The MHC class II transactivator ( CIITA ) requires conserved leucine charged domains for interactions with the conserved W box promoter element .

The <protein>MHC class II transactivator</protein> ( <protein>CIITA</protein> ) requires conserved <protein>leucine charged domains</protein> for interactions with the conserved <dna>W box promoter element</dna> .


The class II transactivator CIITA is required for transcriptional activation of the major histocompatibility complex ( MHC ) class II genes .

The <protein>class II transactivator</protein> <protein>CIITA</protein> is required for transcriptional activation of the <dna>major histocompatibility complex ( MHC ) class II genes</dna> .


Aside from an N-terminal acidic transcriptional activation domain , little is known about how this factor functions .

Aside from an <dna>N-terminal acidic transcriptional activation domain</dna> , little is known about how this factor functions .


Extensive mutagenesis of CIITA was undertaken to identify structural motifs required for function .

Extensive mutagenesis of <protein>CIITA</protein> was undertaken to identify structural motifs required for function .


The ability of mutants to activate a reporter gene under the control of MHC class II conserved W-X-Y or X-Y regulatory elements was determined .

The ability of mutants to activate a reporter gene under the control of <protein>MHC class II</protein> conserved <dna>W-X-Y or X-Y regulatory elements</dna> was determined .


Two mutants displayed differential activity between the two promoters , activating transcription with the W-X-Y but not the X-Y elements .

Two mutants displayed differential activity between the two <dna>promoters</dna> , activating transcription with the <dna>W-X-Y but not the X-Y elements</dna> .


All mutants were tested for their ability to interfere with wild-type CIITA activity .

All mutants were tested for their ability to interfere with wild-type <protein>CIITA</protein> activity .


Five CIITA mutant constructions were able to down-regulate wild-type CIITA activity .

Five <dna>CIITA mutant constructions</dna> were able to down-regulate wild-type <protein>CIITA</protein> activity .


Three of these mutants contained targeted disruptions of potential functional motifs : the acidic activation domain , a putative GTP-binding motif and two leucine charged domains ( LCD motifs ) .

Three of these mutants contained targeted disruptions of potential functional motifs : the <protein>acidic activation domain</protein> , a putative <protein>GTP-binding motif</protein> and two <protein>leucine charged domains</protein> ( <protein>LCD motifs</protein> ) .


The other two contained mutations in regions that do not have homology to described proteins .


The characterization of CIITA mutants that are able to discriminate between promoters with or without the W box strongly suggests that CIITA requires such interactions for function .

The characterization of <protein>CIITA mutants</protein> that are able to discriminate between promoters with or without the <dna>W box</dna> strongly suggests that <protein>CIITA</protein> requires such interactions for function .


The identification of LCD motifs required for CIITA function brings to light a previously undefined role of these motifs in CIITA function .

The identification of <protein>LCD motifs</protein> required for <protein>CIITA</protein> function brings to light a previously undefined role of these motifs in <protein>CIITA</protein> function .


The peroxisome proliferator-activated receptor alpha ( PPARalpha ) ligand WY 14 , 643 does not interfere with leukotriene B4 induced adhesion of neutrophils to endothelial cells .

The <protein>peroxisome proliferator-activated receptor alpha</protein> ( <protein>PPARalpha</protein> ) ligand WY 14 , 643 does not interfere with leukotriene B4 induced adhesion of <cell_type>neutrophils</cell_type> to <cell_type>endothelial cells</cell_type> .


Peroxisome proliferator-activated receptors ( PPAR ) control discrete genes involved in fatty acid and lipid metabolism .

<protein>Peroxisome proliferator-activated receptors</protein> ( <protein>PPAR</protein> ) control discrete genes involved in fatty acid and lipid metabolism .


Recently , it was suggested that activation of the alpha isoform of PPAR by the potent proinflammatory mediator leukotriene B4 ( LTB4 ) enhanced degradation of this eicosanoid , offersuggesting a new aspect of down-regulation of inflammation .

Recently , it was suggested that activation of the <protein>alpha isoform</protein> of <protein>PPAR</protein> by the potent proinflammatory mediator leukotriene B4 ( LTB4 ) enhanced degradation of this eicosanoid , offersuggesting a new aspect of down-regulation of inflammation .


Here , we studied whether PPARalpha activation ( by means of the selective agonist WY 14 , 643 ) of endothelial cells , pivotal in the regulation of inflammatory responses , interfered with LTB4 induced adhesion of PMN neutrophil granulocytes in vitro .

Here , we studied whether <protein>PPARalpha</protein> activation ( by means of the selective agonist WY 14 , 643 ) of <cell_type>endothelial cells</cell_type> , pivotal in the regulation of inflammatory responses , interfered with LTB4 induced adhesion of <cell_type>PMN neutrophil granulocytes</cell_type> in vitro .


When endothelial cells were treated with WY 14 , 643 prior to activation with LTB4 ( or fMLP , IL-1beta or TNFalpha , as controls ) we could not document any effect on the number of adhering PMN or duration of the response .

When <cell_type>endothelial cells</cell_type> were treated with WY 14 , 643 prior to activation with LTB4 ( or <protein>fMLP</protein> , <protein>IL-1beta</protein> or <protein>TNFalpha</protein> , as controls ) we could not document any effect on the number of <cell_type>adhering PMN</cell_type> or duration of the response .


Thus , this study provides no evidence indicating a regulatory function of PPARalpha in LTB4 induced adhesive interactions between endothelial cells and neutrophils

Thus , this study provides no evidence indicating a regulatory function of <protein>PPARalpha</protein> in LTB4 induced adhesive interactions between <cell_type>endothelial cells</cell_type> and <cell_type>neutrophils</cell_type>


Interaction of sickle erythrocytes with endothelial cells in the presence of endothelial cell conditioned medium induces oxidant stress leading to transendothelial migration of monocytes .

Interaction of <cell_type>sickle erythrocytes</cell_type> with <cell_type>endothelial cells</cell_type> in the presence of endothelial cell conditioned medium induces oxidant stress leading to transendothelial migration of <cell_type>monocytes</cell_type> .


The abnormal adherence of sickle red blood cells ( SS RBC ) to endothelial cells has been thought to contribute to vascular occlusion , a major cause of morbidity in sickle cell disease ( SCD ) .

The abnormal adherence of <cell_type>sickle red blood cells</cell_type> ( <cell_type>SS RBC</cell_type> ) to <cell_type>endothelial cells</cell_type> has been thought to contribute to vascular occlusion , a major cause of morbidity in sickle cell disease ( SCD ) .


We determined whether the interaction of SS RBC with cultured endothelial cells induced cellular oxidant stress that would culminate in expression of cell adhesion molecules ( CAMs ) involved in the adhesion and diapedesis of monocytes and the adherence of SS reticulocytes .

We determined whether the interaction of <cell_type>SS RBC</cell_type> with cultured <cell_type>endothelial cells</cell_type> induced cellular oxidant stress that would culminate in expression of <protein>cell adhesion molecules</protein> ( <protein>CAMs</protein> ) involved in the adhesion and diapedesis of <cell_type>monocytes</cell_type> and the adherence of <cell_type>SS reticulocytes</cell_type> .


We showed that the interaction of SS RBC at 2 % concentration in the presence of multimers of von Willebrand factor ( vWf ) , derived from endothelial cell-derived conditioned medium ( E-CM ) with cultured human umbilical vein endothelial cells ( HUVEC ) , resulted in a fivefold increased formation of thiobarbituric acid-reactive substances ( TBARS ) and activation of the transcription factor NF-kB , both indicators of cellular oxidant stress .

We showed that the interaction of <cell_type>SS RBC</cell_type> at 2 % concentration in the presence of multimers of <protein>von Willebrand factor</protein> ( <protein>vWf</protein> ) , derived from endothelial cell-derived conditioned medium ( E-CM ) with <cell_line>cultured human umbilical vein endothelial cells</cell_line> ( <cell_line>HUVEC</cell_line> ) , resulted in a fivefold increased formation of thiobarbituric acid-reactive substances ( TBARS ) and activation of the <protein>transcription factor</protein> <protein>NF-kB</protein> , both indicators of cellular oxidant stress .


Normal RBC show none of these phenomena .

<cell_type>Normal RBC</cell_type> show none of these phenomena .


The oxidant stress-induced signaling resulted in an increased surface expression of a subset of CAMs , ICAM-1 , E-selectin , and VCAM-1 in HUVEC .

The oxidant stress-induced signaling resulted in an increased surface expression of a subset of <protein>CAMs</protein> , <protein>ICAM-1</protein> , <protein>E-selectin</protein> , and <protein>VCAM-1</protein> in <cell_line>HUVEC</cell_line> .


The addition of oxygen radical scavenger enzymes ( catalase , superoxide dismutase ) and antioxidant ( probucol ) inhibited these events .

The addition of <protein>oxygen radical scavenger enzymes</protein> ( <protein>catalase</protein> , <protein>superoxide dismutase</protein> ) and antioxidant ( probucol ) inhibited these events .


Additionally , preincubation of HUVEC with a synthetic peptide Arg-Gly-Asp ( RGD ) that prevents vWf -mediated adhesion of SS RBC reduced the surface expression of VCAM-1 and NF-kB activation .

Additionally , preincubation of <cell_line>HUVEC</cell_line> with a synthetic peptide Arg-Gly-Asp ( RGD ) that prevents <protein>vWf</protein> -mediated adhesion of <cell_type>SS RBC</cell_type> reduced the surface expression of <protein>VCAM-1</protein> and <protein>NF-kB</protein> activation .


Furthermore , SS RBC -induced oxidant stress resulted in a twofold increase in the transendothelial migration of both monocyte-like HL-60 cells and human peripheral blood monocytes , and approximately a sixfold increase in platelet-endothelial cell adhesion molecule-1 ( PECAM-1 ) phosphorylation , each of which was blocked by protein kinase C inhibitor and antioxidants .

Furthermore , <cell_type>SS RBC</cell_type> -induced oxidant stress resulted in a twofold increase in the transendothelial migration of both <cell_line>monocyte-like HL-60 cells</cell_line> and <cell_type>human peripheral blood monocytes</cell_type> , and approximately a sixfold increase in <protein>platelet-endothelial cell adhesion molecule-1</protein> ( <protein>PECAM-1</protein> ) phosphorylation , each of which was blocked by <protein>protein kinase C</protein> inhibitor and antioxidants .


These results suggest that the adherence/contact of SS RBC to endothelial cells in large vessel can generate enhanced oxidant stress leading to increased adhesion and diapedesis of monocytes , as well as heightened adherence of SS reticulocytes , indicating that injury/activation of endothelium can contribute to vaso-occlusion in SCD .

These results suggest that the adherence/contact of <cell_type>SS RBC</cell_type> to <cell_type>endothelial cells</cell_type> in large vessel can generate enhanced oxidant stress leading to increased adhesion and diapedesis of <cell_type>monocytes</cell_type> , as well as heightened adherence of <cell_type>SS reticulocytes</cell_type> , indicating that injury/activation of endothelium can contribute to vaso-occlusion in SCD .


Signal transduction abnormalities in T lymphocytes from patients with advanced renal carcinoma : clinical relevance and effects of cytokine therapy .

Signal transduction abnormalities in <cell_type>T lymphocytes</cell_type> from patients with advanced renal carcinoma : clinical relevance and effects of <protein>cytokine</protein> therapy .


Studies have demonstrated abnormalities of the CD3/T-cell antigen receptor ( TCR ) and pathways of signal transduction in T lymphocytes from animals and patients with advanced malignancy .

Studies have demonstrated abnormalities of the <protein>CD3/T-cell antigen receptor</protein> ( <protein>TCR</protein> ) and pathways of signal transduction in <cell_type>T lymphocytes</cell_type> from animals and patients with advanced malignancy .


Diminished expression of TCRzeta and p56 ( lck ) that are associated with the TCR and reduced nuclear localization of RelA containing nuclear factor kappaB ( NFkappaB ) complexes have been noted .

Diminished expression of <protein>TCRzeta</protein> and <protein>p56 ( lck )</protein> that are associated with the <protein>TCR</protein> and reduced nuclear localization of <protein>RelA containing nuclear factor kappaB ( NFkappaB ) complexes</protein> have been noted .


These defects have been described in T cells from patients with malignant melanoma , renal cell carcinoma ( RCC ) , ovarian cancer , and colorectal cancer .

These defects have been described in <cell_type>T cells</cell_type> from patients with malignant melanoma , renal cell carcinoma ( RCC ) , ovarian cancer , and colorectal cancer .


Preliminary observations also indicate possible correlation with clinical variables such as stage in selected instances .


To further characterize altered expression of TCRzeta , p56 ( lck ) , and impaired activation of NFkappaB , T lymphocytes were obtained from 65 patients with RCC , the majority of whom were receiving combination cytokine therapy [ interleukin ( IL ) -2 , IFN alpha -containing regimens ] and 37 control individuals .

To further characterize altered expression of <protein>TCRzeta</protein> , <protein>p56 ( lck )</protein> , and impaired activation of <protein>NFkappaB</protein> , <cell_type>T lymphocytes</cell_type> were obtained from 65 patients with RCC , the majority of whom were receiving combination <protein>cytokine</protein> therapy [ <protein>interleukin ( IL ) -2</protein> , <protein>IFN alpha</protein> -containing regimens ] and 37 control individuals .


In 29 of these patients , levels of TCRzeta and p56 ( lck ) were determined by Western blots of T-cell lysates and semiquantitated using densitometry .

In 29 of these patients , levels of <protein>TCRzeta</protein> and <protein>p56 ( lck )</protein> were determined by Western blots of T-cell lysates and semiquantitated using densitometry .


Relative levels were then correlated with a series of clinical variables including response to therapy , performance status , survival , disease sites , age , and others .


In another group of 28 patients ( three individuals from the first group ) , the frequency of abnormal NFkappaB activation was studied using electrophoretic mobility shift assays after activation of T cells with phorbol myristate acetate/ionomycin or anti-CD3 monoclonal antibody .

In another group of 28 patients ( three individuals from the first group ) , the frequency of abnormal <protein>NFkappaB</protein> activation was studied using electrophoretic mobility shift assays after activation of <cell_type>T cells</cell_type> with phorbol myristate acetate/ionomycin or <protein>anti-CD3 monoclonal antibody</protein> .


Changes in these signaling molecules during cytokine treatment were also investigated .

Changes in these signaling molecules during <protein>cytokine</protein> treatment were also investigated .


TCRzeta and p56 ( lck ) were detected in the peripheral blood T cells in 27 of 29 patients , and overall , reduced levels were noted visually in 12 of 29 ( 41 % ) and 13 of 29 ( 45 % ) individuals , respectively .

<protein>TCRzeta</protein> and <protein>p56 ( lck )</protein> were detected in the <cell_type>peripheral blood T cells</cell_type> in 27 of 29 patients , and overall , reduced levels were noted visually in 12 of 29 ( 41 % ) and 13 of 29 ( 45 % ) individuals , respectively .


When levels were semiquantitated using densitometry , significant decreases of TCRzeta ( P = 0.029 ) and p56 ( lck ) ( P = 0.029 ) but not CD3epsilon ( P = 0.131 ) , compared with control levels , were found .

When levels were semiquantitated using densitometry , significant decreases of <protein>TCRzeta</protein> ( P = 0.029 ) and <protein>p56 ( lck )</protein> ( P = 0.029 ) but not <protein>CD3epsilon</protein> ( P = 0.131 ) , compared with control levels , were found .


In patients treated with IL-2/ IFN alpha -based therapy , relative levels of TCRzeta increased significantly ( P = 0.002 ) on day 15 of cycle one compared with the baseline .

In patients treated with IL-2/ <protein>IFN alpha</protein> -based therapy , relative levels of <protein>TCRzeta</protein> increased significantly ( P = 0.002 ) on day 15 of cycle one compared with the baseline .


Correlations of TCRzeta or p56 ( lck ) levels with response or disease variables , except for lower TCRzeta levels ( P < 0.001 ) in the presence of bone metastases , were not found .

Correlations of <protein>TCRzeta</protein> or <protein>p56 ( lck )</protein> levels with response or disease variables , except for lower <protein>TCRzeta</protein> levels ( P < 0.001 ) in the presence of bone metastases , were not found .


Abnormal NFkappaB activation after stimulation with phorbol myristate acetate/ionomycin and/or anti-CD3 monoclonal antibody was found in 59 % of patients ( 17 of 28 ) and was not accounted for by the advanced age of the study cohort .

Abnormal <protein>NFkappaB</protein> activation after stimulation with phorbol myristate acetate/ionomycin and/or <protein>anti-CD3 monoclonal antibody</protein> was found in 59 % of patients ( 17 of 28 ) and was not accounted for by the advanced age of the study cohort .


Activation of NFkappaB in peripheral blood T cells was inducible during cytokine therapy in four of six individuals who displayed impaired NFkappaB activity prior to therapy .

Activation of <protein>NFkappaB</protein> in <cell_type>peripheral blood T cells</cell_type> was inducible during <protein>cytokine</protein> therapy in four of six individuals who displayed impaired <protein>NFkappaB</protein> activity prior to therapy .


Moreover , impaired activation of NFkappaB does not appear linked to a reduction of TCRzeta expression , because in five patients , normal TCRzeta levels were present although kappaB binding was not inducible .

Moreover , impaired activation of <protein>NFkappaB</protein> does not appear linked to a reduction of <protein>TCRzeta</protein> expression , because in five patients , normal <protein>TCRzeta</protein> levels were present although <protein>kappaB</protein> binding was not inducible .


In the majority of patients with advanced RCC , peripheral blood T cells express TCRzeta and p56 ( lck ) , and in a subset , reduced levels of these TCRzeta associated molecules are seen that may increase during cytokine -based therapy .

In the majority of patients with advanced RCC , <cell_type>peripheral blood T cells</cell_type> express <protein>TCRzeta</protein> and <protein>p56 ( lck )</protein> , and in a subset , reduced levels of these <protein>TCRzeta associated molecules</protein> are seen that may increase during <protein>cytokine</protein> -based therapy .


Abnormal activation of NFkappaB is also present in > 50 % of patients and may also revert to normal during IL-2/ IFN alpha -based treatment .

Abnormal activation of <protein>NFkappaB</protein> is also present in > 50 % of patients and may also revert to normal during IL-2/ <protein>IFN alpha</protein> -based treatment .


This alteration in NFkappaB activation occurred in the presence of normal expression of TCRzeta-associated signaling elements .

This alteration in <protein>NFkappaB</protein> activation occurred in the presence of normal expression of <dna>TCRzeta-associated signaling elements</dna> .


The clinical significance of these findings remains unclear .


Identification of transcription factors expressed during ATRA-induced neutrophil differentiation of HL60 cells .

Identification of <protein>transcription factors</protein> expressed during ATRA-induced neutrophil differentiation of <cell_line>HL60 cells</cell_line> .


A recent clinical therapeutic initiative has been the use of chemical agents which induce the leukaemic cells to overcome their block in differentiation .

A recent clinical therapeutic initiative has been the use of chemical agents which induce the <cell_type>leukaemic cells</cell_type> to overcome their block in differentiation .


In order to understand this block the cascade of molecular events needs to be characterized .


Haemopoietic differentiation is ultimately controlled at the level of gene transcription which is mediated by an array of transcription factors .

Haemopoietic differentiation is ultimately controlled at the level of gene transcription which is mediated by an array of <protein>transcription factors</protein> .


Many transcription factors contain similar structural protein sequences , and we have used an RT-PCR-based approach to isolate sequences , from transcription factor gene families which share similar domains .

Many <protein>transcription factors</protein> contain similar <protein>structural protein sequences</protein> , and we have used an RT-PCR-based approach to isolate sequences , from <protein>transcription factor</protein> gene families which share similar domains .


Degenerate primers corresponding to the TFIIIA zinc-finger consensus amino acid sequences and to the POU-homeodomain and POU-specific domain were used to amplify genes on the basis that they contained similarities in structural motifs shared within these families of transcription factors .

Degenerate primers corresponding to the <dna>TFIIIA zinc-finger consensus amino acid sequences</dna> and to the <protein>POU-homeodomain</protein> and <protein>POU-specific domain</protein> were used to amplify genes on the basis that they contained similarities in structural motifs shared within these families of <protein>transcription factors</protein> .


A serum-independent HL60 cell line was induced towards the neutrophil lineage by treatment with all-trans retinoic acid ( ATRA ) for 24 h .

A <cell_line>serum-independent HL60 cell line</cell_line> was induced towards the neutrophil lineage by treatment with all-trans retinoic acid ( ATRA ) for 24 h .


CD38+ cells committed towards this lineage were enriched and a population of these cells treated with dihydroxyvitamin D3 to induce neutrophil maturation .

<cell_type>CD38+ cells</cell_type> committed towards this lineage were enriched and a population of these cells treated with dihydroxyvitamin D3 to induce neutrophil maturation .


RNA extracted from uninduced , ATRA-induced CD38+ cells , and vitamin D3 treated maturing cell cultures were amplified using the degenerate primers .

RNA extracted from uninduced , <cell_line>ATRA-induced CD38+ cells</cell_line> , and <cell_line>vitamin D3 treated maturing cell cultures</cell_line> were amplified using the degenerate primers .


PCR fragments were cloned , sequenced , clustered into homologous groups , and the group sequences searched on the GenBank database .

<dna>PCR fragments</dna> were cloned , sequenced , clustered into homologous groups , and the group sequences searched on the GenBank database .


The Oct 1 transcription factor , and a very close homologue , KIAA0144 , was identified using the POU family primers .

The Oct 1 <protein>transcription factor</protein> , and a very close homologue , <dna>KIAA0144</dna> , was identified using the POU family primers .


The zinc-finger primers identified three zinc-finger genes .


The pattern of gene expression was suggested from the number of clones in each group at neutrophil commitment and maturation .


The differential expression of the genes in the zinc finger and POU families will lead to a better understanding of the cascade of gene expression which occurs following ATRA-induced differentiation .

The differential expression of the genes in the <protein>zinc finger and POU families</protein> will lead to a better understanding of the cascade of gene expression which occurs following ATRA-induced differentiation .


GATA-3 -dependent enhancer activity in IL-4 gene regulation .

<protein>GATA-3</protein> -dependent enhancer activity in <dna>IL-4 gene</dna> regulation .


Previously , we analyzed the proximal IL-4 promoter in directing Th2-specific activity .

Previously , we analyzed the <dna>proximal IL-4 promoter</dna> in directing Th2-specific activity .


An 800-base pair proximal promoter conferred some Th2-selective expression in transgenic mice .

An <dna>800-base pair proximal promoter</dna> conferred some Th2-selective expression in transgenic mice .


However , this region directed extremely low reporter mRNA levels relative to endogenous IL-4 mRNA , suggesting that full gene activity requires additional enhancer elements .

However , this region directed extremely low reporter mRNA levels relative to endogenous <rna>IL-4 mRNA</rna> , suggesting that full gene activity requires additional <dna>enhancer elements</dna> .


Here , we analyzed large genomic IL-4 regions for enhancer activity and interaction with transcription factors .

Here , we analyzed large <dna>genomic IL-4 regions</dna> for enhancer activity and interaction with <protein>transcription factors</protein> .


The proximal IL-4 promoter is only moderately augmented by GATA-3 , but certain genomic regions significantly enhanced GATA-3 promoter transactivation .

The proximal <dna>IL-4 promoter</dna> is only moderately augmented by <protein>GATA-3</protein> , but certain <dna>genomic regions</dna> significantly enhanced <dna>GATA-3 promoter</dna> transactivation .


Some enhancing regions contained consensus , GATA sites that bound Th2-specific complexes .

Some enhancing regions contained consensus , <dna>GATA sites</dna> that bound <protein>Th2-specific complexes</protein> .


However , retroviral transduction of GATA-3 into developing T cells induced IL-5 to full Th2 levels , but only partially restored IL-4 production .

However , retroviral transduction of <protein>GATA-3</protein> into <cell_type>developing T cells</cell_type> induced <protein>IL-5</protein> to full <protein>Th2</protein> levels , but only partially restored <protein>IL-4</protein> production .


Thus , we propose that GATA-3 is permissive , but not sufficient , for full IL-4 enhancement and may act through GATA elements surrounding the IL-13/IL-4 gene locus .

Thus , we propose that <protein>GATA-3</protein> is permissive , but not sufficient , for full <protein>IL-4</protein> enhancement and may act through <dna>GATA elements</dna> surrounding the <dna>IL-13/IL-4 gene locus</dna> .


Position effect of translocations involving the inactive X chromosome : physical linkage to XIC/XIST does not lead to long-range de novo inactivation in human differentiated cells .

Position effect of translocations involving the <dna>inactive X chromosome</dna> : physical linkage to <dna>XIC/XIST</dna> does not lead to long-range de novo inactivation in <cell_type>human differentiated cells</cell_type> .


Given the reported long-range cis-inactivating effect of the XIST gene in early embryonic development and the lack of requirement of X-chromosome-specific elements for propagating the inactive state , there exists the possibility of cis inactivation of autosomal material after de novo translocation to an inactive X chromosome ( Xi ) in differentiated cells .

Given the reported long-range cis-inactivating effect of the <dna>XIST gene</dna> in early embryonic development and the lack of requirement of <dna>X-chromosome-specific elements</dna> for propagating the inactive state , there exists the possibility of cis inactivation of autosomal material after de novo translocation to an <dna>inactive X chromosome</dna> ( <dna>Xi</dna> ) in <cell_type>differentiated cells</cell_type> .


We have analyzed de novo radiation-induced translocations between the Xi and autosomes to study the maintenance and spreading of X-chromosome inactivation ( X inactivation ) in relation to the position of the X-inactivation center ( XIC ) /XIST in differentiated cells .

We have analyzed de novo radiation-induced translocations between the <dna>Xi</dna> and <dna>autosomes</dna> to study the maintenance and spreading of <dna>X-chromosome</dna> inactivation ( X inactivation ) in relation to the position of the X-inactivation center <dna>( XIC ) /XIST</dna> in <cell_type>differentiated cells</cell_type> .


Autosome/ Xi translocations were detected by fluorescence in situ hybridization ( FISH ) .

Autosome/ <dna>Xi</dna> translocations were detected by fluorescence in situ hybridization ( FISH ) .


The activation status of the chromosomes involved in the translocation was determined by simultaneous immunocytogenetic studies using antibodies against either BrdU incorporated at late S phase or acetylated histone H4 .

The activation status of the <dna>chromosomes</dna> involved in the translocation was determined by simultaneous immunocytogenetic studies using <protein>antibodies</protein> against either <protein>BrdU</protein> incorporated at late S phase or <protein>acetylated histone H4</protein> .


The position of XIC/XIST in the reciprocal products of the translocation was determined by XIST-specific FISH and computer enhancement .

The position of <dna>XIC/XIST</dna> in the reciprocal products of the translocation was determined by XIST-specific FISH and computer enhancement .


In other experiments , the Xq13 region carrying XIC/XIST was localized by computer enhancement of the DAPI banding pattern .

In other experiments , the <dna>Xq13 region</dna> carrying <dna>XIC/XIST</dna> was localized by computer enhancement of the DAPI banding pattern .


Our study in differentiated cells provides a visual demonstration that physical separation from XIC/XIST does not result in reactivation of inactive X-chromosome material and that X inactivation is not spread to the translocated autosomes irrespective of the position of XIC/XIST .

Our study in <cell_type>differentiated cells</cell_type> provides a visual demonstration that physical separation from <dna>XIC/XIST</dna> does not result in reactivation of <dna>inactive X-chromosome</dna> material and that X inactivation is not spread to the <dna>translocated autosomes</dna> irrespective of the position of <dna>XIC/XIST</dna> .


This observation suggests that physical linkage to XIC/XIST does not lead to de novo inactivation of autosomal material .

This observation suggests that physical linkage to <dna>XIC/XIST</dna> does not lead to de novo inactivation of autosomal material .


Interleukin-4 and -13 induce upregulation of the murine macrophage 12/15-lipoxygenase activity : evidence for the involvement of transcription factor STAT6 .

<protein>Interleukin-4 and -13</protein> induce upregulation of the murine macrophage <protein>12/15-lipoxygenase activity</protein> : evidence for the involvement of <protein>transcription factor</protein> <protein>STAT6</protein> .


When human monocytes or alveolar macrophages are cultured in the presence of interleukin ( IL ) -4 or IL-13 , the expression of the reticulocyte-type 15-lipoxygenase is induced .

When human <cell_type>monocytes</cell_type> or <cell_type>alveolar macrophages</cell_type> are cultured in the presence of <protein>interleukin ( IL ) -4</protein> or <protein>IL-13</protein> , the expression of the <protein>reticulocyte-type 15-lipoxygenase</protein> is induced .


In mice a 15-lipoxygenase is not expressed , but a leukocyte-type 12-lipoxygenase is present in peritoneal macrophages .

In mice a <protein>15-lipoxygenase</protein> is not expressed , but a <protein>leukocyte-type 12-lipoxygenase</protein> is present in <cell_type>peritoneal macrophages</cell_type> .


To investigate whether both lipoxygenase isoforms exhibit a similar regulatory response toward cytokine stimulation , we studied the regulation of the leukocyte-type 12-lipoxygenase of murine peritoneal macrophages by interleukins and found that the activity of this enzyme is upregulated in a dose-dependent manner when the cells were cultured in the presence of the IL-4 or IL-13 but not by IL-10 .

To investigate whether both <protein>lipoxygenase isoforms</protein> exhibit a similar regulatory response toward <protein>cytokine</protein> stimulation , we studied the regulation of the <protein>leukocyte-type 12-lipoxygenase</protein> of <cell_type>murine peritoneal macrophages</cell_type> by <protein>interleukins</protein> and found that the activity of this <protein>enzyme</protein> is upregulated in a dose-dependent manner when the cells were cultured in the presence of the <protein>IL-4</protein> or <protein>IL-13</protein> but not by <protein>IL-10</protein> .


When peripheral murine monocytes that do not express the lipoxygenase were treated with IL-4 expression of 12/15-lipoxygenase mRNA was induced , suggesting pretranslational control mechanisms .

When peripheral murine <cell_type>monocytes</cell_type> that do not express the <protein>lipoxygenase</protein> were treated with <protein>IL-4</protein> expression of <rna>12/15-lipoxygenase mRNA</rna> was induced , suggesting pretranslational control mechanisms .


In contrast , no upregulation of the lipoxygenase activity was observed when the macrophages were prepared from homozygous STAT6 -deficient mice .

In contrast , no upregulation of the <protein>lipoxygenase</protein> activity was observed when the <cell_type>macrophages</cell_type> were prepared from homozygous <protein>STAT6</protein> -deficient mice .


Peritoneal macrophages of transgenic mice that systemically overexpress IL-4 exhibited a threefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals .

<cell_type>Peritoneal macrophages</cell_type> of transgenic mice that systemically overexpress <protein>IL-4</protein> exhibited a threefold to fourfold higher <protein>12-lipoxygenase</protein> activity than cells prepared from control animals .


A similar upregulation of 12-lipoxygenase activity was detected in heart , spleen , and lung of the transgenic animals .

A similar upregulation of <protein>12-lipoxygenase</protein> activity was detected in heart , spleen , and lung of the transgenic animals .


Moreover , a strong induction of the enzyme was observed in red cells during experimental anemia in mice .

Moreover , a strong induction of the enzyme was observed in <cell_type>red cells</cell_type> during experimental anemia in mice .


The data presented here indicate that ( 1 ) the 12-lipoxygenase activity of murine macrophages is upregulated in vitro and in vivo by IL-4 and/or IL-13 , ( 2 ) this upregulation requires expression of the transcription factor STAT6 , and ( 3 ) the constitutive expression of the enzyme appears to be STAT6 independent .

The data presented here indicate that ( 1 ) the <protein>12-lipoxygenase</protein> activity of murine macrophages is upregulated in vitro and in vivo by <protein>IL-4</protein> and/or <protein>IL-13</protein> , ( 2 ) this upregulation requires expression of the <protein>transcription factor</protein> <protein>STAT6</protein> , and ( 3 ) the constitutive expression of the enzyme appears to be <protein>STAT6</protein> independent .


The cytokine -dependent upregulation of the murine macrophage 12-lipoxygenase and its induction during experimental anemia suggests its close relatedness with the human reticulocyte-type 15-lipoxygenase despite their differences in the positional specificity of arachidonic acid oxygenation .

The <protein>cytokine</protein> -dependent upregulation of the <protein>murine macrophage 12-lipoxygenase</protein> and its induction during experimental anemia suggests its close relatedness with the <protein>human reticulocyte-type 15-lipoxygenase</protein> despite their differences in the positional specificity of arachidonic acid oxygenation .


Interferon-gamma-induced factor binding to the interleukin-4-responsive element of CD23b promoter in human tonsillar mononuclear cells : role in transient up-regulation of the interleukin-4-induced CD23b mRNA .

<protein>Interferon-gamma-induced factor</protein> binding to the <dna>interleukin-4-responsive element</dna> of <dna>CD23b promoter</dna> in <cell_type>human tonsillar mononuclear cells</cell_type> : role in transient up-regulation of the <rna>interleukin-4-induced CD23b mRNA</rna> .


Stimulation of human tonsillar mononuclear cells with interleukin-4 ( IL-4 ) and interferon-gamma ( IFN-gamma ) rapidly induced the activation of distinct nuclear factors with different mobilities , both of which bind the IL-4 response element ( IL-4RE ) of CD23b promoter as examined by electrophoretic mobility shift assays ( EMSA ) .

Stimulation of <cell_type>human tonsillar mononuclear cells</cell_type> with <protein>interleukin-4</protein> ( <protein>IL-4</protein> ) and <protein>interferon-gamma</protein> ( <protein>IFN-gamma</protein> ) rapidly induced the activation of distinct <protein>nuclear factors</protein> with different mobilities , both of which bind the <dna>IL-4 response element</dna> ( <dna>IL-4RE</dna> ) of <dna>CD23b promoter</dna> as examined by electrophoretic mobility shift assays ( EMSA ) .


Co-treatment of IL-4 and IFN-gamma induced , in addition to the two distinct complexes , a new complex with an intermediate mobility .

Co-treatment of <protein>IL-4</protein> and <protein>IFN-gamma</protein> induced , in addition to the two distinct complexes , a new complex with an intermediate mobility .


The IL-4-induced complex reacted with anti-STAT ( signal transducers and activators of transcription ) 6 , resulting in a supershift whereas the formation of the IFN-gamma-induced complex was inhibited by anti-STAT 1 .

The <protein>IL-4-induced complex</protein> reacted with <protein>anti-STAT ( signal transducers and activators of transcription ) 6</protein> , resulting in a supershift whereas the formation of the <protein>IFN-gamma-induced complex</protein> was inhibited by <protein>anti-STAT 1</protein> .


The intermediate complex appeared to react with both anti-STAT 6 and anti-STAT 1 .

The intermediate complex appeared to react with both <protein>anti-STAT 6</protein> and <protein>anti-STAT 1</protein> .


Although IFN-gamma alone did not induce CD23 mRNA transcription , Northern blot analysis revealed a transient up-regulation of the IL-4-induced CD23 mRNA by IFN-gamma within 2 h of IFN-gamma treatment in these tonsillar cells .

Although <protein>IFN-gamma</protein> alone did not induce <rna>CD23 mRNA</rna> transcription , Northern blot analysis revealed a transient up-regulation of the <rna>IL-4-induced CD23 mRNA</rna> by <protein>IFN-gamma</protein> within 2 h of <protein>IFN-gamma</protein> treatment in these <cell_type>tonsillar cells</cell_type> .


The results suggest that the IL-4RE of the IL-4-inducible gene can accommodate both IL-4- and IFN-gamma-activated factors , such as STAT 6 and STAT 1 , either in homodimeric or heterodimeric forms and the binding of these different proteins to the respective promoter may play a potential regulatory role in the IL-4 -inducible gene expression .

The results suggest that the <dna>IL-4RE</dna> of the <dna>IL-4-inducible gene</dna> can accommodate both <protein>IL-4- and IFN-gamma-activated factors</protein> , such as <protein>STAT 6</protein> and <protein>STAT 1</protein> , either in <protein>homodimeric or heterodimeric forms</protein> and the binding of these different proteins to the respective promoter may play a potential regulatory role in the <protein>IL-4</protein> -inducible gene expression .


A p56lck -independent pathway of CD2 signaling involves Jun kinase .

A <protein>p56lck</protein> -independent pathway of <protein>CD2</protein> signaling involves <protein>Jun kinase</protein> .


The p56 Src family non-receptor tyrosine kinase has been shown to be critical for T lymphocyte differentiation and activation .

The <protein>p56 Src family non-receptor tyrosine kinase</protein> has been shown to be critical for T lymphocyte differentiation and activation .


Hence in the absence of p56 , T cell receptor triggered activation does not occur .

Hence in the absence of <protein>p56</protein> , <protein>T cell receptor</protein> triggered activation does not occur .


We now provide evidence for a CD2 -based signaling pathway which , in contrast to that of the T cell receptor , is independent of p56 .

We now provide evidence for a <protein>CD2</protein> -based signaling pathway which , in contrast to that of the <protein>T cell receptor</protein> , is independent of <protein>p56</protein> .


CD2 -mediated interleukin-2 production occurs via activation of Jun kinase in cell lines lacking p56 .

<protein>CD2</protein> -mediated <protein>interleukin-2</protein> production occurs via activation of <protein>Jun kinase</protein> in cell lines lacking <protein>p56</protein> .


Jun kinase then facilitates the binding of c-Jun/c-Fos heterodimers to the AP-1 consensus site and the subsequent transcriptional activity of the interleukin-2 promoter .

<protein>Jun kinase</protein> then facilitates the binding of <protein>c-Jun/c-Fos heterodimers</protein> to the <dna>AP-1 consensus site</dna> and the subsequent transcriptional activity of the <dna>interleukin-2 promoter</dna> .


These data elucidate differences between TCR and CD2 signaling pathways in the same T cells .

These data elucidate differences between <protein>TCR</protein> and <protein>CD2</protein> signaling pathways in the same <cell_type>T cells</cell_type> .


Activation of E2F -mediated transcription by human T-cell leukemia virus type I Tax protein in a p16 ( INK4A ) -negative T-cell line .

Activation of <protein>E2F</protein> -mediated transcription by <protein>human T-cell leukemia virus type I Tax protein</protein> in a <cell_line>p16 ( INK4A ) -negative T-cell line</cell_line> .


The human T-cell leukemia virus type I ( HTLV-I ) is a causative agent of adult T-cell leukemia .


Although the exact mechanism by which HTLV-I contributes to leukemogenesis is still unclear , the Tax protein is thought to play a major role in this process .

Although the exact mechanism by which HTLV-I contributes to leukemogenesis is still unclear , the <protein>Tax protein</protein> is thought to play a major role in this process .


This 40-kDa polypeptide is able to interact with the tumor suppressor p16 ( INK4A ) .

This 40-kDa polypeptide is able to interact with the <protein>tumor suppressor</protein> <protein>p16 ( INK4A )</protein> .


Consequently , Tax can activate the signaling pathway that lead to the release of E2F that in turn induces expression of factors required for cell cycle progression .

Consequently , <protein>Tax</protein> can activate the signaling pathway that lead to the release of <protein>E2F</protein> that in turn induces expression of factors required for cell cycle progression .


In this paper , we demonstrate that Tax can also activate E2F -mediated transcription independently of p16 ( INK4A ) .

In this paper , we demonstrate that <protein>Tax</protein> can also activate <protein>E2F</protein> -mediated transcription independently of <protein>p16 ( INK4A )</protein> .


Indeed , when Tax is coexpressed with the E2F-1 transcription factor in CEM T-cells , which lack expression of p16 ( INK4A ) , it strongly potentiates the E2F -dependent activation of a reporter construct driven by a promoter containing E2F binding sites .

Indeed , when <protein>Tax</protein> is coexpressed with the <protein>E2F-1</protein> <protein>transcription factor</protein> in <cell_line>CEM T-cells</cell_line> , which lack expression of <protein>p16 ( INK4A )</protein> , it strongly potentiates the <protein>E2F</protein> -dependent activation of a reporter construct driven by a promoter containing <dna>E2F binding sites</dna> .


This stimulation is abrogated by mutations affecting the E2F-binding sites .

This stimulation is abrogated by mutations affecting the <dna>E2F-binding sites</dna> .


In addition , Tax also stimulates the transcription of the E2F-1 gene itself .

In addition , <protein>Tax</protein> also stimulates the transcription of the <dna>E2F-1 gene</dna> itself .


Using Tax mutants that fail to activate either ATF -or NF-kappaB-dependent promoters and different 5 ' truncation mutants of the E2F-1 promoter , we show that the Tax -dependent transcriptional control of the E2F1 gene involves , at least in part , the ATF binding site located in the E2F-1 promoter .

Using <protein>Tax</protein> mutants that fail to activate either <protein>ATF</protein> -or <dna>NF-kappaB-dependent promoters</dna> and different <dna>5 ' truncation mutants</dna> of the <dna>E2F-1 promoter</dna> , we show that the <protein>Tax</protein> -dependent transcriptional control of the <dna>E2F1 gene</dna> involves , at least in part , the <dna>ATF binding site</dna> located in the <dna>E2F-1 promoter</dna> .


Inducible nitric oxide : an autoregulatory feedback inhibitor of vascular inflammation .


Inducible nitric oxide ( iNO ) is produced at sites of vascular inflammation by resident and nonresident vascular wall cells , but its role in the inflammatory process is not known .

Inducible nitric oxide ( iNO ) is produced at sites of vascular inflammation by resident and nonresident <cell_type>vascular wall cells</cell_type> , but its role in the inflammatory process is not known .


In this study , we show that a novel function of iNO is to terminate inflammatory processes .


We find that iNO produced by murine macrophage-like cells , RAW264.7 , can inhibit cytokine -induced endothelial cell activation in a separated and mixed endothelial-RAW264.7 coculture system .

We find that iNO produced by <cell_line>murine macrophage-like cells</cell_line> , <cell_line>RAW264.7</cell_line> , can inhibit <protein>cytokine</protein> -induced endothelial cell activation in a separated and mixed <cell_line>endothelial-RAW264.7 coculture system</cell_line> .


Both iNO production and endothelial VCAM-1 expression were induced simultaneously with bacterial LPS and murine-specific IFN-gamma .

Both iNO production and endothelial <protein>VCAM-1</protein> expression were induced simultaneously with bacterial LPS and <protein>murine-specific IFN-gamma</protein> .


Inhibition of iNO synthase ( iNOS ) activity with N omega-monomethyl-L-arginine in endothelial-RAW264.7 cocultures , stimulated with murine-specific IFN-gamma and LPS , decreased iNO production by 86 % , augmented VCAM-1 and iNOS expression in endothelial and RAW264.7 cells , respectively , and increased monocyte adhesion to the endothelial cell surface .

Inhibition of <protein>iNO synthase</protein> ( <protein>iNOS</protein> ) activity with N omega-monomethyl-L-arginine in <cell_line>endothelial-RAW264.7 cocultures</cell_line> , stimulated with <protein>murine-specific IFN-gamma</protein> and LPS , decreased iNO production by 86 % , augmented <protein>VCAM-1</protein> and <protein>iNOS</protein> expression in endothelial and <cell_line>RAW264.7 cells</cell_line> , respectively , and increased monocyte adhesion to the endothelial cell surface .


Transient transfection studies using various VCAM-1 promoter constructs demonstrated that inhibitory effects of iNO on VCAM-1 gene transcription were mediated , in part , by inhibitory effects of iNO on kappa B cis-acting elements .

Transient transfection studies using various <dna>VCAM-1 promoter</dna> constructs demonstrated that inhibitory effects of iNO on <protein>VCAM-1</protein> gene transcription were mediated , in part , by inhibitory effects of iNO on <dna>kappa B cis-acting elements</dna> .


Immunofluorescence studies using an Ab to the RelA ( p65 ) subunit of nuclear factor-kappa B revealed that iNO inhibited the activation of nuclear factor-kappa B .

Immunofluorescence studies using an Ab to the <protein>RelA ( p65 ) subunit</protein> of nuclear <protein>factor-kappa B</protein> revealed that iNO inhibited the activation of <protein>nuclear factor-kappa B</protein> .


These studies indicate that iNO attenuates iNOS expression in macrophages and inhibits monocyte adhesion to endothelial cells , and suggest that endogenously derived iNO may be an important autoregulatory inhibitor of vascular inflammation

These studies indicate that iNO attenuates <protein>iNOS</protein> expression in <cell_type>macrophages</cell_type> and inhibits monocyte adhesion to <cell_type>endothelial cells</cell_type> , and suggest that endogenously derived iNO may be an important autoregulatory inhibitor of vascular inflammation


Detection of oestrogen receptor variants in endometrium , myometrium , leiomyoma and peripheral blood mononuclear cells : comparison to variants present in breast cancer .

Detection of <protein>oestrogen receptor variants</protein> in endometrium , myometrium , leiomyoma and <cell_type>peripheral blood mononuclear cells</cell_type> : comparison to variants present in breast cancer .


Oestradiol has mitogenic and regulatory effects on various organs and cells , mediated mainly by its nuclear receptor ( ER ) .

Oestradiol has mitogenic and regulatory effects on various organs and cells , mediated mainly by its <protein>nuclear receptor</protein> ( <protein>ER</protein> ) .


The presence of aberrant ER forms in Oestrogen-dependent tumours has been discussed in correlation with tumour progression .

The presence of aberrant <protein>ER</protein> forms in Oestrogen-dependent tumours has been discussed in correlation with tumour progression .


ER variants , generated by alternative splicing , have been detected in human breast cancer , but also in normal mammary glands , therefore their role in tumorigenesis has been questioned .

<protein>ER</protein> variants , generated by alternative splicing , have been detected in human breast cancer , but also in normal mammary glands , therefore their role in tumorigenesis has been questioned .


We have investigated , by the use of the reverse transcription polymerase chain reaction amplification technique , the possible existence of ER variants in other normal oestrogen target organs and cells , such as uterus ( myometrium and endometrium ) , in peripheral blood mononuclear cells and in a benign uterus tumour ( leiomyoma ) .

We have investigated , by the use of the reverse transcription polymerase chain reaction amplification technique , the possible existence of <protein>ER</protein> variants in other normal oestrogen target organs and cells , such as uterus ( myometrium and endometrium ) , in <cell_type>peripheral blood mononuclear cells</cell_type> and in a benign uterus tumour ( leiomyoma ) .


We have detected variant ER in these samples and have compared the variant profile to that observed in breast cancer .

We have detected variant <protein>ER</protein> in these samples and have compared the variant profile to that observed in breast cancer .


All tissues and cells studied expressed both wild-type ER and variant species .

All tissues and cells studied expressed both <protein>wild-type ER</protein> and <protein>variant species</protein> .


Variant forms encompassed ER with deletions of exons 2 , 5 and 7 .

Variant forms encompassed <protein>ER</protein> with deletions of <dna>exons 2 , 5 and 7</dna> .


Variants with exon 5 deleted were detected only in peripheral blood mononuclear cells and in breast cancer .

Variants with <dna>exon 5</dna> deleted were detected only in <cell_type>peripheral blood mononuclear cells</cell_type> and in breast cancer .


Variants with exons 2 and 7 deleted were present in all specimens tested .

Variants with <dna>exons 2 and 7</dna> deleted were present in all specimens tested .


These results corroborate previous findings that the presence of ER variants is not a characteristic of breast cancer .

These results corroborate previous findings that the presence of <protein>ER</protein> variants is not a characteristic of breast cancer .


The physiological significance and possible clinical relevance of the variant ER forms remain to be elucidated .

The physiological significance and possible clinical relevance of the variant <protein>ER</protein> forms remain to be elucidated .


p21ras initiates Rac-1 but not phosphatidyl inositol 3 kinase/PKB , mediated signaling pathways in T lymphocytes .

<protein>p21ras</protein> initiates <protein>Rac-1</protein> but not <protein>phosphatidyl inositol 3 kinase/PKB</protein> , mediated signaling pathways in <cell_type>T lymphocytes</cell_type> .


p21ras is activated by the T cell antigen receptor ( TCR ) and then co-ordinates important signaling pathways for T lymphocyte activation .

<protein>p21ras</protein> is activated by the <protein>T cell antigen receptor</protein> ( <protein>TCR</protein> ) and then co-ordinates important signaling pathways for <protein>T lymphocyte</protein> activation .


Effector pathways for this guanine nucleotide binding protein in T cells are mediated by the serine/threonine kinase Raf-1 and the Ras-related GTPase Rac-1 .

Effector pathways for this <protein>guanine nucleotide binding protein</protein> in <cell_type>T cells</cell_type> are mediated by the <protein>serine/threonine kinase</protein> <protein>Raf-1</protein> and the <protein>Ras-related GTPase</protein> <protein>Rac-1</protein> .


In fibroblasts , an important effector for the Ras oncogene is Phosphatidylinositol 3-kinase ( PtdIns 3-kinase ) .

In <cell_type>fibroblasts</cell_type> , an important effector for the <dna>Ras oncogene</dna> is <protein>Phosphatidylinositol 3-kinase</protein> ( <protein>PtdIns 3-kinase</protein> ) .


Activation of this lipid kinase is able to induce critical Rac-1 signaling pathways and can couple p21ras to cell survival mechanisms via the serine/threonine kinase Akt/PKB .

Activation of this <protein>lipid kinase</protein> is able to induce critical <protein>Rac-1</protein> signaling pathways and can couple <protein>p21ras</protein> to cell survival mechanisms via the <protein>serine/threonine kinase Akt/PKB</protein> .


The role of PtdIns 3-kinase in Ras signaling in T cells has not been explored .

The role of <protein>PtdIns 3-kinase</protein> in <protein>Ras</protein> signaling in <cell_type>T cells</cell_type> has not been explored .


In the present study , we examined the ability of PtdIns 3-kinase to initiate the Rac-1 signaling pathways important for T cell activation .

In the present study , we examined the ability of <protein>PtdIns 3-kinase</protein> to initiate the <protein>Rac-1</protein> signaling pathways important for T cell activation .


We also examined the possibility that Akt/PKB is regulated by Ras signaling pathways in T lymphocytes .

We also examined the possibility that <protein>Akt/PKB</protein> is regulated by Ras signaling pathways in <cell_type>T lymphocytes</cell_type> .


The results show that Ras can initiate a Rac-1 mediated pathway that regulates the transcriptional function of AP-1 complexes .

The results show that <protein>Ras</protein> can initiate a <protein>Rac-1</protein> mediated pathway that regulates the transcriptional function of <protein>AP-1 complexes</protein> .


PtdIns 3-kinase signals can not mimic p21ras and induce the Rac mediated responses of AP-1 transcriptional activation .

<protein>PtdIns 3-kinase</protein> signals can not mimic <protein>p21ras</protein> and induce the <protein>Rac</protein> mediated responses of <protein>AP-1</protein> transcriptional activation .


Moreover , neither TCR or Ras activation of AP-1 is dependent on PtdIns 3-kinase .

Moreover , neither <protein>TCR</protein> or <protein>Ras</protein> activation of <protein>AP-1</protein> is dependent on <protein>PtdIns 3-kinase</protein> .


PKB is activated in response to triggering of the T cell antigen receptor ; PtdIns 3-kinase activity is both required and sufficient for this TCR response .

<protein>PKB</protein> is activated in response to triggering of the <protein>T cell antigen receptor</protein> ; <protein>PtdIns 3-kinase</protein> activity is both required and sufficient for this <protein>TCR</protein> response .


In contrast , p21ras signals are unable to induce Akt/PKB activity in T cell nor is Ras function required for Akt/PKB activation in response to the TCR .

In contrast , <protein>p21ras</protein> signals are unable to induce <protein>Akt/PKB</protein> activity in <cell_type>T cell</cell_type> nor is <protein>Ras</protein> function required for <protein>Akt/PKB</protein> activation in response to the <protein>TCR</protein> .


The present data thus highlight that PtdIns 3-kinase and Akt/PKB are not universal Ras effector molecules .

The present data thus highlight that <protein>PtdIns 3-kinase</protein> and <protein>Akt/PKB</protein> are not universal <protein>Ras effector molecules</protein> .


Ras can initiate Rac-1 regulated signaling pathways in the context of T cell antigen receptor function independently of PtdIns 3-kinase activity .

<protein>Ras</protein> can initiate <protein>Rac-1</protein> regulated signaling pathways in the context of <protein>T cell antigen receptor</protein> function independently of <protein>PtdIns 3-kinase</protein> activity .


Interleukin 1beta mediates the modulatory effects of monocytes on LNCaP human prostate cancer cells .

<protein>Interleukin 1beta</protein> mediates the modulatory effects of <cell_type>monocytes</cell_type> on <cell_type>LNCaP human prostate cancer cells</cell_type> .


Proliferative and secretory responses in androgen-sensitive prostate cancer LNCaP cells are regulated by steroid and peptide hormones and by differentiation-promoting substances .

Proliferative and secretory responses in <cell_type>androgen-sensitive prostate cancer LNCaP cells</cell_type> are regulated by steroid and peptide hormones and by differentiation-promoting substances .


In the present study , we evaluated whether peripheral blood monocytes that exhibit anti-tumour activity in haematopoietic and solid tumours influence growth and secretion in the LNCaP cell line .

In the present study , we evaluated whether <cell_type>peripheral blood monocytes</cell_type> that exhibit anti-tumour activity in haematopoietic and solid tumours influence growth and secretion in the <cell_line>LNCaP cell line</cell_line> .


For this purpose , LNCaP cells were incubated with monocyte-conditioned medium ( MCM ) , and proliferation as well as expression of androgen receptor ( AR ) and secretion of prostate-specific antigen ( PSA ) were assessed .

For this purpose , <cell_line>LNCaP cells</cell_line> were incubated with monocyte-conditioned medium ( MCM ) , and proliferation as well as expression of <protein>androgen receptor</protein> ( <protein>AR</protein> ) and secretion of <protein>prostate-specific antigen</protein> ( <protein>PSA</protein> ) were assessed .


Conditioned medium from monocytes reduced proliferation in a dose-dependent manner .

Conditioned medium from <cell_type>monocytes</cell_type> reduced proliferation in a dose-dependent manner .


Incubation with 40 % MCM caused a 50 % reduction in cell proliferation .


AR protein decreased by 70 % and PSA levels in supernatants from LNCaP cells were reduced by approximately 80 % following treatment with MCM .

<protein>AR protein</protein> decreased by 70 % and <protein>PSA</protein> levels in supernatants from <cell_line>LNCaP cells</cell_line> were reduced by approximately 80 % following treatment with MCM .


We focused on the contribution of two major products of activated monocytes , prostaglandin E2 and interleukin 1beta ( IL-1beta ) , to the MCM modulatory action .

We focused on the contribution of two major products of activated <cell_type>monocytes</cell_type> , prostaglandin E2 and <protein>interleukin 1beta</protein> ( <protein>IL-1beta</protein> ) , to the MCM modulatory action .


LNCaP cells treated with prostaglandin E2 showed neither a reduction in proliferation nor a down-regulation of AR and PSA levels .

<cell_line>LNCaP cells</cell_line> treated with prostaglandin E2 showed neither a reduction in proliferation nor a down-regulation of <protein>AR</protein> and <protein>PSA</protein> levels .


The effects of MCM on cellular proliferation , AR protein and PSA secretion were abolished by pretreatment of MCM with a neutralizing anti-IL-1beta antibody .

The effects of MCM on cellular proliferation , <protein>AR protein</protein> and <protein>PSA</protein> secretion were abolished by pretreatment of MCM with a neutralizing <protein>anti-IL-1beta antibody</protein> .


In addition , recombinant IL-1beta was able to replace MCM for the inhibition of proliferation and down-regulation of AR and PSA proteins .

In addition , recombinant <protein>IL-1beta</protein> was able to replace MCM for the inhibition of proliferation and down-regulation of <protein>AR</protein> and <protein>PSA</protein> proteins .


LNCaP cells were shown to express the IL-1beta receptor type 1 , which transduces IL-1beta signal .

<cell_line>LNCaP cells</cell_line> were shown to express the <protein>IL-1beta</protein> receptor type 1 , which transduces <protein>IL-1beta</protein> signal .


Our findings reveal that monocyte-derived IL-1beta inhibits the proliferation of androgen-responsive prostate tumour cells and reduces AR and PSA levels .

Our findings reveal that <protein>monocyte-derived IL-1beta</protein> inhibits the proliferation of <cell_type>androgen-responsive prostate tumour cells</cell_type> and reduces <protein>AR</protein> and <protein>PSA</protein> levels .


Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3 .

Differential responsiveness of the <dna>IL-5 and IL-4 genes</dna> to <protein>transcription factor GATA-3</protein> .


The cytokines IL-4 and IL-5 are often coordinately produced by Th2 cells as in asthma .

The <protein>cytokines</protein> <protein>IL-4</protein> and <protein>IL-5</protein> are often coordinately produced by <cell_line>Th2 cells</cell_line> as in asthma .


However , it is unclear whether similar molecular mechanisms underlie transcription of the two genes .

However , it is unclear whether similar molecular mechanisms underlie transcription of the two <dna>genes</dna> .


We have previously shown that the transcription factor GATA-3 is expressed in Th2 but not Th1 cells and is crucial for activation of the IL-5 promoter by different stimuli .

We have previously shown that the <protein>transcription factor GATA-3</protein> is expressed in <cell_line>Th2 but not Th1 cells</cell_line> and is crucial for activation of the <dna>IL-5 promoter</dna> by different stimuli .


In a different study , GATA-3 was shown to be sufficient for the expression of IL-4 and other Th2 cytokine genes .

In a different study , <protein>GATA-3</protein> was shown to be sufficient for the expression of <protein>IL-4</protein> and other <dna>Th2 cytokine genes</dna> .


Here , we show that ectopic expression of GATA-3 is sufficient to drive IL-5 but not IL-4 gene expression .

Here , we show that ectopic expression of <protein>GATA-3</protein> is sufficient to drive <protein>IL-5</protein> but not <protein>IL-4</protein> gene expression .


Also , in Th2 cells , antisense GATA-3 RNA inhibits IL-5 but not IL-4 promoter activation .

Also , in <cell_line>Th2 cells</cell_line> , antisense <protein>GATA-3</protein> RNA inhibits <protein>IL-5</protein> but not <protein>IL-4</protein> promoter activation .


The induction of IL-5 gene expression by GATA-3 involves high affinity binding of GATA-3 to an inverted GATA repeat in the IL-5 promoter .

The induction of <dna>IL-5 gene</dna> expression by <protein>GATA-3</protein> involves high affinity binding of <protein>GATA-3</protein> to an inverted <dna>GATA repeat</dna> in the <dna>IL-5 promoter</dna> .


The interleukin 2 receptor alpha chain/CD25 promoter is a target for nuclear factor of activated T cells .

The <dna>interleukin 2 receptor alpha chain/CD25 promoter</dna> is a target for <protein>nuclear factor of activated T cells</protein> .


The expression of the murine interleukin ( IL ) -2 receptor alpha chain/CD25 is strongly induced at the transcriptional level after T cell activation .

The expression of the <protein>murine interleukin ( IL ) -2 receptor alpha chain/CD25</protein> is strongly induced at the transcriptional level after T cell activation .


We show here that nuclear factor of activated T cell ( NF-AT ) factors are involved in the control of CD25 promoter induction in T cells .

We show here that <protein>nuclear factor of activated T cell ( NF-AT ) factors</protein> are involved in the control of <dna>CD25 promoter</dna> induction in <cell_type>T cells</cell_type> .


NF-ATp and NF-ATc bind to two sites around positions -585 and -650 located upstream of the proximal CD25 promoter .

<protein>NF-ATp</protein> and <protein>NF-ATc</protein> bind to two sites around <dna>positions -585 and -650</dna> located upstream of the <dna>proximal CD25 promoter</dna> .


Immediately 3 ' from these NF-AT motifs , nonconsensus sites are located for the binding of AP-1-like factors .

Immediately 3 ' from these <dna>NF-AT motifs</dna> , <dna>nonconsensus sites</dna> are located for the binding of <protein>AP-1-like factors</protein> .


Mutations of sites that suppress NF-AT binding impair the induction and strong NF-ATp -mediated transactivation of the CD25 promoter in T cells .

Mutations of sites that suppress <protein>NF-AT</protein> binding impair the induction and strong <protein>NF-ATp</protein> -mediated transactivation of the <dna>CD25 promoter</dna> in <cell_type>T cells</cell_type> .


In T lymphocytes from NF-ATp -deficient mice , the expression of CD25 is severely impaired , leading to a delayed IL-2 receptor expression after T cell receptor ( TCR ) / CD3 stimulation .

In <cell_type>T lymphocytes</cell_type> from <protein>NF-ATp</protein> -deficient mice , the expression of <protein>CD25</protein> is severely impaired , leading to a delayed <protein>IL-2 receptor</protein> expression after T cell receptor ( <protein>TCR</protein> ) / <protein>CD3</protein> stimulation .


Our data indicate an important role for NF-AT in the faithful expression of high affinity IL-2 receptors and a close link between the TCR -mediated induction of IL-2 and IL-2 receptor alpha chain promoters , both of which are regulated by NF-AT factors .

Our data indicate an important role for <protein>NF-AT</protein> in the faithful expression of <protein>high affinity IL-2 receptors</protein> and a close link between the <protein>TCR</protein> -mediated induction of <protein>IL-2</protein> and <dna>IL-2 receptor alpha chain promoters</dna> , both of which are regulated by <protein>NF-AT factors</protein> .


A novel mutation in the coding sequence of the FY*B allele of the Duffy chemokine receptor gene is associated with an altered erythrocyte phenotype .

A novel mutation in the coding sequence of the <dna>FY*B allele</dna> of the <dna>Duffy chemokine receptor gene</dna> is associated with an altered erythrocyte phenotype .


The Duffy blood group system is of clinical and biological significance .


Antibodies to Duffy antigens are responsible for some cases of transfusion incompatibility and newborn hemolytic disease .

<protein>Antibodies</protein> to <protein>Duffy antigens</protein> are responsible for some cases of transfusion incompatibility and newborn hemolytic disease .


The Duffy protein is a receptor for the Plasmodium vivax erythrocyte-binding protein and is also a receptor for various chemokines ( thus renamed Duffy Antigen Receptor for Chemokines [ DARC ] ) .

The <protein>Duffy protein</protein> is a receptor for the <protein>Plasmodium vivax erythrocyte-binding protein</protein> and is also a receptor for various <protein>chemokines</protein> ( thus renamed <protein>Duffy Antigen Receptor for Chemokines</protein> [ <protein>DARC</protein> ] ) .


The two Duffy polymorphic antigens , Fya and Fyb ( coded by the FY*A and FY*B alleles ) , are present on erythrocyte membranes .

The two <protein>Duffy polymorphic antigens</protein> , <protein>Fya</protein> and <protein>Fyb</protein> ( coded by the <dna>FY*A and FY*B alleles</dna> ) , are present on <protein>erythrocyte membranes</protein> .


The Fy ( a-b- ) phenotype is the predominant one in populations of black people and also occurs in other populations , including some non-Ashkenazi Jewish groups .


The Fy ( a-b- ) phenotype has been associated with a mutation in the FY*B promoter at the GATA box that abolishes the expression of erythrocyte Duffy protein .

The Fy ( a-b- ) phenotype has been associated with a mutation in the <dna>FY*B promoter</dna> at the <dna>GATA box</dna> that abolishes the expression of <protein>erythrocyte Duffy protein</protein> .


We describe here a novel mutation , present in the FY*B coding sequence ( 271C -- > T ) , that is associated with some Fy ( b- ) phenotypes among non-Ashkenazi Jews and among Brazilian blacks .

We describe here a novel mutation , present in the <dna>FY*B coding sequence</dna> ( 271C -- > T ) , that is associated with some Fy ( b- ) phenotypes among non-Ashkenazi Jews and among Brazilian blacks .


The mutation is present in Fy ( b- ) individuals , who have wild-type FY*B GATA and carry the previously described 304G -- > A substitution .

The mutation is present in Fy ( b- ) individuals , who have <dna>wild-type FY*B GATA</dna> and carry the previously described 304G -- > A substitution .


The 271C -- > T and 304G -- > A can be identified by restriction enzyme-generated restriction fragment length polymorphisms .

The 271C -- > T and 304G -- > A can be identified by <dna>restriction enzyme-generated restriction fragment length polymorphisms</dna> .


The 271C -- > T substitution represents a considerable change in chemical nature ( Arg91 -- > Cys ) , one which may affect the antigenic determinants of DARC , and thus be of clinical significance .

The 271C -- > T substitution represents a considerable change in chemical nature ( Arg91 -- > Cys ) , one which may affect the antigenic determinants of <protein>DARC</protein> , and thus be of clinical significance .


The mutation may have implications for some physiological roles of DARC and be of interest in malaria research and in studies of population genetics .

The mutation may have implications for some physiological roles of <protein>DARC</protein> and be of interest in malaria research and in studies of population genetics .


Establishment and characterization of EBV-positive and EBV-negative primary effusion lymphoma cell lines harbouring human herpesvirus type-8 .

Establishment and characterization of <cell_line>EBV-positive and EBV-negative primary effusion lymphoma cell lines</cell_line> harbouring human herpesvirus type-8 .


In this study we report on the establishment and characterization of two novel lymphoma cell lines ( CRO-AP/3 and CRO-AP/5 ) which carry infection by human herpesvirus type-8 ( HHV-8 ) and have derived from AIDS-related primary effusion lymphoma ( PEL ) .

In this study we report on the establishment and characterization of two novel <cell_line>lymphoma cell lines</cell_line> ( <cell_line>CRO-AP/3</cell_line> and <cell_line>CRO-AP/5</cell_line> ) which carry infection by human herpesvirus type-8 ( HHV-8 ) and have derived from AIDS-related primary effusion lymphoma ( <cell_line>PEL</cell_line> ) .


These two cell lines are representative of different virologic subtypes of PEL , i.e . HHV-8+/EBV- PEL in the case of CRO-AP/3 and HHV-8+/EBV+ PEL in the case of CRO-AP/5 .

These two <cell_line>cell lines</cell_line> are representative of different virologic subtypes of <cell_line>PEL</cell_line> , i.e . <cell_line>HHV-8+/EBV- PEL</cell_line> in the case of <cell_line>CRO-AP/3 and HHV-8+/EBV+ PEL</cell_line> in the case of <cell_line>CRO-AP/5</cell_line> .


Consistent with the diagnosis of PEL , both CRO-AP/3 and CRO-AP/5 expressed indeterminate ( i.e. non-B , non-T ) phenotypes although immunogenotypic studies documented their B-cell origin .

Consistent with the diagnosis of <cell_line>PEL</cell_line> , both <cell_line>CRO-AP/3</cell_line> and <cell_line>CRO-AP/5</cell_line> expressed indeterminate ( i.e. non-B , non-T ) phenotypes although immunogenotypic studies documented their <cell_type>B-cell origin</cell_type> .


Both cell lines are devoid of genetic lesions of c-MYC , BCL-2 and p53 as well as gross rearrangements of BCL-6 .

Both <cell_line>cell lines</cell_line> are devoid of genetic lesions of <protein>c-MYC</protein> , <protein>BCL-2</protein> and <protein>p53</protein> as well as gross rearrangements of <protein>BCL-6</protein> .


Detailed histogenetic characterization of these novel PEL cell lines suggests that PEL may derive from a post-germinal centre B cell which has undergone pre-terminal differentiation .

Detailed histogenetic characterization of these novel <cell_line>PEL cell lines</cell_line> suggests that <cell_line>PEL</cell_line> may derive from a <cell_line>post-germinal centre B cell</cell_line> which has undergone pre-terminal differentiation .


The CRO-AP/3 and CRO-AP/5 cell lines may provide a valuable model for clarifying the pathogenesis of PEL .

The <cell_line>CRO-AP/3</cell_line> and <cell_line>CRO-AP/5 cell lines</cell_line> may provide a valuable model for clarifying the pathogenesis of <cell_line>PEL</cell_line> .


In particular , these cell lines may help understand the relative contribution of HHV-8 and EBV to PEL growth and development and may facilitate the identification of recurrent cytogenetic abnormalities highlighting putative novel cancer related loci relevant to PEL .

In particular , these <cell_line>cell lines</cell_line> may help understand the relative contribution of HHV-8 and EBV to PEL growth and development and may facilitate the identification of recurrent cytogenetic abnormalities highlighting putative novel cancer related loci relevant to <cell_line>PEL</cell_line> .


Two-site interaction of nuclear factor of activated T cells with activated calcineurin .

Two-site interaction of <protein>nuclear factor of activated T cells</protein> with activated <protein>calcineurin</protein> .


Transcription factors belonging to the nuclear factor of activated T cells ( NFAT ) family regulate the expression of cytokine genes and other inducible genes during the immune response .

<protein>Transcription factors</protein> belonging to the <protein>nuclear factor of activated T cells ( NFAT ) family</protein> regulate the expression of <dna>cytokine genes</dna> and other inducible genes during the immune response .


The functions of NFAT proteins are directly controlled by the calcium- and calmodulin- dependent phosphatase calcineurin .

The functions of <protein>NFAT proteins</protein> are directly controlled by the <protein>calcium- and calmodulin- dependent phosphatase</protein> <protein>calcineurin</protein> .


Here we show that the binding of calcineurin to NFAT is substantially increased when calcineurin is activated with calmodulin and calcium .

Here we show that the binding of <protein>calcineurin</protein> to <protein>NFAT</protein> is substantially increased when <protein>calcineurin</protein> is activated with <protein>calmodulin</protein> and calcium .


FK506.FKBP12 drug-immunophilin complexes inhibited the interaction of NFAT with activated calcineurin much more effectively than they inhibited the interaction with inactive calcineurin , suggesting that part of the interaction with activated calcineurin involved the enzyme active site .

FK506.FKBP12 drug-immunophilin complexes inhibited the interaction of <protein>NFAT</protein> with activated <protein>calcineurin</protein> much more effectively than they inhibited the interaction with inactive <protein>calcineurin</protein> , suggesting that part of the interaction with activated <protein>calcineurin</protein> involved the <dna>enzyme active site</dna> .


We have previously shown that NFAT is targeted to inactive calcineurin at a region distinct from the calcineurin active site ( Aramburu , J. , Garcia-Cozar , F. J. , Raghavan , A. , Okamura , H. , Rao , A. , and Hogan , P. G. ( 1998 ) Mol. Cell 1 , 627-637 ) ; this region is also involved in NFAT binding to activated calcineurin , since binding is inhibited by an NFAT peptide spanning the calcineurin docking site on NFAT .

We have previously shown that <protein>NFAT</protein> is targeted to inactive <protein>calcineurin</protein> at a region distinct from the <dna>calcineurin active site</dna> ( Aramburu , J. , Garcia-Cozar , F. J. , Raghavan , A. , Okamura , H. , Rao , A. , and Hogan , P. G. ( 1998 ) Mol. Cell 1 , 627-637 ) ; this region is also involved in <protein>NFAT</protein> binding to activated <protein>calcineurin</protein> , since binding is inhibited by an NFAT peptide spanning the <protein>calcineurin</protein> docking site on <protein>NFAT</protein> .


The interacting surfaces are located on the catalytic domain of the calcineurin A chain and on an 86-amino acid fragment of the NFAT regulatory domain .

The interacting surfaces are located on the <protein>catalytic domain</protein> of the <protein>calcineurin A chain</protein> and on an <protein>86-amino acid fragment</protein> of the <protein>NFAT regulatory domain</protein> .


NFAT binding to the calcineurin catalytic domain was inhibited by the calcineurin autoinhibitory domain and the RII substrate peptide , which bind in the calcineurin active site , as well as by the NFAT docking site peptide , which binds to a region of calcineurin distinct from the active site .

<protein>NFAT</protein> binding to the <protein>calcineurin catalytic domain</protein> was inhibited by the <protein>calcineurin autoinhibitory domain</protein> and the RII substrate peptide , which bind in the <protein>calcineurin active site</protein> , as well as by the <protein>NFAT</protein> docking site peptide , which binds to a region of <protein>calcineurin</protein> distinct from the <protein>active site</protein> .


We propose that , in resting cells , NFAT is targeted to a region of the calcineurin catalytic domain that does not overlap the calcineurin active site .

We propose that , in <cell_type>resting cells</cell_type> , <protein>NFAT</protein> is targeted to a region of the <protein>calcineurin catalytic domain</protein> that does not overlap the <protein>calcineurin active site</protein> .


Upon cell activation , displacement of the autoinhibitory domain by calmodulin binding allows NFAT to bind additionally to the calcineurin active site , thus positioning NFAT for immediate dephosphorylation at functional phosphoserine residues .

Upon cell activation , displacement of the <protein>autoinhibitory domain</protein> by <protein>calmodulin</protein> binding allows <protein>NFAT</protein> to bind additionally to the <protein>calcineurin active site</protein> , thus positioning <protein>NFAT</protein> for immediate dephosphorylation at functional phosphoserine residues .


Nuclear factor-kappaB induction in CD45RO+ and CD45RA+ T cell subsets during aging .

<protein>Nuclear factor-kappaB</protein> induction in <cell_type>CD45RO+ and CD45RA+ T cell subsets</cell_type> during aging .


An increase in the ratio of memory to naive T cells has been postulated to underlie immune hyporesponsiveness accompanying aging .

An increase in the ratio of <cell_type>memory to naive T cells</cell_type> has been postulated to underlie immune hyporesponsiveness accompanying aging .


Our analyses of the induction of nuclear factor-kappaB ( NFkappaB ) in activated memory ( CD45RO+ ) and naive ( CD45RA+ ) T cell subsets from young and elderly donors has demonstrated that , regardless of donor age , memory T cells are not significantly altered in their responsiveness to TNF-alpha -mediated induction of NFkappaB .

Our analyses of the induction of <protein>nuclear factor-kappaB</protein> ( <protein>NFkappaB</protein> ) in activated <cell_type>memory ( CD45RO+ ) and naive ( CD45RA+ ) T cell subsets</cell_type> from young and elderly donors has demonstrated that , regardless of donor age , <cell_type>memory T cells</cell_type> are not significantly altered in their responsiveness to <protein>TNF-alpha</protein> -mediated induction of <protein>NFkappaB</protein> .


Although treatment with TNF-alpha induced nuclear localization of NFkappaB in both memory and naive T cell subsets , irrespective of the age of the donor , the levels of induced NFkappaB were significantly lower in both subsets of T cells obtained from the elderly , when compared to those in young .

Although treatment with <protein>TNF-alpha</protein> induced nuclear localization of <protein>NFkappaB</protein> in both <cell_type>memory and naive T cell subsets</cell_type> , irrespective of the age of the donor , the levels of induced <protein>NFkappaB</protein> were significantly lower in both subsets of <cell_type>T cells</cell_type> obtained from the elderly , when compared to those in young .


Examination of IkappaB alpha regulation revealed that TNF-alpha -mediated degradation of IkappaB alpha in both memory and naive T cells from the elderly was severely impaired , thus contributing to the lowered induction of the observed NFkappaB .

Examination of <protein>IkappaB alpha</protein> regulation revealed that <protein>TNF-alpha</protein> -mediated degradation of <protein>IkappaB alpha</protein> in both <cell_type>memory and naive T cells</cell_type> from the elderly was severely impaired , thus contributing to the lowered induction of the observed <protein>NFkappaB</protein> .


In addition , this age-related decrease in induction of nuclear NFkappaB correlated with decrease in intracellular IL-2 receptor expression and anti-CD3 -induced proliferation of both memory and naive T cells subsets .

In addition , this age-related decrease in induction of <protein>nuclear NFkappaB</protein> correlated with decrease in intracellular <protein>IL-2</protein> receptor expression and <protein>anti-CD3</protein> -induced proliferation of both <cell_type>memory and naive T cells subsets</cell_type> .


Taken together , our results suggest that the age-related hyporesponsiveness can not be attributed to a skewing of the T cell population towards a memory phenotype in the elderly .


Cyclosporin A-resistant transactivation of the IL-2 promoter requires activity of okadaic acid-sensitive serine/threonine phosphatases .

Cyclosporin A-resistant transactivation of the <dna>IL-2 promoter</dna> requires activity of <protein>okadaic acid-sensitive serine/threonine phosphatases</protein> .


Expression of the IL-2 gene requires activation of T cells through stimulation of the TCR and costimulation through accessory receptors .

Expression of the <dna>IL-2 gene</dna> requires activation of <cell_type>T cells</cell_type> through stimulation of the <protein>TCR</protein> and costimulation through <protein>accessory receptors</protein> .


We have found recently that okadaic acid-sensitive Ser/Thr phosphatases are involved in a cyclosporin A-insensitive pathway that selectively transmits costimulatory signals .

We have found recently that <protein>okadaic acid-sensitive Ser/Thr phosphatases</protein> are involved in a cyclosporin A-insensitive pathway that selectively transmits costimulatory signals .


In this study , we analyzed whether activities of these phosphatases are necessary for the expression of the IL-2 gene .

In this study , we analyzed whether activities of these phosphatases are necessary for the expression of the <dna>IL-2 gene</dna> .


In both activated peripheral blood T lymphocytes and activated tumorigenic T cell lines , IL-2 gene expression was blocked at the transcriptional level by okadaic acid .

In both <cell_type>activated peripheral blood T lymphocytes</cell_type> and <cell_line>activated tumorigenic T cell lines</cell_line> , <protein>IL-2</protein> gene expression was blocked at the transcriptional level by okadaic acid .


The transcription factors active at the IL-2 promoter were differentially influenced : upon down-modulation of okadaic acid-sensitive phosphatases , transactivation by octamer , NF-kappa B , and NF of activated T cells proteins was abrogated , while transactivation by AP-1 proteins was even enhanced .

The <protein>transcription factors</protein> active at the <dna>IL-2 promoter</dna> were differentially influenced : upon down-modulation of <protein>okadaic acid-sensitive phosphatases</protein> , transactivation by octamer , <protein>NF-kappa B</protein> , and <protein>NF of activated T cells proteins</protein> was abrogated , while transactivation by <protein>AP-1 proteins was even enhanced .</protein>


YM268 increases the glucose uptake , cell differentiation , and mRNA expression of glucose transporter in 3T3-L1 adipocytes .

YM268 increases the glucose uptake , cell differentiation , and mRNA expression of <protein>glucose transporter</protein> in <cell_type>3T3-L1 adipocytes</cell_type> .


The purpose of this study was to examine the effects of bis [ 4- [ 2 , 4-dioxo-5-thiazolidinyl ) methyl ] phenyl ] methane ( YM-268 ) , a thiazolidinedione derivative , on glucose uptake , adipocyte differentiation through peroxisome proliferator-activated receptor gamma ( PPARgamma ) , and phosphatidylinositol 3-kinase ( PI 3-kinase ) activity in cultured cells .

The purpose of this study was to examine the effects of bis [ 4- [ 2 , 4-dioxo-5-thiazolidinyl ) methyl ] phenyl ] methane ( YM-268 ) , a thiazolidinedione derivative , on glucose uptake , <cell_type>adipocyte</cell_type> differentiation through <protein>peroxisome proliferator-activated receptor gamma</protein> ( <protein>PPARgamma</protein> ) , and <protein>phosphatidylinositol 3-kinase</protein> ( <protein>PI 3-kinase</protein> ) activity in <cell_line>cultured cells</cell_line> .


YM268 and pioglitazone dose-dependently increased the 2-deoxyglucose uptake in 3T3-L1 cells .

YM268 and pioglitazone dose-dependently increased the 2-deoxyglucose uptake in <cell_line>3T3-L1 cells</cell_line> .


YM268 facilitated the insulin-stimulated triglyceride accumulation in 3T3-L1 adipocytes and increased the mRNA expression of fatty acid-binding protein .

YM268 facilitated the insulin-stimulated triglyceride accumulation in <cell_type>3T3-L1 adipocytes</cell_type> and increased the mRNA expression of <protein>fatty acid-binding protein</protein> .


YM268 , with and without insulin , increased the mRNA expression of glucose transporter isoforms such as GLUT1 and GLUT4 , indicating enhancement of adipocyte differentiation .

YM268 , with and without insulin , increased the mRNA expression of <protein>glucose transporter</protein> isoforms such as <protein>GLUT1</protein> and <protein>GLUT4</protein> , indicating enhancement of <cell_type>adipocyte</cell_type> differentiation .


Additionally , YM268 and pioglitazone showed activity of the PPARgamma ligand , a member of the nuclear receptor superfamily responsible for adipogenesis .

Additionally , YM268 and pioglitazone showed activity of the <protein>PPARgamma ligand</protein> , a member of the <protein>nuclear receptor superfamily</protein> responsible for adipogenesis .


To examine the possible involvement of the increased activity of PI 3-kinase in YM268-stimulated glucose uptake , the enzyme activity was estimated by measuring the phosphatidylinositol-3 , 4 , 5-trisphosphate ( PI-3 , 4 , 5-P3 ) concentration in human monocytic cells .

To examine the possible involvement of the increased activity of <protein>PI 3-kinase</protein> in YM268-stimulated glucose uptake , the enzyme activity was estimated by measuring the phosphatidylinositol-3 , 4 , 5-trisphosphate ( PI-3 , 4 , 5-P3 ) concentration in <cell_type>human monocytic cells</cell_type> .


Insulin dose-dependently increased the PI-3 , 4 , 5-P3 production but YM268 had no significant effect on the insulin-dependent and -independent PI 3-kinase activation .


These results indicate that the mechanism by which YM268 increased glucose uptake , may be accounted for in part by the enhancement of GLUT1 and GLUT4 expression through PPARgamma activation .

These results indicate that the mechanism by which YM268 increased glucose uptake , may be accounted for in part by the enhancement of <protein>GLUT1</protein> and <protein>GLUT4</protein> expression through <protein>PPARgamma</protein> activation .


The nuclear receptor PPARgamma - bigger than fat .

The <protein>nuclear receptor</protein> <protein>PPARgamma</protein> - bigger than fat .


Work reported over the past year has provided insights into the mechanisms whereby ligand activation of the nuclear receptor peroxisome proliferator-activated receptor gamma ( PPARgamma ) regulates systemic glucose and lipid homeostasis .

Work reported over the past year has provided insights into the mechanisms whereby ligand activation of the <protein>nuclear receptor peroxisome proliferator-activated receptor gamma</protein> ( <protein>PPARgamma</protein> ) regulates systemic glucose and lipid homeostasis .


PPARgamma has also been implicated recently in the biology of monocytes and in cell-cycle regulation and cancer .

<protein>PPARgamma</protein> has also been implicated recently in the biology of monocytes and in cell-cycle regulation and cancer .


Polyunsaturated fatty acids and eicosanoids bind and activate PPARgamma , suggesting that these lipids may serve as hormonal regulators of a variety of biological processes .

Polyunsaturated fatty acids and eicosanoids bind and activate <protein>PPARgamma</protein> , suggesting that these lipids may serve as hormonal regulators of a variety of biological processes .


The role of caspases in T cell development and the control of immune responses .


Apoptosis is responsible for the removal of potentially autoreactive or useless T cells during thymic selection and activated T cells in the periphery .

Apoptosis is responsible for the removal of potentially autoreactive or useless T cells during thymic selection and <cell_type>activated T cells</cell_type> in the periphery .


Specific families of receptors , kinases , transcription factors , and cysteine proteases , termed caspases , are involved in the apoptotic cascade leading to proteolysis of specific substrates and to morphological changes associated with programmed cell death .

Specific families of <protein>receptors</protein> , <protein>kinases</protein> , <protein>transcription factors</protein> , and <protein>cysteine proteases</protein> , <protein>termed caspases</protein> , are involved in the apoptotic cascade leading to proteolysis of specific substrates and to morphological changes associated with programmed cell death .


Although common members of the apoptotic cascade are shared between different cell types , it appears that cell-specific factors can influence the response to a given apoptotic stimuli .

Although common members of the apoptotic cascade are shared between different cell types , it appears that <protein>cell-specific factors</protein> can influence the response to a given apoptotic stimuli .


Characterization and understanding of the basic mechanisms involved in the different pathways protecting or leading to cell death may provide novel ways to control inappropriate apoptosis involved in several diseases .


Cross-priming of CTL responses in vivo does not require antigenic peptides in the endoplasmic reticulum of immunizing cells .

Cross-priming of CTL responses in vivo does not require antigenic peptides in the endoplasmic reticulum of <cell_type>immunizing cells</cell_type> .


It has been proposed that the cross-priming of CTL responses in vivo involves the transfer to host APCs of heat shock protein glycoprotein 96 -chaperoned antigenic peptides released from the endoplasmic reticulum ( ER ) of dying or infected cells .

It has been proposed that the cross-priming of CTL responses in vivo involves the transfer to host <cell_type>APCs</cell_type> of <protein>heat shock protein glycoprotein 96</protein> -chaperoned antigenic peptides released from the endoplasmic reticulum ( ER ) of <cell_type>dying or infected cells</cell_type> .


We have tested this possibility directly using TAP-deficient cell lines lacking antigenic ER peptides derived from two model Ags , the human adenovirus type 5 early regions E1A and E1B .

We have tested this possibility directly using <cell_line>TAP-deficient cell lines</cell_line> lacking antigenic ER peptides derived from two model <protein>Ags</protein> , the <protein>human adenovirus type 5 early regions E1A and E1B</protein> .


Although both proteins were well expressed , the cells were not recognized by E1A- or E1B-specific CTLs unless the relevant epitope was either provided exogenously as a synthetic peptide or targeted to the ER in a TAP-independent fashion .

Although both proteins were well expressed , the cells were not recognized by <cell_type>E1A- or E1B-specific CTLs</cell_type> unless the relevant epitope was either provided exogenously as a synthetic peptide or targeted to the ER in a TAP-independent fashion .


Despite the absence of these ER peptides , the TAP1-/- cells were able to efficiently cross-prime E1A- and E1B-specific CTLs following immunization of syngeneic mice .

Despite the absence of these ER peptides , the <cell_type>TAP1-/- cells</cell_type> were able to efficiently <cell_type>cross-prime E1A- and E1B-specific CTLs</cell_type> following immunization of syngeneic mice .


These results indicate that , although purified peptide/glycoprotein 96 complexes are potent immunogens , the mechanism of CTL cross-priming in vivo does not depend upon antigenic peptides in the ER of immunizing cells .

These results indicate that , although purified <protein>peptide/glycoprotein 96 complexes</protein> are potent immunogens , the mechanism of CTL cross-priming in vivo does not depend upon antigenic peptides in the ER of <cell_type>immunizing cells</cell_type> .


A critical role of the p75 tumor necrosis factor receptor ( p75TNF-R ) in organ inflammation independent of TNF , lymphotoxin alpha , or the p55TNF-R .

A critical role of the <protein>p75 tumor necrosis factor receptor</protein> ( <protein>p75TNF-R</protein> ) in organ inflammation independent of <protein>TNF</protein> , <protein>lymphotoxin alpha</protein> , or the <protein>p55TNF-R .</protein>


Despite overwhelming evidence that enhanced production of the p75 tumor necrosis factor receptor ( p75TNF-R ) accompanies development of specific human inflammatory pathologies such as multi-organ failure during sepsis , inflammatory liver disease , pancreatitis , respiratory distress syndrome , or AIDS , the function of this receptor remains poorly defined in vivo .

Despite overwhelming evidence that enhanced production of the <protein>p75 tumor necrosis factor receptor</protein> ( <protein>p75TNF-R</protein> ) accompanies development of specific human inflammatory pathologies such as multi-organ failure during sepsis , inflammatory liver disease , pancreatitis , respiratory distress syndrome , or AIDS , the function of this receptor remains poorly defined in vivo .


We show here that at levels relevant to human disease , production of the human p75TNF-R in transgenic mice results in a severe inflammatory syndrome involving mainly the pancreas , liver , kidney , and lung , and characterized by constitutively increased NF-kappaB activity in the peripheral blood mononuclear cell compartment .

We show here that at levels relevant to human disease , production of the <protein>human p75TNF-R</protein> in transgenic mice results in a severe inflammatory syndrome involving mainly the pancreas , liver , kidney , and lung , and characterized by constitutively increased <protein>NF-kappaB</protein> activity in the <cell_type>peripheral blood mononuclear cell</cell_type> compartment .


This process is shown to evolve independently of the presence of TNF , lymphotoxin alpha , or the p55TNF-R , although coexpression of a human TNF transgene accelerated pathology .

This process is shown to evolve independently of the presence of <protein>TNF</protein> , <protein>lymphotoxin alpha</protein> , or the <protein>p55TNF-R</protein> , although coexpression of a <dna>human TNF transgene</dna> accelerated pathology .


These results establish an independent role for enhanced p75TNF-R production in the pathogenesis of inflammatory disease and implicate the direct involvement of this receptor in a wide range of human inflammatory pathologies .

These results establish an independent role for enhanced <protein>p75TNF-R</protein> production in the pathogenesis of inflammatory disease and implicate the direct involvement of this receptor in a wide range of human inflammatory pathologies .


Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin 's disease .

Expression status of <protein>BCL-6</protein> and <protein>syndecan-1</protein> identifies distinct histogenetic subtypes of Hodgkin 's disease .


The tumor cells in most cases of Hodgkin 's disease ( HD ) have been recently recognized to originate from the B-cell lineage , but their precise differentiation stage is not fully clarified .

The <cell_type>tumor cells</cell_type> in most cases of Hodgkin 's disease ( HD ) have been recently recognized to originate from the <cell_type>B-cell lineage</cell_type> , but their precise differentiation stage is not fully clarified .


Recently , we have reported that the histogenesis of B-cell lymphomas may be assessed by monitoring the expression pattern of BCL-6 , a transcription factor expressed in germinal center ( GC ) B cells , and CD138/syndecan-1 ( syn-1 ) , a proteoglycan associated with post-GC , terminal B-cell differentiation .

Recently , we have reported that the histogenesis of <cell_type>B-cell lymphomas</cell_type> may be assessed by monitoring the expression pattern of <protein>BCL-6</protein> , a <protein>transcription factor</protein> expressed in <cell_type>germinal center ( GC ) B cells</cell_type> , and <protein>CD138/syndecan-1</protein> ( <protein>syn-1</protein> ) , a proteoglycan associated with post-GC , terminal B-cell differentiation .


In this study , we have applied these two markers to the study of HD histogenesis .


We have found that in nodular lymphocyte predominance HD ( NLPHD ) tumor cells consistently display the BCL-6 ( + ) / syn-1 ( - ) phenotype , indicating their derivation from GC B cells .

We have found that in nodular lymphocyte predominance HD ( NLPHD ) <cell_type>tumor cells</cell_type> consistently display the <protein>BCL-6</protein> ( + ) / <protein>syn-1</protein> ( - ) phenotype , indicating their derivation from <cell_type>GC B cells</cell_type> .