We first demonstrate , in <cell_line>human and mouse intraspecies hybrids</cell_line> , the coordinate suppression of <protein>MHC class II</protein> , <protein>Ii</protein> ( <protein>invariant chain</protein> ) and <dna>HLA-DM gene</dna> transcription , and the release of the silencing by the addition of <protein>interferon gamma</protein> .


Using interspecies hybrids , the segregation of human chromosomes allowed us to establish that MHC class II extinction is linked to the presence in the hybrids of the chromosomes from the epithelial fusion partner .

Using interspecies hybrids , the segregation of <dna>human chromosomes</dna> allowed us to establish that <protein>MHC class II</protein> extinction is linked to the presence in the hybrids of the <dna>chromosomes</dna> from the <cell_type>epithelial fusion partner</cell_type> .


Moreover , our data provide evidence that the expression pattern of MHC class II mRNA is correlated with that of the class II transactivator ( CIITA ) , suggesting that CIITA is the actual target of the silencing .

Moreover , our data provide evidence that the expression pattern of <rna>MHC class II mRNA</rna> is correlated with that of the <protein>class II transactivator</protein> ( <protein>CIITA</protein> ) , suggesting that <protein>CIITA</protein> is the actual target of the silencing .


To gain further insight into the suppression phenomenon we performed luciferase assays which show that silencing affects the activity of the B-cell-specific promoter of CIITA .

To gain further insight into the suppression phenomenon we performed luciferase assays which show that silencing affects the activity of the <dna>B-cell-specific promoter</dna> of <protein>CIITA</protein> .


These results therefore demonstrate that the MHC class II gene silencing in somatic cell hybrids is due to an active suppression of one of the promoters of the CIITA gene , mediated by the epithelial cell fusion partner .

These results therefore demonstrate that the <protein>MHC class II</protein> gene silencing in <cell_line>somatic cell hybrids</cell_line> is due to an active suppression of one of the <dna>promoters</dna> of the <dna>CIITA gene</dna> , mediated by the <cell_type>epithelial cell fusion partner</cell_type> .


Class II transactivator-independent endothelial cell MHC class II gene activation induced by lymphocyte adhesion .

Class II transactivator-independent endothelial cell <protein>MHC class II</protein> gene activation induced by lymphocyte adhesion .


NK cells induce MHC class II molecules on the surface of allogeneic endothelial cells in an adhesion-dependent , IFN-gamma -independent manner .

NK cells induce <protein>MHC class II</protein> molecules on the surface of allogeneic endothelial cells in an adhesion-dependent , <protein>IFN-gamma</protein> -independent manner .


Here , we demonstrate that NK cells induce HLA-DR on the surface of a mutant cell line that is defective in IFN-gamma -induced MHC class II expression .

Here , we demonstrate that <cell_line>NK cells</cell_line> induce <protein>HLA-DR</protein> on the surface of a <cell_line>mutant cell line</cell_line> that is defective in <protein>IFN-gamma</protein> -induced <protein>MHC class II</protein> expression .


RNA analysis in these cells and in a cell line that is defective in class II transactivator ( CIITA ) demonstrates that NK cell-induced HLA-DR alpha mRNA expression is also CIITA -independent .

RNA analysis in these cells and in a cell line that is defective in <protein>class II transactivator</protein> ( <protein>CIITA</protein> ) demonstrates that NK cell-induced <rna>HLA-DR alpha mRNA</rna> expression is also <protein>CIITA</protein> -independent .


The Janus kinase-1-deficient cell line U4A expresses HLA-DR alpha mRNA in response to NK cell activation , and HLA-DR alpha promoter constructs transfected into these cells are induced by NK cells but not IFN-gamma .

The <cell_line>Janus kinase-1-deficient cell line U4A</cell_line> expresses <rna>HLA-DR alpha mRNA</rna> in response to NK cell activation , and <dna>HLA-DR alpha promoter constructs</dna> transfected into these cells are induced by <cell_line>NK cells</cell_line> but not <protein>IFN-gamma</protein> .


These data indicate that the IFN-gamma -independent component of the target cell HLA-DR expression induced by lymphocyte adhesion uses a signaling pathway that is distinct from the IFN-gamma -dependent mechanism and also suggest that CIITA is not required .

These data indicate that the <protein>IFN-gamma</protein> -independent component of the target cell <protein>HLA-DR</protein> expression induced by lymphocyte adhesion uses a signaling pathway that is distinct from the <protein>IFN-gamma</protein> -dependent mechanism and also suggest that <protein>CIITA</protein> is not required .


Effects of overexpression of IL-1 receptor-associated kinase on NFkappaB activation , IL-2 production and stress-activated protein kinases in the murine T cell line EL4 .

Effects of overexpression of <protein>IL-1 receptor-associated kinase</protein> on <protein>NFkappaB</protein> activation , <protein>IL-2</protein> production and stress-activated protein kinases in the <cell_line>murine T cell line EL4</cell_line> .


The association and activation of the IL-1 receptor-associated protein kinase ( IRAK ) to the IL-1 receptor complex is one of the earliest events detectable in IL-1 signal transduction .

The association and activation of the <protein>IL-1 receptor-associated protein kinase</protein> ( <protein>IRAK</protein> ) to the <protein>IL-1 receptor complex</protein> is one of the earliest events detectable in <protein>IL-1</protein> signal transduction .


We generated permanent clones of the murine T cell line EL4 6.1 overexpressing human ( h ) IRAK to evaluate the role of this kinase in IL-1 signaling .

We generated permanent clones of the <cell_line>murine T cell line EL4 6.1</cell_line> overexpressing <protein>human ( h ) IRAK</protein> to evaluate the role of this kinase in <protein>IL-1</protein> signaling .


Overexpression of hIRAK enhanced IL-1 -stimulated activation of the transcription factor NFkappaB , whereas a truncated form ( N-IRAK ) specifically inhibited IL-1 -dependent NFkappaB activity .

Overexpression of <protein>hIRAK</protein> enhanced <protein>IL-1</protein> -stimulated activation of the <protein>transcription factor NFkappaB</protein> , whereas a truncated form ( <protein>N-IRAK</protein> ) specifically inhibited <protein>IL-1</protein> -dependent <protein>NFkappaB</protein> activity .


In clones stably overexpressing hIRAK a weak constitutive activation of NFkappaB correlated with a low basal IL-2 production which was enhanced in an IL-1 -dependent manner .

In clones stably overexpressing <protein>hIRAK</protein> a weak constitutive activation of <protein>NFkappaB</protein> correlated with a low basal <protein>IL-2</protein> production which was enhanced in an <protein>IL-1</protein> -dependent manner .


Compared to the parental cell line the dose-response curve of IL-1 -induced IL-2 production was shifted in both potency and efficacy .

Compared to the <cell_line>parental cell line</cell_line> the dose-response curve of <protein>IL-1</protein> -induced <protein>IL-2</protein> production was shifted in both potency and efficacy .


These results demonstrate that IRAK directly triggers NFkappaB -mediated gene expression in EL4 cells .

These results demonstrate that <protein>IRAK</protein> directly triggers <protein>NFkappaB</protein> -mediated gene expression in <cell_line>EL4 cells</cell_line> .


Qualitatively different effects were observed for the IL-1 -induced activation of stress-activated protein ( SAP ) kinases : permanent overexpression of IRAK did not affect the dose dependence but prolonged the kinetics of IL-1 -induced activation of SAP kinases , suggesting that this signaling branch may be regulated by distinct mechanisms .

Qualitatively different effects were observed for the <protein>IL-1</protein> -induced activation of <protein>stress-activated protein ( SAP ) kinases</protein> : permanent overexpression of <protein>IRAK</protein> did not affect the dose dependence but prolonged the kinetics of <protein>IL-1</protein> -induced activation of <protein>SAP kinases</protein> , suggesting that this signaling branch may be regulated by distinct mechanisms .


The role of protein kinase C signaling in activated DRA transcription .

The role of <protein>protein kinase C</protein> signaling in activated <dna>DRA</dna> transcription .


Expression of human MHC HLA-DRA class II gene can be up-regulated in B cells by Ig cross-linking as well as by phorbol esters such as 12-O-tetradecanoyl phorbol 13-acetate ( TPA ) .

Expression of <dna>human MHC HLA-DRA class II gene</dna> can be up-regulated in <cell_type>B cells</cell_type> by Ig cross-linking as well as by phorbol esters such as 12-O-tetradecanoyl phorbol 13-acetate ( TPA ) .


Induced DRA expression involves activation of restricted protein kinase C ( PKC ) isoforms , resulting in activated activator protein-1 -dependent transcription .

Induced <dna>DRA</dna> expression involves activation of <protein>restricted protein kinase C ( PKC ) isoforms</protein> , resulting in activated activator <protein>protein-1</protein> -dependent transcription .


In this report expression profiles and activation of PKC were analyzed in human Raji B lymphoblastoid cells .

In this report expression profiles and activation of <protein>PKC</protein> were analyzed in <cell_line>human Raji B lymphoblastoid cells</cell_line> .


Transient transfection analysis with target plasmids containing either DRA promoter ( wild-type or mutated ) or TPA response elements demonstrated that pretreatment with the selective PKC inhibitor GF 109203X repressed TPA-mediated activation .

Transient transfection analysis with <dna>target plasmids</dna> containing either <dna>DRA promoter</dna> ( wild-type or mutated ) or <dna>TPA response elements</dna> demonstrated that pretreatment with the selective <protein>PKC</protein> inhibitor GF 109203X repressed TPA-mediated activation .


Western analysis performed on cellular fractions of resting cells and of TPA-activated cells revealed abundant expression of classical PKC-alpha ( cPKC-alpha ) , cPKC-betaII , and atypical PKC-zeta isoforms and identified a sustained translocation of cPKC-alpha and cPKC-betaII from the cytosolic compartment to membranes .

Western analysis performed on cellular fractions of <cell_type>resting cells</cell_type> and of <cell_type>TPA-activated cells</cell_type> revealed abundant expression of <protein>classical PKC-alpha</protein> ( <protein>cPKC-alpha</protein> ) , <protein>cPKC-betaII</protein> , and <protein>atypical PKC-zeta isoforms</protein> and identified a sustained translocation of <protein>cPKC-alpha</protein> and <protein>cPKC-betaII</protein> from the cytosolic compartment to membranes .


As expected , the distribution of atypical PKC-zeta was unaffected by TPA treatment and displayed an even distribution between cytosol and membranes .

As expected , the distribution of <protein>atypical PKC-zeta</protein> was unaffected by TPA treatment and displayed an even distribution between cytosol and membranes .


This finding was confirmed by immunofluorescence microscopy .


The TPA-mediated translocation of cPKC-alpha and cPKC-betaII was not influenced by pretreatment with GF 109203X .

The TPA-mediated translocation of <protein>cPKC-alpha</protein> and <protein>cPKC-betaII</protein> was not influenced by pretreatment with GF 109203X .


Finally , functional activation and translocation of PKC were investigated with a selective in vitro kinase assay .

Finally , functional activation and translocation of <protein>PKC</protein> were investigated with a selective in vitro kinase assay .


Together , these results show that activated HLA-DRA expression in response to TPA treatment is strictly dependent on PKC activation acting on the X2 box of the DRA promoter and that selective inhibition of PKC enzymatic activity does not influence subcellular localization of expressed PKC isoenzymes .

Together , these results show that activated <protein>HLA-DRA</protein> expression in response to TPA treatment is strictly dependent on <protein>PKC</protein> activation acting on the <dna>X2 box</dna> of the <dna>DRA promoter</dna> and that selective inhibition of <protein>PKC</protein> enzymatic activity does not influence subcellular localization of expressed <protein>PKC isoenzymes</protein> .


Thus , the translocation event per se occurs independently of PKC activation in these cells .

Thus , the translocation event per se occurs independently of <protein>PKC</protein> activation in these cells .


Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands [ see comments ]

Inhibition of <protein>RNA polymerase II</protein> transcription in <cell_type>human cells</cell_type> by synthetic DNA-binding ligands [ see comments ]


Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes .

Sequence-specific DNA-binding small molecules that can permeate <cell_type>human cells</cell_type> potentially could regulate transcription of specific genes .


Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis .

Multiple <protein>cellular DNA-binding transcription factors</protein> are required by HIV type 1 for RNA synthesis .


Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-1 , lymphoid-enhancer binding factor 1 , and TATA-box binding protein .

Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the <protein>transcription factors</protein> <protein>Ets-1</protein> , <protein>lymphoid-enhancer binding factor 1</protein> , and <protein>TATA-box binding protein</protein> .


These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays .

These synthetic ligands specifically inhibit DNA-binding of each <protein>transcription factor</protein> and HIV type 1 transcription in cell-free assays .


When used in combination , the polyamides inhibit virus replication by > 99 % in isolated human peripheral blood lymphocytes , with no detectable cell toxicity .

When used in combination , the polyamides inhibit virus replication by > 99 % in <cell_type>isolated human peripheral blood lymphocytes</cell_type> , with no detectable cell toxicity .


The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression , as well as a mechanism for the inhibition of viral replication .

The ability of small molecules to target predetermined <dna>DNA sequences</dna> located within <dna>RNA polymerase II promoters</dna> suggests a general approach for regulation of gene expression , as well as a mechanism for the inhibition of viral replication .


musculin : a murine basic helix-loop-helix transcription factor gene expressed in embryonic skeletal muscle .

<dna>musculin</dna> : a <dna>murine basic helix-loop-helix transcription factor gene</dna> expressed in embryonic skeletal muscle .


We describe the embryonic expression of musculin , a new murine member of the bHLH family of transcription factors .

We describe the embryonic expression of <protein>musculin</protein> , a new murine member of the <protein>bHLH family</protein> of <protein>transcription factors</protein> .


Musculin protein is closely related to human ABF-1 , which is expressed in activated B cells , and to epicardin/capsulin/Pod-1 , which is expressed in branchial myoblasts , visceral and urogenital mesoderm and epicardium .

Musculin protein is closely related to <protein>human ABF-1</protein> , which is expressed in activated <cell_type>B cells</cell_type> , and to <protein>epicardin/capsulin/Pod-1</protein> , which is expressed in <cell_type>branchial myoblasts</cell_type> , visceral and urogenital mesoderm and epicardium .


In situ hybridisation revealed musculin expression in embryos was largely restricted to the embryonic skeletal muscle lineage .

In situ hybridisation revealed <protein>musculin</protein> expression in embryos was largely restricted to the <cell_type>embryonic skeletal muscle lineage</cell_type> .


While all skeletal muscles expressed the gene , only a subset of myocytes within each muscle were positive , indicating molecular heterogeneity within fetal muscle .


Copyright 1998 Elsevier Science Ireland Ltd .


All Rights Reserved .


Induction of T cell anergy by high concentrations of immunodominant native peptide is accompanied by IL-10 production and a block in JNK activity .

Induction of T cell anergy by high concentrations of immunodominant native peptide is accompanied by <protein>IL-10</protein> production and a block in <protein>JNK</protein> activity .


The ability to induce anergy in antigen-specific T cells has potential therapeutic value for altering pathologic immune responses .

The ability to induce anergy in <cell_type>antigen-specific T cells</cell_type> has potential therapeutic value for altering pathologic immune responses .


This study was undertaken to further analyze changes in cytokine production and intracellular signaling during anergy induction using high concentrations of native peptide ligand of tetanus toxoid ( TT ) - and myelin basic protein ( MBP ) -specific human T cell lines .

This study was undertaken to further analyze changes in <protein>cytokine</protein> production and intracellular signaling during anergy induction using high concentrations of native peptide ligand of <cell_line>tetanus toxoid ( TT ) - and myelin basic protein ( MBP ) -specific human T cell lines</cell_line> .


The TT-selected T cell line could be rendered unresponsive to its dominant epitope in a dose-dependent manner ( IC50 = 0.03 microg/ml ) .

The <cell_line>TT-selected T cell line</cell_line> could be rendered unresponsive to its dominant epitope in a dose-dependent manner ( IC50 = 0.03 microg/ml ) .


The TT-selected line , as well as three T cell clones established from this line , continued to produce IFN-gamma and significantly increased IL-4 and IL-10 production when anergy was induced with high concentrations of the immunodominant epitope .

The <cell_line>TT-selected line</cell_line> , as well as three T cell clones established from this line , continued to produce <protein>IFN-gamma</protein> and significantly increased <protein>IL-4</protein> and <protein>IL-10</protein> production when anergy was induced with high concentrations of the immunodominant epitope .


JNK enzymatic activity was blocked in anergized T cells .

<protein>JNK</protein> enzymatic activity was blocked in <cell_line>anergized T cells</cell_line> .


The MBP -selected line could likewise be rendered unresponsive by incubation with supraoptimal concentrations of immunodominant peptide and anergy induction was accompanied by IL-10 release .

The <protein>MBP</protein> -selected line could likewise be rendered unresponsive by incubation with supraoptimal concentrations of immunodominant peptide and anergy induction was accompanied by <protein>IL-10</protein> release .


Both T cell lines could be anergized by the autopresentation of native peptide since anergy was induced in cultures lacking fresh antigen-presenting cells .

Both <cell_line>T cell lines</cell_line> could be anergized by the autopresentation of native peptide since anergy was induced in cultures lacking fresh <cell_type>antigen-presenting cells</cell_type> .


This study shows that the mitogen-activated protein kinase cascade is blocked when anergy is induced to high concentrations of soluble peptide .

This study shows that the <protein>mitogen-activated protein kinase</protein> cascade is blocked when anergy is induced to high concentrations of soluble peptide .


Copyright 1998 Academic Press .


Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha ( C/EBP alpha ) is critical for granulopoiesis .

Upregulation of <protein>interleukin 6</protein> and <protein>granulocyte colony-stimulating factor receptors</protein> by <protein>transcription factor</protein> <protein>CCAAT enhancer binding protein alpha</protein> ( <protein>C/EBP alpha</protein> ) is critical for granulopoiesis .


Cytokines stimulate granulopoiesis through signaling via receptors whose expression is controlled by lineage-specific transcription factors .

Cytokines stimulate granulopoiesis through signaling via receptors whose expression is controlled by lineage-specific <protein>transcription factors</protein> .


Previously , we demonstrated that granulocyte colony-stimulating factor ( G-CSF ) receptor mRNA was undetectable and granulocyte maturation blocked in CCAAT enhancer binding protein alpha ( C/EBPalpha ) -deficient mice .

Previously , we demonstrated that <rna>granulocyte colony-stimulating factor ( G-CSF ) receptor mRNA</rna> was undetectable and granulocyte maturation blocked in <protein>CCAAT enhancer binding protein alpha</protein> ( <protein>C/EBPalpha</protein> ) -deficient mice .


This phenotype is distinct from that of G-CSF receptor-/- mice , suggesting that other genes are likely to be adversely affected by loss of C/EBPalpha .

This phenotype is distinct from that of G-CSF receptor-/- mice , suggesting that other genes are likely to be adversely affected by loss of <protein>C/EBPalpha</protein> .


Here we demonstrate loss of interleukin 6 ( IL-6 ) receptor and IL-6-responsive colony-forming units ( CFU-IL6 ) in C/EBPalpha -/- mice .

Here we demonstrate loss of <protein>interleukin 6 ( IL-6 ) receptor</protein> and <protein>IL-6-responsive colony-forming units</protein> ( <protein>CFU-IL6</protein> ) in <protein>C/EBPalpha</protein> -/- mice .


The observed failure of granulopoiesis could be rescued by the addition of soluble IL-6 receptor and IL-6 or by retroviral transduction of G-CSF receptors , demonstrating that loss of both of these receptors contributes to the absolute block in granulocyte maturation observed in C/EBPalpha-deficient hematopoietic cells .

The observed failure of granulopoiesis could be rescued by the addition of soluble <protein>IL-6 receptor</protein> and <protein>IL-6</protein> or by retroviral transduction of <protein>G-CSF receptors</protein> , demonstrating that loss of both of these receptors contributes to the absolute block in granulocyte maturation observed in <cell_type>C/EBPalpha-deficient hematopoietic cells</cell_type> .


The results of these and other studies suggest that additional C/EBPalpha target genes , possibly other cytokine receptors , are also important for the block in granulocyte differentiation observed in vivo in C/EBPalpha -deficient mice .

The results of these and other studies suggest that additional <dna>C/EBPalpha target genes</dna> , possibly other cytokine receptors , are also important for the block in granulocyte differentiation observed in vivo in <protein>C/EBPalpha</protein> -deficient mice .


Phosphatidylinositides bind to plasma membrane CD14 and can prevent monocyte activation by bacterial lipopolysaccharide .

Phosphatidylinositides bind to <protein>plasma membrane CD14</protein> and can prevent monocyte activation by bacterial lipopolysaccharide .


Although bacterial lipopolysaccharides ( LPS ) and several other microbial agonists can bind to mCD14 ( membrane CD14 ) , a cell-surface receptor found principally on monocytes and neutrophils , host-derived mCD14 ligands are poorly defined .

Although bacterial lipopolysaccharides ( LPS ) and several other microbial agonists can bind to <protein>mCD14</protein> ( <protein>membrane CD14</protein> ) , a cell-surface receptor found principally on <cell_type>monocytes</cell_type> and <cell_type>neutrophils</cell_type> , host-derived <protein>mCD14</protein> ligands are poorly defined .


We report here that phosphatidylinositol ( PtdIns ) , phosphatidylinositol-4-phosphate , and other phosphatidylinositides can bind to mCD14 .

We report here that phosphatidylinositol ( PtdIns ) , phosphatidylinositol-4-phosphate , and other phosphatidylinositides can bind to <protein>mCD14</protein> .


Phosphatidylserine ( PS ) , another anionic glycerophospholipid , binds to mCD14 with lower apparent affinity than does PtdIns .

Phosphatidylserine ( PS ) , another anionic glycerophospholipid , binds to <protein>mCD14</protein> with lower apparent affinity than does PtdIns .


LPS-binding protein , a lipid transfer protein found in serum , facilitates both PS -and PtdIns- mCD14 binding .

<protein>LPS-binding protein</protein> , a lipid transfer protein found in serum , facilitates both PS -and PtdIns- <protein>mCD14</protein> binding .


PtdIns binding to mCD14 can be blocked by anti-CD14 monoclonal antibodies that inhibit LPS -mCD14 binding , and PtdIns can inhibit both LPS -mCD14 binding and LPS-induced responses in monocytes .

PtdIns binding to <protein>mCD14</protein> can be blocked by <protein>anti-CD14 monoclonal antibodies</protein> that inhibit LPS <protein>-mCD14</protein> binding , and PtdIns can inhibit both LPS <protein>-mCD14</protein> binding and LPS-induced responses in <cell_type>monocytes</cell_type> .


Serum-equilibrated PtdIns also binds to mCD14-expressing cells , raising the possibility that endogenous PtdIns may modulate cellular responses to LPS and other mCD14 ligands in vivo .

<cell_type>Serum-equilibrated PtdIns also binds to mCD14-expressing cells</cell_type> , raising the possibility that endogenous PtdIns may modulate cellular responses to LPS and other <protein>mCD14</protein> ligands in vivo .


Protein kinase C regulates Fas ( CD95/APO-1 ) expression .

<protein>Protein kinase C</protein> regulates <protein>Fas</protein> ( <protein>CD95/APO-1</protein> ) expression .


Fas ( CD95/APO-1 ) is a transmembrane protein of the TNF/neuron growth factor receptor family .

<protein>Fas</protein> ( <protein>CD95/APO-1</protein> ) is a <protein>transmembrane protein</protein> of the <protein>TNF/neuron growth factor receptor family</protein> .


Ligation of Fas by specific Abs or Fas ligand ( FasL/CD95 ligand ) induces rapid apoptotic cell death in a variety of cell types .

Ligation of <protein>Fas</protein> by <protein>specific Abs</protein> or <protein>Fas ligand</protein> ( <protein>FasL/CD95 ligand</protein> ) induces rapid apoptotic cell death in a variety of cell types .


Despite progress in understanding the death signals transduced from Fas , very little is known with regard to the mechanisms by which Fas expression is regulated .

Despite progress in understanding the death signals transduced from <protein>Fas</protein> , very little is known with regard to the mechanisms by which <protein>Fas</protein> expression is regulated .


Using our previously established murine T cell hybridoma model A1.1 , we show that specific protein kinase C ( PKC ) inhibitors could block activation-induced Fas expression and apoptosis .

Using our previously established <cell_line>murine T cell hybridoma model</cell_line> <cell_line>A1.1</cell_line> , we show that specific <protein>protein kinase C</protein> ( <protein>PKC</protein> ) inhibitors could block activation-induced <protein>Fas</protein> expression and apoptosis .


The activation of PKC with PMA or 1-oleoyl-2-acetyl-sn-glycerol could mimic the TCR signal by inducing the expression of Fas but not FasL .

The activation of <protein>PKC</protein> with PMA or 1-oleoyl-2-acetyl-sn-glycerol could mimic the <protein>TCR</protein> signal by inducing the expression of <protein>Fas</protein> but not FasL .


PKC -dependent Fas expression was also observed in several murine and human tumor cell lines .

<protein>PKC</protein> -dependent <protein>Fas</protein> expression was also observed in several <cell_line>murine and human tumor cell lines</cell_line> .


Since the inhibition of Ca2+ redistribution by an inhibitor of intracellular Ca2+ mobilization , 8- ( diethylamino ) -octyl-3 , 4 , 5-trimethoxybenzoate hydrochloride , inhibited TCR-induced FasL but not Fas , the expression of Fas appears to be independent of Ca2+ mobilization .

Since the inhibition of Ca2+ redistribution by an inhibitor of intracellular Ca2+ mobilization , 8- ( diethylamino ) -octyl-3 , 4 , 5-trimethoxybenzoate hydrochloride , inhibited <protein>TCR-induced FasL</protein> but not <protein>Fas</protein> , the expression of <protein>Fas</protein> appears to be independent of Ca2+ mobilization .


Significantly , expression of the newly identified Fas-regulatory gene , TDAG51 , was found to be dependent upon the activity of PKC .

Significantly , expression of the newly identified <dna>Fas-regulatory gene</dna> , <dna>TDAG51</dna> , was found to be dependent upon the activity of <protein>PKC</protein> .


PKC activation only induced Fas expression in cells expressing wild-type TDAG51 .

<protein>PKC</protein> activation only induced <protein>Fas</protein> expression in cells expressing wild-type <dna>TDAG51</dna> .


Thus , Fas expression is likely mediated by PKC through TDAG51 .

Thus , <protein>Fas</protein> expression is likely mediated by <protein>PKC</protein> through <dna>TDAG51</dna> .


Retinoic acid inhibits CD40 + interleukin-4 -mediated IgE production in vitro .

Retinoic acid inhibits <protein>CD40</protein> + <protein>interleukin-4</protein> -mediated <protein>IgE</protein> production in vitro .


To elucidate the role of retinoic acid ( RA ) in anti-CD40 + interleukin-4 ( IL-4 ) -mediated B-cell activation , the effect of 10 ( -12 ) to 10 ( -6 ) mol/L RA was studied in anti-CD40 ( 1 microgram/mL ) + IL-4 ( 5 ng/mL ) -mediated proliferation and Ig synthesis by human peripheral blood mononuclear cells ( PBMC ) and B cells in healthy donors .

To elucidate the role of retinoic acid ( RA ) in <protein>anti-CD40</protein> + <protein>interleukin-4</protein> ( <protein>IL-4</protein> ) -mediated B-cell activation , the effect of 10 ( -12 ) to 10 ( -6 ) mol/L RA was studied in <protein>anti-CD40</protein> ( 1 microgram/mL ) + <protein>IL-4</protein> ( 5 ng/mL ) -mediated proliferation and Ig synthesis by <cell_type>human peripheral blood mononuclear cells</cell_type> ( <cell_type>PBMC</cell_type> ) and <cell_type>B cells</cell_type> in healthy donors .


Anti-CD40 + IL-4 -mediated proliferation of PBMC and B cells was inhibited by RA in a dose-dependent manner , with maximal inhibition of 62 % +/- 5 % in PBMC and 55 % +/- 4.4 % in B cells by all-trans RA , and 58 % +/- 6.7 % and 51 % +/- 4.7 % , respectively by 13-cis RA .

<protein>Anti-CD40</protein> + <protein>IL-4</protein> -mediated proliferation of <cell_type>PBMC</cell_type> and <cell_type>B cells</cell_type> was inhibited by RA in a dose-dependent manner , with maximal inhibition of 62 % +/- 5 % in <cell_type>PBMC</cell_type> and 55 % +/- 4.4 % in <cell_type>B cells</cell_type> by all-trans RA , and 58 % +/- 6.7 % and 51 % +/- 4.7 % , respectively by 13-cis RA .


IgE synthesis was even more markedly inhibited by RA starting at concentrations of > 10 ( -14 ) mol/L for B cells and > 10 ( -10 ) mol/L for PBMC .

<protein>IgE</protein> synthesis was even more markedly inhibited by RA starting at concentrations of > 10 ( -14 ) mol/L for <cell_type>B cells</cell_type> and > 10 ( -10 ) mol/L for <cell_type>PBMC</cell_type> .


Maximal inhibition of IgE production for B cells was at 10 ( -8 ) mol/L for all-trans RA ( 94 % +/- 1.8 % ) and 96 % +/- 3.2 % for 13-cis RA .

Maximal inhibition of <protein>IgE</protein> production for <cell_type>B cells</cell_type> was at 10 ( -8 ) mol/L for all-trans RA ( 94 % +/- 1.8 % ) and 96 % +/- 3.2 % for 13-cis RA .


Low concentrations of RA inhibiting IgE synthesis ( 10 ( -10 ) mol/L ) affected neither B-cell proliferation nor the production of IgA , IgG , and IgM .

Low concentrations of RA inhibiting <protein>IgE</protein> synthesis ( 10 ( -10 ) mol/L ) affected neither B-cell proliferation nor the production of <protein>IgA</protein> , <protein>IgG</protein> , and <protein>IgM</protein> .


Elucidation of the mechanism involved in this inhibition of IgE production shows that epsilon germline transcription is decreased by RA , whereas production of interferon-gamma ( IFN-gamma ) was not enhanced in the presence of RA .

Elucidation of the mechanism involved in this inhibition of <protein>IgE</protein> production shows that epsilon <dna>germline</dna> transcription is decreased by RA , whereas production of <protein>interferon-gamma</protein> ( <protein>IFN-gamma</protein> ) was not enhanced in the presence of RA .


To differentiate whether the RA effect was mediated by RA receptors alpha , beta , and gamma , the expression of the retinoic acid receptors ( RAR ) was examined by reverse transcriptase -polymerase chain reaction ( RT-PCR ) .

To differentiate whether the RA effect was mediated by <protein>RA receptors alpha , beta , and gamma</protein> , the expression of the <protein>retinoic acid receptors</protein> ( <protein>RAR</protein> ) was examined by <protein>reverse transcriptase</protein> -polymerase chain reaction ( RT-PCR ) .


The data show that unstimulated human peripheral B cells express mRNA of the RA receptor alpha , beta , and gamma .

The data show that <cell_type>unstimulated human peripheral B cells</cell_type> express mRNA of the <protein>RA receptor alpha , beta , and gamma</protein> .


Using retinoids with different receptor binding specificity ( CD336 , CD437 , CD2019 , CD367 ) , dose-dependent inhibition of IgE synthesis was shown by all four derivates , but was most marked by an RA binding the alpha receptor with high specificity .

Using retinoids with different receptor binding specificity ( CD336 , CD437 , CD2019 , CD367 ) , dose-dependent inhibition of <protein>IgE</protein> synthesis was shown by all four derivates , but was most marked by an RA binding the <protein>alpha receptor</protein> with high specificity .


Taken together , this study shows that RA inhibits IgE production of anti-CD40 + IL-4-stimulated B cells in vitro .

Taken together , this study shows that RA inhibits <protein>IgE</protein> production of <cell_line>anti-CD40 + IL-4-stimulated B cells</cell_line> in vitro .


Copyright 1998 by The American Society of Hematology .


Human T-cell leukemia virus type 1 Tax induction of NF-kappaB involves activation of the IkappaB kinase alpha ( IKKalpha ) and IKKbeta cellular kinases .

Human T-cell leukemia virus type 1 <protein>Tax</protein> induction of <protein>NF-kappaB</protein> involves activation of the <protein>IkappaB kinase alpha</protein> ( <protein>IKKalpha</protein> ) and <protein>IKKbeta</protein> <protein>cellular kinases</protein> .


Tax corresponds to a 40-kDa transforming protein from the pathogenic retrovirus human T-cell leukemia virus type 1 ( HTLV-1 ) that activates nuclear expression of the NF-kappaB/Rel family of transcription factors by an unknown mechanism .

<protein>Tax</protein> corresponds to a <protein>40-kDa transforming protein</protein> from the pathogenic retrovirus human T-cell leukemia virus type 1 ( HTLV-1 ) that activates nuclear expression of the <protein>NF-kappaB/Rel family</protein> of <protein>transcription factors</protein> by an unknown mechanism .


Tax expression promotes N-terminal phosphorylation and degradation of IkappaB alpha , a principal cytoplasmic inhibitor of NF-kappaB .

<protein>Tax</protein> expression promotes N-terminal phosphorylation and degradation of <protein>IkappaB alpha</protein> , a principal cytoplasmic inhibitor of <protein>NF-kappaB</protein> .


Our studies now demonstrate that HTLV-1 Tax activates the recently identified cellular kinases IkappaB kinase alpha ( IKKalpha ) and IKKbeta , which normally phosphorylate IkappaB alpha on both of its N-terminal regulatory serines in response to tumor necrosis factor alpha ( TNF-alpha ) and interleukin-1 ( IL-1 ) stimulation .

Our studies now demonstrate that HTLV-1 <protein>Tax</protein> activates the recently identified <protein>cellular kinases</protein> <protein>IkappaB kinase alpha</protein> ( <protein>IKKalpha</protein> ) and <protein>IKKbeta</protein> , which normally phosphorylate <protein>IkappaB alpha</protein> on both of its N-terminal regulatory serines in response to <protein>tumor necrosis factor alpha</protein> ( <protein>TNF-alpha</protein> ) and <protein>interleukin-1</protein> ( <protein>IL-1</protein> ) stimulation .


In contrast , a mutant of Tax termed M22 , which does not induce NF-kappaB , fails to activate either IKKalpha or IKKbeta .

In contrast , a mutant of <protein>Tax</protein> termed <protein>M22</protein> , which does not induce <protein>NF-kappaB</protein> , fails to activate either <protein>IKKalpha</protein> or <protein>IKKbeta</protein> .


Furthermore , endogenous IKK enzymatic activity was significantly elevated in HTLV-1-infected and Tax-expressing T-cell lines .

Furthermore , endogenous IKK enzymatic activity was significantly elevated in <cell_line>HTLV-1-infected and Tax-expressing T-cell lines</cell_line> .


Transfection of kinase-deficient mutants of IKKalpha and IKKbeta into either human Jurkat T or 293 cells also inhibits NF-kappaB -dependent reporter gene expression induced by Tax .

Transfection of kinase-deficient mutants of <protein>IKKalpha</protein> and <protein>IKKbeta</protein> into either <cell_line>human Jurkat T or 293 cells</cell_line> also inhibits <protein>NF-kappaB</protein> -dependent <dna>reporter gene</dna> expression induced by <protein>Tax</protein> .


Similarly , a kinase-deficient mutant of NIK ( NF-kappaB-inducing kinase ) , which represents an upstream kinase in the TNF-alpha and IL-1 signaling pathways leading to IKKalpha and IKKbeta activation , blocks Tax induction of NF-kappaB .

Similarly , a <protein>kinase-deficient mutant</protein> of <protein>NIK</protein> ( <protein>NF-kappaB-inducing kinase</protein> ) , which represents an upstream kinase in the TNF-alpha and IL-1 signaling pathways leading to <protein>IKKalpha</protein> and <protein>IKKbeta</protein> activation , blocks <protein>Tax</protein> induction of <protein>NF-kappaB</protein> .


However , plasma membrane-proximal elements in these proinflammatory cytokine pathways are apparently not involved since dominant negative mutants of the TRAF2 and TRAF6 adaptors , which effectively block signaling through the cytoplasmic tails of the TNF-alpha and IL-1 receptors , respectively , do not inhibit Tax induction of NF-kappaB .

However , <dna>plasma membrane-proximal elements</dna> in these <protein>proinflammatory cytokine</protein> pathways are apparently not involved since dominant negative mutants of the <protein>TRAF2 and TRAF6 adaptors</protein> , which effectively block signaling through the <protein>cytoplasmic tails</protein> of the <protein>TNF-alpha</protein> and <protein>IL-1</protein> receptors , respectively , do not inhibit <protein>Tax</protein> induction of <protein>NF-kappaB</protein> .


Together , these studies demonstrate that HTLV-1 Tax exploits a distal part of the proinflammatory cytokine signaling cascade leading to induction of NF-kappaB .

Together , these studies demonstrate that HTLV-1 <protein>Tax</protein> exploits a distal part of the <protein>proinflammatory cytokine</protein> signaling cascade leading to induction of <protein>NF-kappaB</protein> .


The pathological alteration of this cytokine pathway leading to NF-kappaB activation by Tax may play a central role in HTLV-1-mediated transformation of human T cells , clinically manifested as the adult T-cell leukemia

The pathological alteration of this cytokine pathway leading to <protein>NF-kappaB</protein> activation by <protein>Tax</protein> may play a central role in HTLV-1-mediated transformation of <cell_type>human T cells</cell_type> , clinically manifested as the adult T-cell leukemia


Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells .

Role of <protein>IKK1</protein> and <protein>IKK2</protein> in lipopolysaccharide signaling in <cell_type>human monocytic cells</cell_type> .


Mononuclear phagocytes play a major role in immune and inflammatory responses .

<cell_type>Mononuclear phagocytes</cell_type> play a major role in immune and inflammatory responses .


Bacterial lipopolysaccharide ( LPS ) induces monocytes to express a variety of genes by activating the NF-kappaB/Rel transcription factor family .

Bacterial lipopolysaccharide ( LPS ) induces <cell_type>monocytes</cell_type> to express a variety of genes by activating the <protein>NF-kappaB/Rel transcription factor family</protein> .


Recently , we have reported that the tumor necrosis factor and interleukin 1 signaling pathways activate two kinases , IKK1 and IKK2 .

Recently , we have reported that the <protein>tumor necrosis factor</protein> and <protein>interleukin 1</protein> signaling pathways activate two kinases , <protein>IKK1</protein> and <protein>IKK2</protein> .


Phosphorylation of the IkappaB cytoplasmic inhibitors , IkappaBalpha , IkappaBbeta , and IkappaBepsilon , by these kinases triggers proteolytic degradation and the release of NF-kappaB/Rel proteins into the nucleus .

Phosphorylation of the <protein>IkappaB cytoplasmic inhibitors</protein> , <protein>IkappaBalpha</protein> , <protein>IkappaBbeta</protein> , and <protein>IkappaBepsilon</protein> , by these kinases triggers proteolytic degradation and the release of <protein>NF-kappaB/Rel proteins</protein> into the nucleus .


At present , the role of the IKKs in LPS signaling has not been investigated .


Here , we report that LPS induces IKK activity in human monocytes and THP-1 monocytic cells .

Here , we report that LPS induces <protein>IKK</protein> activity in <cell_type>human monocytes</cell_type> and <cell_line>THP-1 monocytic cells</cell_line> .


The kinetics of activation of kinase activity in monocytic cells are relatively slow with maximal activity observed at 60 min , which coincides with the degradation of IkappaBs and the nuclear translocation of NF-kappaB .

The kinetics of activation of kinase activity in <cell_type>monocytic cells</cell_type> are relatively slow with maximal activity observed at 60 min , which coincides with the degradation of <protein>IkappaBs</protein> and the nuclear translocation of <protein>NF-kappaB</protein> .


In transfection experiments , overexpression of wild type IKK1 , a dominant negative mutant IKK1 ( K44M ) , or wild type IKK2 did not affect LPS-induced kappaB -dependent transcription in monocytic cells .

In transfection experiments , overexpression of wild type <protein>IKK1</protein> , a <protein>dominant negative mutant IKK1</protein> ( <protein>K44M</protein> ) , or <protein>wild type IKK2</protein> did not affect LPS-induced <protein>kappaB</protein> -dependent transcription in <cell_type>monocytic cells</cell_type> .


In contrast , a dominant negative mutant of IKK2 inhibited LPS induction of kappaB -dependent transcription in a dose-dependent manner .

In contrast , a dominant negative mutant of <protein>IKK2</protein> inhibited LPS induction of <protein>kappaB</protein> -dependent transcription in a dose-dependent manner .


These results indicate that LPS induction of kappaB-dependent gene expression in human monocytic cells requires activation of IKK2 .

These results indicate that LPS induction of kappaB-dependent gene expression in <cell_type>human monocytic cells</cell_type> requires activation of <protein>IKK2</protein> .


IL-7 reconstitutes multiple aspects of v-Abl -mediated signaling .

<protein>IL-7</protein> reconstitutes multiple aspects of <protein>v-Abl</protein> -mediated signaling .


The mechanism by which early lymphoid cells are selectively transformed by v-Abl is currently unknown .

The mechanism by which <cell_type>early lymphoid cells</cell_type> are selectively transformed by <protein>v-Abl</protein> is currently unknown .


Previous studies have shown constitutive activation of IL-4 and IL-7 signaling pathways , as measured by activation of Janus protein kinase ( JAK ) 1 , JAK3 , STAT5 , and STAT6 , in pre-B cells transformed by v-Abl .

Previous studies have shown constitutive activation of <protein>IL-4</protein> and <protein>IL-7</protein> signaling pathways , as measured by activation of <protein>Janus protein kinase ( JAK ) 1</protein> , <protein>JAK3</protein> , <protein>STAT5</protein> , and <protein>STAT6</protein> , in <cell_type>pre-B cells</cell_type> transformed by <protein>v-Abl</protein> .


To determine whether activation of these cytokine signaling pathways by v-Abl is important in the cellular events induced by the Abelson murine leukemia virus , the effects of IL-4 and IL-7 on pre-B cells transformed with a temperature-sensitive v-Abl mutant were examined .

To determine whether activation of these cytokine signaling pathways by <protein>v-Abl</protein> is important in the cellular events induced by the Abelson murine leukemia virus , the effects of <protein>IL-4</protein> and <protein>IL-7</protein> on <cell_type>pre-B cells</cell_type> transformed with a <protein>temperature-sensitive v-Abl mutant</protein> were examined .


Whereas IL-4 had little or no effect , IL-7 delayed both the apoptosis and cell cycle arrest that occur upon v-Abl kinase inactivation .

Whereas <protein>IL-4</protein> had little or no effect , <protein>IL-7</protein> delayed both the apoptosis and cell cycle arrest that occur upon <protein>v-Abl</protein> kinase inactivation .


IL-7 also delayed the decreases in the levels of c-Myc , Bcl-2 , and Bcl-xL that occur upon loss of v-Abl kinase activity .

<protein>IL-7</protein> also delayed the decreases in the levels of <protein>c-Myc</protein> , <protein>Bcl-2</protein> , and <protein>Bcl-xL</protein> that occur upon loss of <protein>v-Abl</protein> kinase activity .


IL-7 did not maintain v-Abl -mediated differentiation arrest of the pre-B cells , as activation of NF-kappaB and RAG gene transcription was unaffected by IL-7 .

<protein>IL-7</protein> did not maintain <protein>v-Abl</protein> -mediated differentiation arrest of the <cell_type>pre-B cells</cell_type> , as activation of <protein>NF-kappaB</protein> and <dna>RAG gene</dna> transcription was unaffected by <protein>IL-7</protein> .


These results identify a potential role for IL-7 signaling pathways in transformation by v-Abl while demonstrating that a combination of IL-4 and IL-7 signaling can not substitute for an active v-Abl kinase in transformed pre-B cells .

These results identify a potential role for <protein>IL-7</protein> signaling pathways in transformation by <protein>v-Abl</protein> while demonstrating that a combination of <protein>IL-4</protein> and <protein>IL-7</protein> signaling can not substitute for an active <protein>v-Abl</protein> kinase in <cell_type>transformed pre-B cells</cell_type> .


Differential regulation of coproporphyrinogen oxidase gene between erythroid and nonerythroid cells .

Differential regulation of <dna>coproporphyrinogen oxidase gene</dna> between <cell_type>erythroid and nonerythroid cells</cell_type> .


Coproporphyrinogen oxidase ( CPO ) catalyzes the sixth step of the heme biosynthetic pathway .

<protein>Coproporphyrinogen oxidase</protein> ( <protein>CPO</protein> ) catalyzes the sixth step of the <protein>heme</protein> biosynthetic pathway .


To assess the tissue-specific regulation of the CPO gene promoter , mouse genomic DNA clones for CPO were isolated .

To assess the tissue-specific regulation of the <dna>CPO gene promoter</dna> , <dna>mouse genomic DNA clones</dna> for <protein>CPO</protein> were isolated .


Structural analysis demonstrated that the mouse CPO gene spans approximately 11 kb and consists of seven exons , just like its human counterpart .

Structural analysis demonstrated that the <dna>mouse CPO gene</dna> spans approximately 11 kb and consists of <dna>seven exons</dna> , just like its human counterpart .


Functional analysis of the promoter by transient transfection assays indicated that synergistic action between an SP-1-like element at -21/-12 , a GATA site at -59/-54 , and a novel regulatory element , CPRE ( - GGACTACAG - ) at -49/-41 , is essential for the promoter activity in murine erythroleukemia ( MEL ) cells .

Functional analysis of the promoter by transient transfection assays indicated that synergistic action between an <dna>SP-1-like element</dna> at -21/-12 , a <dna>GATA site</dna> at -59/-54 , and a <dna>novel regulatory element</dna> , <dna>CPRE</dna> ( - <dna>GGACTACAG</dna> - ) at -49/-41 , is essential for the promoter activity in <cell_type>murine erythroleukemia ( MEL ) cells</cell_type> .


In nonerythroid NIH3T3 cells , however , the GATA site is not required .

In <cell_line>nonerythroid NIH3T3 cells</cell_line> , however , the <dna>GATA site</dna> is not required .


Gel mobility shift assays demonstrated that specific DNA-protein complexes can be formed with each element , and that there are cell-specific differences in factors , which bind to the SP-1-like element between MEL and NIH3T3 cells .

Gel mobility shift assays demonstrated that specific <protein>DNA-protein complexes</protein> can be formed with each element , and that there are cell-specific differences in factors , which bind to the <dna>SP-1-like element</dna> between <cell_line>MEL and NIH3T3 cells</cell_line> .


These results provide evidence for differential regulation of the promoter function of CPO gene between erythroid and nonerythroid cells .

These results provide evidence for differential regulation of the promoter function of <protein>CPO</protein> gene between <cell_type>erythroid and nonerythroid cells</cell_type> .


Copyright 1998 by The American Society of Hematology


Tumor suppressor proteins as regulators of cell differentiation .

<protein>Tumor suppressor proteins</protein> as regulators of cell differentiation .


The products of the tumor suppressor genes are considered to function as specific inhibitors of tumor cell growth .

The products of the <dna>tumor suppressor genes</dna> are considered to function as specific inhibitors of tumor cell growth .


In this communication , we present evidence to show that these proteins inhibit tumor cell proliferation by participating in the activation of tumor cell differentiation .