Our results demonstrate that in resting and PMA-activated human PBL , I ( kappa ) B ( alpha ) is present in the nucleus in an apparently inactive form unable to disrupt NF-kappaB binding from DNA .

Our results demonstrate that in resting and <cell_type>PMA-activated human PBL</cell_type> , <protein>I ( kappa ) B ( alpha )</protein> is present in the nucleus in an apparently inactive form unable to disrupt <protein>NF-kappaB</protein> binding from DNA .


Impaired fetal thymocyte development after efficient adenovirus-mediated inhibition of NF-kappa B activation .

Impaired <cell_type>fetal thymocyte</cell_type> development after efficient adenovirus-mediated inhibition of <protein>NF-kappa B</protein> activation .


We introduce a new experimental system combining adenovirus-mediated gene transfer and fetal thymic organ culture ( FTOC ) .


This system allowed us to efficiently express in developing thymocytes a mutant form of the NF-kappa B inhibitor I kappa B alpha ( mut-I kappa B ) and to study the maturation defects occurring when NF-kappa B activation is inhibited during fetal development .

This system allowed us to efficiently express in developing thymocytes a mutant form of the <protein>NF-kappa B</protein> inhibitor <protein>I kappa B alpha</protein> ( <protein>mut-I kappa B</protein> ) and to study the maturation defects occurring when <protein>NF-kappa B</protein> activation is inhibited during fetal development .


Fetal thymocytes infected with adenovirus containing mut-I kappa B were found to develop normally until the CD44 -CD25+ , CD4 - CD8 - double-negative stage , while production of more mature double-positive and single-positive populations was strongly decreased .

<cell_type>Fetal thymocytes</cell_type> infected with adenovirus containing <protein>mut-I kappa B</protein> were found to develop normally until the <protein>CD44</protein> -CD25+ , <protein>CD4</protein> - <protein>CD8</protein> - double-negative stage , while production of more mature double-positive and single-positive populations was strongly decreased .


Proliferation , as measured by the percentage of cells in cycle appeared normal , as did rearrangement and expression of the TCR beta-chain .

Proliferation , as measured by the percentage of cells in cycle appeared normal , as did rearrangement and expression of the <protein>TCR beta-chain</protein> .


However , apoptosis was much higher in FTOC infected with adenovirus containing mut-I kappa B than in FTOC infected with a control virus .

However , apoptosis was much higher in FTOC infected with adenovirus containing <protein>mut-I kappa B</protein> than in FTOC infected with a control virus .


Taken together , these results suggest that NF-kappa B plays a crucial role in ensuring the differentiation and survival of thymocytes in the early stages of their development .

Taken together , these results suggest that <protein>NF-kappa B</protein> plays a crucial role in ensuring the differentiation and survival of <cell_type>thymocytes</cell_type> in the early stages of their development .


The relationship between Ca2+-ATPase and freely exchangeable Ca2+ in the dense tubules : a study in platelets from women .

The relationship between <protein>Ca2+-ATPase</protein> and freely exchangeable Ca2+ in the dense tubules : a study in <cell_type>platelets</cell_type> from women .


The main aims of this work were to examine in women : the relationship between the freely exchangeable Ca2+ ( FECa2+ ) in the dense tubules and the activity of the sarco ( endo ) plasmic reticulum ( SER ) Ca2+-ATPase ( SERCA ) in platelets , and the relationship of these parameters with blood pressure and serum lipoproteins .

The main aims of this work were to examine in women : the relationship between the freely exchangeable Ca2+ ( FECa2+ ) in the dense tubules and the activity of the <protein>sarco ( endo ) plasmic reticulum ( SER ) Ca2+-ATPase ( SERCA )</protein> in <cell_type>platelets</cell_type> , and the relationship of these parameters with blood pressure and <protein>serum lipoproteins</protein> .


Platelets from 14 white and 13 black women in good health were studied .


The FECa2+ was measured as the ionomycin-evoked Ca2+ release ( in the presence of thapsigargin ) in Ca2+-free medium .


SERCA activity was measured as the thapsigargin sensitive , Ca2+ dependent and ouabain resistant , ATP hydrolyses in platelet membranes .

<protein>SERCA</protein> activity was measured as the thapsigargin sensitive , Ca2+ dependent and ouabain resistant , ATP hydrolyses in platelet membranes .


Relative expressions of SERCA 2 and 3 isoforms and Ras-related protein ( Rap ) 1 in platelet membranes were determined by Western immunoblots .

Relative expressions of <protein>SERCA</protein> 2 and 3 isoforms and <protein>Ras-related protein ( Rap ) 1</protein> in platelet membranes were determined by Western immunoblots .


Highly significant correlations were observed for FECa2+ in the dense tubules with : 1 ) the maximal reaction velocity ( Vmax ) of the SERCA ( r = 0.592 , P = .0014 ) , and 2 ) Rapl ( r = 0.551 , P = .0035 ) .

Highly significant correlations were observed for FECa2+ in the dense tubules with : 1 ) the maximal reaction velocity ( Vmax ) of the <protein>SERCA</protein> ( r = 0.592 , P = .0014 ) , and 2 ) <protein>Rapl</protein> ( r = 0.551 , P = .0035 ) .


In addition , negative correlations were observed between FECa2+ in the dense tubules and age .


No correlations were observed for these variables with blood pressure or serum lipoproteins .

No correlations were observed for these variables with blood pressure or <protein>serum lipoproteins</protein> .


We conclude the FECa2+ and the Vmax of the SERCA are reliable indicators of Ca2+ load in platelets from women .

We conclude the FECa2+ and the Vmax of the <protein>SERCA</protein> are reliable indicators of Ca2+ load in <cell_type>platelets</cell_type> from women .


However , in women , unlike previous observations in men , these platelet parameters are not correlated with blood pressure and serum lipoproteins .

However , in women , unlike previous observations in men , these platelet parameters are not correlated with blood pressure and <protein>serum lipoproteins</protein> .


Cobalt chloride-induced signaling in endothelium leading to the augmented adherence of sickle red blood cells and transendothelial migration of monocyte-like HL-60 cells is blocked by PAF-receptor antagonist .

Cobalt chloride-induced signaling in endothelium leading to the augmented adherence of <cell_type>sickle red blood cells</cell_type> and transendothelial migration of <cell_line>monocyte-like HL-60 cells</cell_line> is blocked by PAF-receptor antagonist .


In response to hypoxia , sickle red blood cells ( SS RBC ) and leukocytes exhibit increased adherence to the vascular endothelium , while diapedesis of leukocytes through the blood vessel increases .

In response to hypoxia , <cell_type>sickle red blood cells</cell_type> ( <cell_type>SS RBC</cell_type> ) and <cell_type>leukocytes</cell_type> exhibit increased adherence to the vascular endothelium , while diapedesis of <cell_type>leukocytes</cell_type> through the blood vessel increases .


However , the cellular signaling pathway ( s ) caused by hypoxia is poorly understood .


We utilized CoCl2 as a mimetic molecule for hypoxia to study cellular signaling pathways .


We found that in human umbilical vein endothelial cells ( HUVEC ) , CoCl2 at 2 mM concentration induced the surface expression of a subset of CAMs ( VCAM-1 ) and activation of transcription factor NF-kappaB in the nuclear extracts of HUVEC .

We found that in <cell_type>human umbilical vein endothelial cells</cell_type> ( <cell_type>HUVEC</cell_type> ) , CoCl2 at 2 mM concentration induced the surface expression of a subset of <protein>CAMs</protein> ( <protein>VCAM-1</protein> ) and activation of <protein>transcription factor</protein> <protein>NF-kappaB</protein> in the nuclear extracts of <cell_type>HUVEC</cell_type> .


Furthermore , CoCl2 also caused time-dependent tyrosine phosphorylation of mitogen-activated protein ( MAP ) kinase isoform ERK2 without significantly affecting ERK1 , indicating ERK2 is the preferred substrate for upstream kinase of the MAPK pathway .

Furthermore , CoCl2 also caused time-dependent tyrosine phosphorylation of <protein>mitogen-activated protein ( MAP ) kinase</protein> isoform <protein>ERK2</protein> without significantly affecting <protein>ERK1</protein> , indicating <protein>ERK2</protein> is the preferred substrate for <protein>upstream kinase</protein> of the <protein>MAPK</protein> pathway .


Inhibitors of MAP kinase ( PD98059 ) or platelet-activating factor ( PAF ) - receptor antagonist ( CV3988 ) inhibited the CoCl2-induced NF-kappaB activation and VCAM-1 expression .

Inhibitors of <protein>MAP kinase</protein> ( PD98059 ) or platelet-activating factor ( PAF ) - receptor antagonist ( CV3988 ) inhibited the CoCl2-induced <protein>NF-kappaB</protein> activation and <protein>VCAM-1</protein> expression .


Augmented expression of VCAM-1 led to increased SS RBC adhesion , inhibitable by a VCAM-1 antibody .

Augmented expression of <protein>VCAM-1</protein> led to increased <cell_type>SS RBC</cell_type> adhesion , inhibitable by a <protein>VCAM-1 antibody</protein> .


Additionally , CoCl2 caused a two- to threefold increase in the rate of transendothelial migration of monocyte-like HL-60 cells and a twentyfold increase in phosphorylation of platelet endothelial cell adhesion molecules ( PECAM-1 ) .

Additionally , CoCl2 caused a two- to threefold increase in the rate of transendothelial migration of <cell_line>monocyte-like HL-60 cells</cell_line> and a twentyfold increase in phosphorylation of <protein>platelet endothelial cell adhesion molecules</protein> ( <protein>PECAM-1</protein> ) .


The transendothelial migration of monocytes was inhibited by an antibody to PECAM-1 .

The transendothelial migration of <cell_type>monocytes</cell_type> was inhibited by an antibody to <protein>PECAM-1</protein> .


Both phosphorylation of PECAM-1 and transendothelial migration of monocytes in response to CoCl2 were inhibited by protein kinase inhibitor ( GF109203X ) and augmented by protein phosphatase inhibitor ( Calyculin A ) .

Both phosphorylation of <protein>PECAM-1</protein> and transendothelial migration of <cell_type>monocytes</cell_type> in response to CoCl2 were inhibited by protein kinase inhibitor ( GF109203X ) and augmented by protein phosphatase inhibitor ( Calyculin A ) .


Our data suggests that CoCl2-induced cellular signals directing increased expression of VCAM-1 in HUVEC involve downstream activation of MAP kinase and NF-kappaB , while the phosphorylation of PECAM-1 occurs as a result of activation of PKC .

Our data suggests that CoCl2-induced cellular signals directing increased expression of <protein>VCAM-1</protein> in <cell_type>HUVEC</cell_type> involve downstream activation of <protein>MAP kinase</protein> and <protein>NF-kappaB</protein> , while the phosphorylation of <protein>PECAM-1</protein> occurs as a result of activation of <protein>PKC</protein> .


We conclude that PAF-receptor antagonist inhibits the CoCl2 -or hypoxia-induced increase in the adhesion of SS RBC , PECAM-1 phosphorylation , and the concomitant transendothelial migration of monocytes .

We conclude that PAF-receptor antagonist inhibits the CoCl2 -or hypoxia-induced increase in the adhesion of <cell_type>SS RBC</cell_type> , <protein>PECAM-1</protein> phosphorylation , and the concomitant transendothelial migration of <cell_type>monocytes</cell_type> .


Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes .

Bacterial lipopolysaccharide activates <protein>nuclear factor-kappaB</protein> through <protein>interleukin-1 signaling mediators</protein> in <cell_line>cultured human dermal endothelial cells</cell_line> and <cell_type>mononuclear phagocytes</cell_type> .


Bacterial lipopolysaccharide ( LPS ) -mediated immune responses , including activation of monocytes , macrophages , and endothelial cells , play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome .

Bacterial lipopolysaccharide ( LPS ) -mediated immune responses , including activation of <cell_type>monocytes</cell_type> , <cell_type>macrophages</cell_type> , and <cell_type>endothelial cells</cell_type> , play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome .


Activation of NF-kappaB is thought to be required for cytokine release from LPS-responsive cells , a critical step for endotoxic effects .

Activation of <protein>NF-kappaB</protein> is thought to be required for cytokine release from <cell_type>LPS-responsive cells</cell_type> , a critical step for endotoxic effects .


Here we investigated the role and involvement of interleukin-1 ( IL-1 ) and tumor necrosis factor ( TNF-alpha ) signal transducer molecules in LPS signaling in human dermal microvessel endothelial cells ( HDMEC ) and THP-1 monocytic cells .

Here we investigated the role and involvement of <protein>interleukin-1</protein> ( <protein>IL-1</protein> ) and <protein>tumor necrosis factor</protein> ( <protein>TNF-alpha</protein> ) <protein>signal transducer molecules</protein> in LPS signaling in <cell_type>human dermal microvessel endothelial cells</cell_type> ( <cell_type>HDMEC</cell_type> ) and <cell_line>THP-1 monocytic cells</cell_line> .


LPS stimulation of HDMEC and THP-1 cells initiated an IL-1 receptor -like NF-kappaB signaling cascade .

LPS stimulation of <cell_type>HDMEC</cell_type> and <cell_line>THP-1 cells</cell_line> initiated an <protein>IL-1 receptor</protein> -like <protein>NF-kappaB</protein> signaling cascade .


In transient cotransfection experiments , dominant negative mutants of the IL-1 signaling pathway , including MyD88 , IRAK , IRAK2 , and TRAF6 inhibited both IL-1 -and LPS-induced NF-kappaB -luciferase activity .

In transient cotransfection experiments , dominant negative mutants of the <protein>IL-1</protein> signaling pathway , including <protein>MyD88</protein> , <protein>IRAK</protein> , <protein>IRAK2</protein> , and <protein>TRAF6</protein> inhibited both <protein>IL-1</protein> -and LPS-induced <protein>NF-kappaB</protein> <protein>-luciferase</protein> activity .


LPS-induced NF-kappaB activation was not inhibited by a dominant negative mutant of TRAF2 that is involved in TNF signaling .

LPS-induced <protein>NF-kappaB</protein> activation was not inhibited by a dominant negative mutant of <protein>TRAF2</protein> that is involved in <protein>TNF</protein> signaling .


LPS-induced activation of NF-kappaB-responsive reporter gene was not inhibited by IL-1 receptor antagonist .

LPS-induced activation of <dna>NF-kappaB-responsive reporter gene</dna> was not inhibited by <protein>IL-1</protein> receptor antagonist .


TLR2 and TLR4 were expressed on the cell surface of HDMEC and THP-1 cells .

<protein>TLR2</protein> and <protein>TLR4</protein> were expressed on the cell surface of <cell_type>HDMEC</cell_type> and <cell_line>THP-1 cells</cell_line> .


These findings suggest that a signal transduction molecule in the LPS receptor complex may belong to the IL-1 receptor/toll-like receptor ( TLR ) super family , and the LPS signaling cascade uses an analogous molecular framework for signaling as IL-1 in mononuclear phagocytes and endothelial cells .

These findings suggest that a <protein>signal transduction molecule</protein> in the LPS receptor complex may belong to the <protein>IL-1</protein> receptor/toll-like receptor ( TLR ) super family , and the LPS signaling cascade uses an analogous molecular framework for signaling as <protein>IL-1</protein> in <cell_type>mononuclear phagocytes</cell_type> and <cell_type>endothelial cells</cell_type> .


Signal transduction through interferon-gamma receptor on human eosinophils .

Signal transduction through <protein>interferon-gamma receptor</protein> on <cell_type>human eosinophils</cell_type> .


BACKGROUND : We reported on the constitutive interferon-gamma receptor ( IFN-gammaR ) expression on eosinophils .

BACKGROUND : We reported on the constitutive <protein>interferon-gamma receptor</protein> ( <protein>IFN-gammaR</protein> ) expression on <cell_type>eosinophils</cell_type> .


But signal transduction through IFN-gammaR on eosinophils remains to be elucidated .

But signal transduction through <protein>IFN-gammaR</protein> on <cell_type>eosinophils</cell_type> remains to be elucidated .


In this study , we examined the involvement of the Jak/Stat pathway in the signaling of eosinophils after IFN-gammaR conjugation by the ligand binding .

In this study , we examined the involvement of the <protein>Jak/Stat</protein> pathway in the signaling of <cell_type>eosinophils</cell_type> after <protein>IFN-gammaR</protein> conjugation by the ligand binding .


METHODS : Purified peripheral eosinophils were stimulated with IFN-gamma at 37 degrees C for 1-60 min .

METHODS : <cell_type>Purified peripheral eosinophils</cell_type> were stimulated with <protein>IFN-gamma</protein> at 37 degrees C for 1-60 min .


Tyrosine phosphorylation of IFN-gammaR , Jak1 , Jak2 , and Stat1alpha was examined by immunoblotting .

Tyrosine phosphorylation of <protein>IFN-gammaR</protein> , <protein>Jak1</protein> , <protein>Jak2</protein> , and <protein>Stat1alpha</protein> was examined by immunoblotting .


Gel-shift assay was also examined to show the formation of Stat1alpha-DNA complexes .

Gel-shift assay was also examined to show the formation of <protein>Stat1alpha-DNA complexes</protein> .


RESULTS : We show that binding of IFN-gamma to human eosinophils initiated a series of events that resulted in the rapid tyrosine phosphorylation of not only the IFN-gammaRalpha chain but also Jak1 , Jak2 , and Stat1alpha .

RESULTS : We show that binding of <protein>IFN-gamma</protein> to <cell_type>human eosinophils</cell_type> initiated a series of events that resulted in the rapid tyrosine phosphorylation of not only the <protein>IFN-gammaRalpha chain</protein> but also <protein>Jak1</protein> , <protein>Jak2</protein> , and <protein>Stat1alpha</protein> .


In addition , IFN-gamma enhanced the DNA-binding activity of Stat1alpha .

In addition , <protein>IFN-gamma</protein> enhanced the DNA-binding activity of <protein>Stat1alpha</protein> .


CONCLUSION : These data indicate that IFN-gamma affects eosinophils through its specific receptor and utilizes the Jak/Stat pathway as its mode of signaling .

CONCLUSION : These data indicate that <protein>IFN-gamma</protein> affects <cell_type>eosinophils</cell_type> through its specific receptor and utilizes the <protein>Jak/Stat</protein> pathway as its mode of signaling .


Expression of E2A-HLF chimeric protein induced T-cell apoptosis , B-cell maturation arrest , and development of acute lymphoblastic leukemia .

Expression of <protein>E2A-HLF chimeric protein</protein> induced T-cell apoptosis , B-cell maturation arrest , and development of acute lymphoblastic leukemia .


The E2A-HLF fusion gene , generated by t ( 17 ; 19 ) ( q22 ; p13 ) in acute lymphoblastic leukemia ( ALL ) , encodes a chimeric transcription factor in which the trans-activating domains of E2A are fused to the DNA- binding and dimerization domains of hepatic leukemic factor ( HLF ) .

The <dna>E2A-HLF fusion gene</dna> , generated by <dna>t ( 17 ; 19 ) ( q22 ; p13 )</dna> in acute lymphoblastic leukemia ( ALL ) , encodes a <protein>chimeric transcription factor</protein> in which the <protein>trans-activating domains</protein> of <protein>E2A</protein> are fused to the <protein>DNA- binding and dimerization domains</protein> of <protein>hepatic leukemic factor</protein> ( <protein>HLF</protein> ) .


To investigate its biological role , we generated transgenic mice expressing E2A-HLF using Ig enhancer and promoter , which direct transgene expression in cells committed to the lymphoid lineage .

To investigate its biological role , we generated transgenic mice expressing <protein>E2A-HLF</protein> using <dna>Ig enhancer and promoter</dna> , which direct transgene expression in cells committed to the lymphoid lineage .


The transgenic mice exhibited abnormal development in the thymus and spleen and were susceptible to infection .


The thymus contained small numbers of thymocytes , and TUNEL staining showed that higher population of thymocytes were undergoing apoptosis .

The thymus contained small numbers of <cell_type>thymocytes</cell_type> , and TUNEL staining showed that higher population of <cell_type>thymocytes</cell_type> were undergoing apoptosis .


The spleen exhibited a marked reduction in splenic lymphocytes and the flow cytometric analyses and the in vitro colony formation assays showed that the B-cell maturation was blocked at a very early developmental stage .

The spleen exhibited a marked reduction in <cell_type>splenic lymphocytes</cell_type> and the flow cytometric analyses and the in vitro colony formation assays showed that the B-cell maturation was blocked at a very early developmental stage .


These findings indicated that the expression of E2A-HLF induced T-cell apoptosis and B-cell maturation arrest in vivo and that the susceptibility of the transgenic mice to infection was due to immunodeficiency .

These findings indicated that the expression of <protein>E2A-HLF</protein> induced T-cell apoptosis and B-cell maturation arrest in vivo and that the susceptibility of the transgenic mice to infection was due to immunodeficiency .


Moreover , several transgenic mice developed acute leukemia , classified as T-ALL based on the surface marker analysis and DNA rearrangements , suggesting that an additional event is required for malignant transformation of lymphoid cells expressing E2A-HLF .

Moreover , several transgenic mice developed acute leukemia , classified as T-ALL based on the surface marker analysis and DNA rearrangements , suggesting that an additional event is required for malignant transformation of <cell_type>lymphoid cells</cell_type> expressing <protein>E2A-HLF</protein> .


Our findings provide insight into the biological function of E2A-HLF in lymphoid development and also its role in leukemogenesis .

Our findings provide insight into the biological function of <protein>E2A-HLF</protein> in lymphoid development and also its role in leukemogenesis .


Retinoid X receptor ( RXR ) agonist-induced activation of dominant-negative RXR -retinoic acid receptor alpha403 heterodimers is developmentally regulated during myeloid differentiation .

<protein>Retinoid X receptor</protein> ( <protein>RXR</protein> ) agonist-induced activation of dominant-negative <protein>RXR</protein> -retinoic acid receptor alpha403 heterodimers is developmentally regulated during myeloid differentiation .


The multiple biologic activities of retinoic acid ( RA ) are mediated through RAR and retinoid X receptor ( RXR ) nuclear receptors that interact with specific DNA target sequences as heterodimers ( RXR-RAR ) or homodimers ( RXR-RXR ) .

The multiple biologic activities of retinoic acid ( RA ) are mediated through <protein>RAR</protein> and <protein>retinoid X receptor ( RXR ) nuclear receptors</protein> that interact with specific <dna>DNA target sequences</dna> as <protein>heterodimers</protein> ( <protein>RXR-RAR</protein> ) or <protein>homodimers</protein> ( <protein>RXR-RXR</protein> ) .


RA receptor activation appears critical to regulating important aspects of hematopoiesis , since transducing a COOH-terminally truncated RARalpha exhibiting dominant-negative activity ( RARalpha403 ) into normal mouse bone marrow generates hematopoietic growth factor-dependent cell lines frozen at the multipotent progenitor ( EML ) or committed promyelocyte ( MPRO ) stages .

RA receptor activation appears critical to regulating important aspects of hematopoiesis , since transducing a <protein>COOH-terminally truncated RARalpha</protein> exhibiting dominant-negative activity ( <protein>RARalpha403</protein> ) into normal mouse bone marrow generates <cell_line>hematopoietic growth factor-dependent cell lines</cell_line> frozen at the multipotent progenitor ( EML ) or committed promyelocyte ( MPRO ) stages .


Nevertheless , relatively high , pharmacological concentrations of RA ( 1 to 10 & mgr ; M ) overcome these differentiation blocks and induce terminal granulocytic differentiation of the MPRO promyelocytes while potentiating interleukin-3 ( IL-3 ) -induced commitment of EML cells to the granulocyte/monocyte lineage .

Nevertheless , relatively high , pharmacological concentrations of RA ( 1 to 10 & mgr ; M ) overcome these differentiation blocks and induce terminal granulocytic differentiation of the <cell_type>MPRO promyelocytes</cell_type> while potentiating <protein>interleukin-3</protein> ( <protein>IL-3</protein> ) -induced commitment of <cell_type>EML cells</cell_type> to the granulocyte/monocyte lineage .


In the present study , we utilized RXR -and RAR -specific agonists and antagonists to determine how RA overcomes the dominant-negative activity of the truncated RARalpha in these different myeloid developmental stages .

In the present study , we utilized <protein>RXR</protein> -and <protein>RAR</protein> -specific agonists and antagonists to determine how RA overcomes the dominant-negative activity of the <protein>truncated RARalpha</protein> in these different myeloid developmental stages .


Unexpectedly , we observed that an RXR -specific , rather than an RAR -specific , agonist induces terminal granulocytic differentiation of MPRO promyelocytes , and this differentiation is associated with activation of DNA response elements corresponding to RAR-RXR heterodimers rather than RXR-RXR homodimers .

Unexpectedly , we observed that an <protein>RXR</protein> -specific , rather than an <protein>RAR</protein> -specific , agonist induces terminal granulocytic differentiation of <cell_type>MPRO promyelocytes</cell_type> , and this differentiation is associated with activation of <dna>DNA response elements</dna> corresponding to <protein>RAR-RXR heterodimers</protein> rather than <protein>RXR-RXR homodimers</protein> .


This RXR agonist activity is blocked by RAR -specific antagonists , suggesting extensive cross-talk between the partners of the RXR -RARalpha403 heterodimer .

This <protein>RXR</protein> agonist activity is blocked by <protein>RAR</protein> -specific antagonists , suggesting extensive cross-talk between the partners of the <protein>RXR -RARalpha403 heterodimer</protein> .


In contrast , in the more immature , multipotent EML cells we observed that this RXR -specific agonist is inactive either in potentiating IL-3 -mediated commitment of EML cells to the granulocyte lineage or in transactivating RAR-RXR response elements .

In contrast , in the more immature , multipotent <cell_type>EML cells</cell_type> we observed that this <protein>RXR</protein> -specific agonist is inactive either in potentiating <protein>IL-3</protein> -mediated commitment of <cell_type>EML cells</cell_type> to the <cell_type>granulocyte lineage</cell_type> or in transactivating <dna>RAR-RXR response elements</dna> .


RA -triggered GALdbd- RARalpha hybrid activity in these cells indicates that the multipotent EML cells harbor substantial nuclear hormone receptor coactivator activity .

RA -triggered GALdbd- <protein>RARalpha</protein> hybrid activity in these cells indicates that the multipotent <cell_type>EML cells</cell_type> harbor substantial nuclear hormone receptor <protein>coactivator</protein> activity .


However , the histone deacetylase ( HDAC ) inhibitor trichostatin A readily activates an RXR-RAR reporter construct in the multipotent EML cells but not in the committed MPRO promyelocytes , indicating that differences in HDAC-containing repressor complexes in these two closely related but distinct hematopoietic lineages might account for the differential activation of the RXR-RARalpha403 heterodimers that we observed at these different stages of myeloid development .

However , the <protein>histone deacetylase ( HDAC ) inhibitor</protein> trichostatin A readily activates an <dna>RXR-RAR reporter construct</dna> in the multipotent <cell_type>EML cells</cell_type> but not in the committed <cell_type>MPRO promyelocytes</cell_type> , indicating that differences in <protein>HDAC-containing repressor complexes</protein> in these two closely related but distinct <cell_type>hematopoietic lineages</cell_type> might account for the differential activation of the <protein>RXR-RARalpha403 heterodimers</protein> that we observed at these different stages of myeloid development .


The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation .

The functional synergy between <protein>IL-12</protein> and <protein>IL-2</protein> involves <protein>p38 mitogen-activated protein kinase</protein> and is associated with the augmentation of STAT serine phosphorylation .


IL-12 and IL-2 can stimulate mitogen- or CD3-activated T cells to proliferate , produce IFN-gamma , and kill tumor cells .

<protein>IL-12</protein> and <protein>IL-2</protein> can stimulate <cell_type>mitogen- or CD3-activated T cells</cell_type> to proliferate , produce <protein>IFN-gamma</protein> , and kill <cell_type>tumor cells</cell_type> .


The magnitude of these functional responses is greatly augmented when T cells are activated by the combination of IL-12 and IL-2 .

The magnitude of these functional responses is greatly augmented when <cell_type>T cells</cell_type> are activated by the combination of <protein>IL-12</protein> and <protein>IL-2</protein> .


Although peripheral blood T cells are largely unresponsive to these cytokines without prior activation , a small subset of CD8+ T cells ( CD8+CD18bright ) is strongly activated by the combination of IL-12 and IL-2 .

Although peripheral blood <cell_type>T cells</cell_type> are largely unresponsive to these <protein>cytokines</protein> without prior activation , a small subset of <cell_type>CD8+ T cells</cell_type> ( <cell_type>CD8+CD18bright</cell_type> ) is strongly activated by the combination of <protein>IL-12</protein> and <protein>IL-2</protein> .


In this report we show that the functional synergy between IL-12 and IL-2 in CD8+CD18bright T cells correlates with the activation of the stress kinases , p38 mitogen-activated protein ( MAP ) kinase and stress-activated protein kinase ( SAPK ) /Jun N-terminal kinase , but not with the activation of the extracellular signal-regulated kinases .

In this report we show that the functional synergy between <protein>IL-12</protein> and <protein>IL-2</protein> in <cell_type>CD8+CD18bright T cells</cell_type> correlates with the activation of the <protein>stress kinases</protein> , <protein>p38 mitogen-activated protein ( MAP ) kinase</protein> and <protein>stress-activated protein kinase ( SAPK ) /Jun N-terminal kinase</protein> , but not with the activation of the <protein>extracellular signal-regulated kinases</protein> .


The functional synergy between IL-2 and IL-12 is also associated with a prominent increase in STAT1 and STAT3 serine phosphorylation over that observed with IL-12 or IL-2 alone .

The functional synergy between <protein>IL-2</protein> and <protein>IL-12</protein> is also associated with a prominent increase in <protein>STAT1</protein> and <protein>STAT3</protein> serine phosphorylation over that observed with <protein>IL-12</protein> or <protein>IL-2</protein> alone .


By contrast , STAT tyrosine phosphorylation is not augmented over that seen with either cytokine alone .

By contrast , <protein>STAT</protein> tyrosine phosphorylation is not augmented over that seen with either cytokine alone .


A specific inhibitor of p38 MAP kinase completely inhibits the serine phosphorylation of STAT1 and STAT3 induced by IL-12 and IL-2 and abrogates the functional synergy between IL-12 and IL-2 without affecting STAT tyrosine phosphorylation .

A specific inhibitor of p38 MAP kinase completely inhibits the serine phosphorylation of <protein>STAT1</protein> and <protein>STAT3</protein> induced by <protein>IL-12</protein> and <protein>IL-2</protein> and abrogates the functional synergy between <protein>IL-12</protein> and <protein>IL-2</protein> without affecting STAT tyrosine phosphorylation .


This suggests that p38 MAP kinase may play an important role in regulating STAT serine phosphorylation in response to the combination of IL-12 and IL-2 .

This suggests that p38 MAP kinase may play an important role in regulating STAT serine phosphorylation in response to the combination of <protein>IL-12</protein> and <protein>IL-2</protein> .


Furthermore , these findings indicate that the optimal activation of T cells by IL-12 and IL-2 may depend on an interaction between the p38 MAP kinase and Janus kinase/STAT signaling pathways .

Furthermore , these findings indicate that the optimal activation of <cell_type>T cells</cell_type> by <protein>IL-12</protein> and <protein>IL-2</protein> may depend on an interaction between the <protein>p38 MAP kinase</protein> and <protein>Janus kinase/STAT</protein> signaling pathways .


Activation of NF-kappaB in Mycobacterium tuberculosis -induced interleukin-2 receptor expression in mononuclear phagocytes .

Activation of <protein>NF-kappaB</protein> in Mycobacterium tuberculosis -induced <protein>interleukin-2 receptor</protein> expression in <cell_type>mononuclear phagocytes</cell_type> .


Soluble interleukin-2 receptor-alpha ( IL-2Ralpha ) has been reported to be increased in the sera of patients with advanced tuberculosis , and levels decline after therapy in accordance with improvement of radiologic findings .

Soluble <protein>interleukin-2 receptor-alpha</protein> ( <protein>IL-2Ralpha</protein> ) has been reported to be increased in the sera of patients with advanced tuberculosis , and levels decline after therapy in accordance with improvement of radiologic findings .


We investigated expression of the IL-2Ralpha in bronchoalveolar lavage ( BAL ) cells in active pulmonary tuberculosis , and evaluated the mechanism Mycobacterium tuberculosis induces in the IL-2Ralpha using the THP-1 mononuclear phagocyte cell line .

We investigated expression of the <protein>IL-2Ralpha</protein> in <cell_type>bronchoalveolar lavage ( BAL ) cells</cell_type> in active pulmonary tuberculosis , and evaluated the mechanism Mycobacterium tuberculosis induces in the <protein>IL-2Ralpha</protein> using the <cell_line>THP-1 mononuclear phagocyte cell line</cell_line> .


We found IL-2Ralpha expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis .

We found <protein>IL-2Ralpha</protein> expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis .


Expression of the alpha-chain of IL-2Ralpha on peripheral blood monocytes ( PBM ) was induced by M. tuberculosis by flow cytometry evaluation .

Expression of the <protein>alpha-chain</protein> of <protein>IL-2Ralpha</protein> on <cell_type>peripheral blood monocytes</cell_type> ( <cell_type>PBM</cell_type> ) was induced by M. tuberculosis by flow cytometry evaluation .


Northern analysis demonstrated increased IL-2Ralpha gene expression after stimulation with M. tuberculosis which was further induced by interferon-gamma ( IFN-gamma ) .

Northern analysis demonstrated increased <protein>IL-2Ralpha</protein> gene expression after stimulation with M. tuberculosis which was further induced by <protein>interferon-gamma</protein> ( <protein>IFN-gamma</protein> ) .


The IL-2Ralpha promoter containing the nuclear factor kappa B ( NF-kappaB ) site was transcriptionally induced by M. tuberculosis and this NF-kappaB site could confer inducibility to a heterologous herpes thymidine kinase ( TK ) promoter by M. tuberculosis .

The <dna>IL-2Ralpha promoter</dna> containing the <dna>nuclear factor kappa B ( NF-kappaB ) site</dna> was transcriptionally induced by M. tuberculosis and this <protein>NF-kappaB</protein> site could confer inducibility to a <dna>heterologous herpes thymidine kinase ( TK ) promoter</dna> by M. tuberculosis .


Electrophoretic mobility shift assays ( EMSAs ) revealed specific binding of nuclear protein to the NF-kappaB site upon induction with M. tuberculosis .

Electrophoretic mobility shift assays ( EMSAs ) revealed specific binding of nuclear protein to the <dna>NF-kappaB site</dna> upon induction with M. tuberculosis .


Using antibodies against the p50 and p65 subunits of NF-kappaB in EMSAs , the involvement of both p50 and p65 proteins was further demonstrated .

Using antibodies against the <protein>p50</protein> and <protein>p65 subunits</protein> of <protein>NF-kappaB</protein> in EMSAs , the involvement of both <protein>p50</protein> and <protein>p65 proteins</protein> was further demonstrated .


Functional expression of the IL-2Ralpha on mononuclear phagocytes in M. tuberculosis infection may play an important immunomodulatory role in the host response .

Functional expression of the <protein>IL-2Ralpha</protein> on <cell_type>mononuclear phagocytes</cell_type> in M. tuberculosis infection may play an important immunomodulatory role in the host response .


Vitamin D receptor 3'-untranslated region polymorphisms : lack of effect on mRNA stability .

<protein>Vitamin D receptor</protein> <dna>3'-untranslated region</dna> polymorphisms : lack of effect on mRNA stability .


Allelic variation at the 3'-end of the vitamin D receptor ( VDR ) gene has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization .

Allelic variation at the 3'-end of the <dna>vitamin D receptor ( VDR ) gene</dna> has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization .


This genetic diversity does not alter the VDR protein structurally , but instead may be a marker ( s ) of other , nearby polymorphisms that influence message stability or translation .

This genetic diversity does not alter the <protein>VDR protein</protein> structurally , but instead may be a marker ( s ) of other , nearby polymorphisms that influence message stability or translation .


The work reported here was instigated to identify additional VDR 3'-UTR polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability .

The work reported here was instigated to identify additional <protein>VDR</protein> <dna>3'-UTR</dna> polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability .


Initially , four novel , frequently occurring sequence variants were identified that associated with two common haplotypes that were described previously .

Initially , four novel , frequently occurring <dna>sequence variants</dna> were identified that associated with two common haplotypes that were described previously .


These common sequence variants were not found within three message-destabilizing elements that we mapped within the 3'-UTR of the vitamin D receptor mRNA .

These common sequence variants were not found within three <dna>message-destabilizing elements</dna> that we mapped within the <dna>3'-UTR</dna> of the <rna>vitamin D receptor mRNA</rna> .


Furthermore , the two VDR 3'-UTR haplotypes conferred an identical half-life on a heterologous beta-globin reporter gene , in an in vitro assay .

Furthermore , the two <dna>VDR 3'-UTR</dna> haplotypes conferred an identical half-life on a <dna>heterologous beta-globin reporter gene</dna> , in an in vitro assay .


We therefore conclude that common polymorphisms within the VDR 3'-UTR do not influence message stability .

We therefore conclude that common polymorphisms within the <dna>VDR 3'-UTR</dna> do not influence message stability .


IL-2 -mediated cell cycle progression and inhibition of apoptosis does not require NF-kappa B or activating protein-1 activation in primary human T cells .

<protein>IL-2</protein> -mediated cell cycle progression and inhibition of apoptosis does not require <protein>NF-kappa B</protein> or activating protein-1 activation in primary human T cells .


The IL-2 growth hormone is the major growth factor of activated T lymphocytes during a developing immune response .

The <protein>IL-2</protein> growth hormone is the major growth factor of activated <cell_type>T lymphocytes</cell_type> during a developing immune response .


IL-2 is required not only for cell cycle progression but also to protect Ag-activated T cells from programmed cell death .

<protein>IL-2</protein> is required not only for cell cycle progression but also to protect <cell_type>Ag-activated T cells</cell_type> from programmed cell death .


In several cell types , activation of NF-kappa B and/or activating protein-1 ( AP-1 ) has been demonstrated to be extremely important in blocking apoptosis .

In several cell types , activation of <protein>NF-kappa B</protein> and/or <protein>activating protein-1</protein> ( <protein>AP-1</protein> ) has been demonstrated to be extremely important in blocking apoptosis .


To determine whether either or both of these transcription factors are involved in cell survival or cell cycle progression in response to IL-2 , primary human T cells responsive to the growth factor were analyzed for NF-kappa B and AP-1 activation .

To determine whether either or both of these <protein>transcription factors</protein> are involved in cell survival or cell cycle progression in response to <protein>IL-2</protein> , <cell_type>primary human T cells</cell_type> responsive to the growth factor were analyzed for NF-kappa B and AP-1 activation .


The current study clearly demonstrates that IL-2 does not induce I kappa B alpha degradation or NF-kappa B activation in primary human T cells that respond to IL-2 by entering the cell cycle and avoiding apoptosis .

The current study clearly demonstrates that <protein>IL-2</protein> does not induce <protein>I kappa B</protein> alpha degradation or <protein>NF-kappa B</protein> activation in <cell_type>primary human T cells</cell_type> that respond to <protein>IL-2</protein> by entering the cell cycle and avoiding apoptosis .


Similarly , IL-2 neither activates JNK nor increases AP-1 binding activity to a consensus o-tetradecanoylphorbol 13-acetate ( TPA ) response element .

Similarly , <protein>IL-2</protein> neither activates <protein>JNK</protein> nor increases <protein>AP-1</protein> binding activity to a consensus <dna>o-tetradecanoylphorbol 13-acetate ( TPA ) response element</dna> .


On the other hand , the growth factor does induce the activation of STAT3 and STAT5 in these cells , as has been previously demonstrated .

On the other hand , the <protein>growth factor</protein> does induce the activation of <protein>STAT3</protein> and <protein>STAT5</protein> in these cells , as has been previously demonstrated .


These data show that neither NF-kappa B nor AP-1 activation is required for IL-2 -mediated survival or cell cycle progression in activated primary human T cells .

These data show that neither <protein>NF-kappa B</protein> nor <protein>AP-1</protein> activation is required for <protein>IL-2</protein> -mediated survival or cell cycle progression in activated <cell_type>primary human T cells</cell_type> .


Estrone potentiates myeloid cell differentiation : a role for 17 beta-hydroxysteroid dehydrogenase in modulating hemopoiesis .

Estrone potentiates myeloid cell differentiation : a role for <protein>17 beta-hydroxysteroid dehydrogenase</protein> in modulating hemopoiesis .


Hormones such as 1 alpha , 25-dihydroxy vitamin D3 ( D3 ) , all-trans retinoic acid , and 9-cis retinoic acid stimulate differentiation of myeloid progenitor cells via their interaction with specific hormone receptors .

Hormones such as 1 alpha , 25-dihydroxy vitamin D3 ( D3 ) , all-trans retinoic acid , and 9-cis retinoic acid stimulate differentiation of <cell_type>myeloid progenitor cells</cell_type> via their interaction with specific <protein>hormone receptors</protein> .


However , the sensitivity of cells to these agents is not merely governed by the expression of their receptors and the availability of ligand to bind them .


Recent studies from our group suggested that the actions of D3 and retinoids on myelopoiesis also are influenced by endogenous mechanisms involving other steroid hormones .


In this study we examined the influence of local estrogen metabolism on the differentiation of HL60 cells and normal primitive myeloid progenitor cells .

In this study we examined the influence of local estrogen metabolism on the differentiation of <cell_line>HL60 cells</cell_line> and normal primitive <cell_type>myeloid progenitor cells</cell_type> .


Quantitative thin-layer chromatography ( TLC ) analyses showed that HL60 and normal cells are able to generate estrone ( E1 ) from estradiol ( E2 ) .

Quantitative thin-layer chromatography ( TLC ) analyses showed that <cell_line>HL60</cell_line> and <cell_type>normal cells</cell_type> are able to generate estrone ( E1 ) from estradiol ( E2 ) .


Neither cell population generated significant amounts of E2 from E1 .


Reverse transcriptase polymerase chain reaction and Northern analyses confirmed that normal and leukemic myeloid progenitor cells expressed mRNA for the type I and IV isoforms of 17 beta-hydroxysteroid dehydrogenase .

Reverse transcriptase polymerase chain reaction and Northern analyses confirmed that normal and leukemic <cell_type>myeloid progenitor cells</cell_type> expressed <rna>mRNA</rna> for the type I and IV isoforms of <protein>17 beta-hydroxysteroid dehydrogenase</protein> .


Conversion of E2 to E1 was upregulated within 24 hours when HL60 cells were treated with either all-trans retinoic acid or D3 at doses that induce their differentiation toward neutrophils or monocytes , respectively .

Conversion of E2 to E1 was upregulated within 24 hours when <cell_line>HL60 cells</cell_line> were treated with either all-trans retinoic acid or D3 at doses that induce their differentiation toward <cell_type>neutrophils</cell_type> or <cell_type>monocytes</cell_type> , respectively .


Similarly , D3-induced monocyte differentiation of normal myeloid progenitor cells was associated with increased capacity to generate E1 from E2 .

Similarly , D3-induced monocyte differentiation of normal <cell_type>myeloid progenitor cells</cell_type> was associated with increased capacity to generate E1 from E2 .


When HL60 cells or normal myeloid progenitor cells were exposed to exogenous E1 they became more sensitive to the differentiation-inducing effects of D3 .

When <cell_line>HL60 cells</cell_line> or normal <cell_type>myeloid progenitor cells</cell_type> were exposed to exogenous E1 they became more sensitive to the differentiation-inducing effects of D3 .


Data presented provide further evidence for the local modulation of myelopoiesis by intracrine mechanisms .


In particular , our findings suggest that local metabolism of steroids by normal as well as leukemic myeloid cells influences their responsiveness to D3 and retinoids .

In particular , our findings suggest that local metabolism of steroids by normal as well as <cell_type>leukemic myeloid cells</cell_type> influences their responsiveness to D3 and retinoids .


Phosphorylation of TRAF2 inhibits binding to the CD40 cytoplasmic domain .

Phosphorylation of <protein>TRAF2</protein> inhibits binding to the <protein>CD40 cytoplasmic domain</protein> .


TRAF2 is a signal transducing adaptor molecule which binds to the CD40 cytoplasmic domain .

<protein>TRAF2</protein> is a <protein>signal transducing adaptor molecule</protein> which binds to the <protein>CD40 cytoplasmic domain</protein> .


We have found that it is phosphorylated , predominantly on serine residues , when transiently overexpressed in 293 cells .

We have found that it is phosphorylated , predominantly on serine residues , when transiently overexpressed in <cell_line>293 cells</cell_line> .


The phosphorylation appears to be related to the signaling events that are activated by TRAF2 under these circumstances , since two nonfunctional mutants were found to be phosphorylated significantly less than the wild-type protein .

The phosphorylation appears to be related to the signaling events that are activated by <protein>TRAF2</protein> under these circumstances , since two nonfunctional mutants were found to be phosphorylated significantly less than the <protein>wild-type protein</protein> .


Furthermore , the phosphorylation status of TRAF2 had significant effects on the ability of the protein to bind to CD40 , as evidenced by our observations that the CD40 cytoplasmic domain interacted preferentially with underphosphorylated TRAF2 and that phosphatase treatment significantly enhanced the binding of TRAF2 to CD40 .

Furthermore , the phosphorylation status of <protein>TRAF2</protein> had significant effects on the ability of the protein to bind to <protein>CD40</protein> , as evidenced by our observations that the <protein>CD40 cytoplasmic domain</protein> interacted preferentially with underphosphorylated <protein>TRAF2</protein> and that <protein>phosphatase</protein> treatment significantly enhanced the binding of <protein>TRAF2</protein> to <protein>CD40</protein> .


We conclude from these studies that the phosphorylation of TRAF2 is likely to play an important role in regulating signaling by virtue of its ability to influence the CD40 -TRAF2 interaction .

We conclude from these studies that the phosphorylation of <protein>TRAF2</protein> is likely to play an important role in regulating signaling by virtue of its ability to influence the <protein>CD40</protein> <protein>-TRAF2</protein> interaction .


Copyright 1999 Academic Press .


A direct interaction between the adaptor protein Cbl-b and the kinase zap-70 induces a positive signal in T cells .

A direct interaction between the <protein>adaptor protein</protein> <protein>Cbl-b</protein> and the <protein>kinase</protein> <protein>zap-70</protein> induces a positive signal in <cell_type>T cells</cell_type> .


Engagement of the T-cell receptor ( TCR ) -CD3 complex induces a rapid increase in the activities of Src-family and Syk/Zap-70-family kinases [ 1 ] [ 2 ] .

Engagement of the <protein>T-cell receptor ( TCR ) -CD3 complex</protein> induces a rapid increase in the activities of <protein>Src-family</protein> and <protein>Syk/Zap-70-family kinases</protein> [ 1 ] [ 2 ] .


These activated kinases then induce the tyrosine phosphorylation of multiple intracellular proteins , eventually leading to T-cell activation .

These <protein>activated kinases</protein> then induce the tyrosine phosphorylation of <protein>multiple intracellular proteins</protein> , eventually leading to T-cell activation .


One of the prominent substrates for these kinases is the adaptor protein Cbl [ 3 ] and recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70 [ 4 ] [ 5 ] .

One of the prominent substrates for these <protein>kinases</protein> is the <protein>adaptor protein</protein> Cbl [ 3 ] and recent studies suggest that <protein>Cbl</protein> negatively regulates <protein>upstream kinases</protein> such as <protein>Syk</protein> and <protein>Zap-70</protein> [ 4 ] [ 5 ] .


Cbl-b , a homologue of Cbl , is widely expressed in many tissues and cells including hematopoietic cells [ 6 ] [ 7 ] .

<protein>Cbl-b</protein> , a homologue of <protein>Cbl</protein> , is widely expressed in many tissues and cells including <cell_type>hematopoietic cells</cell_type> [ 6 ] [ 7 ] .


Cbl-b undergoes rapid tyrosine phosphorylation upon stimulation of the TCR and cytokine receptors [ 8 ] [ 9 ] .

<protein>Cbl-b</protein> undergoes rapid tyrosine phosphorylation upon stimulation of the <protein>TCR</protein> and cytokine receptors [ 8 ] [ 9 ] .


The role of Cbl-b is unclear , however .

The role of <protein>Cbl-b</protein> is unclear , however .


Here , we show that overexpression of Cbl-b in T cells induced the constitutive activation of the transcription factor nuclear factor of activated T cells ( NFAT ) .

Here , we show that overexpression of <protein>Cbl-b</protein> in <cell_type>T cells</cell_type> induced the constitutive activation of the <protein>transcription factor nuclear factor of activated T cells</protein> ( <protein>NFAT</protein> ) .


A loss-of-function mutation in Cbl-b disrupted the interaction between Cbl-b and Zap-70 and nearly completely abrogated the Cbl-b -mediated activation of NFAT .

A loss-of-function mutation in <protein>Cbl-b</protein> disrupted the interaction between <protein>Cbl-b</protein> and <protein>Zap-70</protein> and nearly completely abrogated the <protein>Cbl-b</protein> -mediated activation of <protein>NFAT</protein> .


Unlike the proposed role of Cbl as a negative regulator , our results suggest that the Cbl homologue Cbl-b has a positive role in T-cell signaling , most likely via a direct interaction with the upstream kinase Zap-70 .

Unlike the proposed role of <protein>Cbl</protein> as a negative regulator , our results suggest that the <protein>Cbl</protein> homologue <protein>Cbl-b</protein> has a positive role in T-cell signaling , most likely via a direct interaction with the <protein>upstream kinase</protein> <protein>Zap-70</protein> .


Grf40 , A novel Grb2 family member , is involved in T cell signaling through interaction with SLP-76 and LAT .

<protein>Grf40</protein> , A novel <protein>Grb2 family member</protein> , is involved in T cell signaling through interaction with <protein>SLP-76</protein> and <protein>LAT</protein> .


We molecularly cloned a new Grb2 family member , named Grf40 , containing the common SH3-SH2-SH3 motif .

We molecularly cloned a new <protein>Grb2 family member</protein> , named <protein>Grf40</protein> , containing the common <protein>SH3-SH2-SH3 motif</protein> .


Expression of Grf40 is predominant in hematopoietic cells , particularly T cells .

Expression of <protein>Grf40</protein> is predominant in <cell_type>hematopoietic cells</cell_type> , particularly <cell_type>T cells</cell_type> .


Grf40 binds to the SH2 domain-containing leukocyte protein of 76 kD ( SLP-76 ) via its SH3 domain more tightly than Grb2 .

<protein>Grf40</protein> binds to the <protein>SH2 domain-containing leukocyte protein</protein> of 76 kD ( <protein>SLP-76</protein> ) via its SH3 domain more tightly than <protein>Grb2</protein> .


Incidentally , Grf40 binds to linker for activation of T cells ( LAT ) possibly via its SH2 domain .

Incidentally , <protein>Grf40</protein> binds to <protein>linker for activation of T cells</protein> ( <protein>LAT</protein> ) possibly via its <protein>SH2 domain</protein> .


Overexpression of wild-type Grf40 in Jurkat cells induced a significant increase of SLP-76-dependent interleukin ( IL ) -2 promoter and nuclear factor of activated T cell ( NF-AT ) activation upon T cell receptor ( TCR ) stimulation , whereas the COOH-terminal SH3-deleted Grf40 mutant lacked any recognizable increase in IL-2 promoter activity .

Overexpression of <protein>wild-type Grf40</protein> in <cell_line>Jurkat cells</cell_line> induced a significant increase of <dna>SLP-76-dependent interleukin ( IL ) -2 promoter</dna> and <protein>nuclear factor of activated T cell</protein> ( <protein>NF-AT</protein> ) activation upon <protein>T cell receptor</protein> ( <protein>TCR</protein> ) stimulation , whereas the <protein>COOH-terminal SH3-deleted Grf40 mutant</protein> lacked any recognizable increase in <dna>IL-2 promoter</dna> activity .


Furthermore , the SH2-deleted Grf40 mutant led to a marked inhibition of these regulatory activities , the effect of which is apparently stronger than that of the SH2-deleted Grb2 mutant .

Furthermore , the <protein>SH2-deleted Grf40 mutant</protein> led to a marked inhibition of these regulatory activities , the effect of which is apparently stronger than that of the <protein>SH2-deleted Grb2 mutant</protein> .


Our data suggest that Grf40 is an adaptor molecule involved in TCR -mediated signaling through a more efficient interaction than Grb2 with SLP-76 and LAT .

Our data suggest that <protein>Grf40</protein> is an <protein>adaptor molecule</protein> involved in <protein>TCR</protein> -mediated signaling through a more efficient interaction than <protein>Grb2</protein> with <protein>SLP-76</protein> and <protein>LAT</protein> .


Modulation of the immune response and tumor growth by activated Ras .

Modulation of the immune response and tumor growth by activated <protein>Ras</protein> .


As a result of its transforming abilities , activated Ras is expressed in a great number of cancers .

As a result of its transforming abilities , <protein>activated Ras</protein> is expressed in a great number of cancers .


The ras mutation frequency varies between 95 % in pancreatic cancer and 5 % in breast cancer .


In leukemia , the highest frequency ( 30 % ) is found in acute myeloid leukemia .


The presence of ras mutations has been correlated with a poor prognosis and negative clinical outcome .


This suggests that mutated Ras activates mechanisms , which favor tumor growth , enhance the metastatic capacity of tumors or modulate tumor-specific immune responses .

This suggests that <protein>mutated Ras</protein> activates mechanisms , which favor tumor growth , enhance the metastatic capacity of tumors or modulate tumor-specific immune responses .


Several new functions of Ras , such as downregulation of major histocompatibility complex molecules , upregulation of certain cytokines , growth factors and degradative enzymes have been uncovered in the last decade .

Several new functions of <protein>Ras</protein> , such as downregulation of <protein>major histocompatibility complex molecules</protein> , upregulation of certain <protein>cytokines</protein> , <protein>growth factors</protein> and <protein>degradative enzymes</protein> have been uncovered in the last decade .


Additionally , mutated Ras can also serve as a primary target for the development of immunotherapy or drug therapy .

Additionally , <protein>mutated Ras</protein> can also serve as a primary target for the development of immunotherapy or drug therapy .


This review will discuss the mechanisms by which Ras expressing tumors are able to evade destruction by the immune system and enhance their growth and metastatic potential .

This review will discuss the mechanisms by which <protein>Ras</protein> expressing tumors are able to evade destruction by the immune system and enhance their growth and metastatic potential .


It will further elaborate on the attempts to develop successful immunotherapy and drug therapy targeting Ras expressing tumors .

It will further elaborate on the attempts to develop successful immunotherapy and drug therapy targeting <protein>Ras</protein> expressing tumors .


Modulation of E2F complexes during G0 to S phase transition in human primary B-lymphocytes .

Modulation of <protein>E2F complexes</protein> during G0 to S phase transition in <cell_type>human primary B-lymphocytes</cell_type> .


The pocket protein-E2F complexes are convergence points for cell cycle signaling .

The <protein>pocket protein-E2F complexes</protein> are convergence points for cell cycle signaling .


In the present report , we identified and monitored the pocket protein-E2F complexes in human primary B-lymphocytes after activation by phorbol 12-myristate 13-acetate .

In the present report , we identified and monitored the <protein>pocket protein-E2F complexes</protein> in <cell_type>human primary B-lymphocytes</cell_type> after activation by phorbol 12-myristate 13-acetate .


Consistent with previous data from human and mouse fibroblasts and T-lymphocytes , E2F4 and DP1 form the predominant E2F heterodimers both in G0 and G1 phases of the human B-lymphocyte cell cycle , whereas E2F1 and -3 are first detected in late G1 , and their expression levels increase towards S phase .

Consistent with previous data from <cell_type>human and mouse fibroblasts</cell_type> and <cell_type>T-lymphocytes</cell_type> , <protein>E2F4</protein> and <protein>DP1</protein> form the predominant <protein>E2F heterodimers</protein> both in G0 and G1 phases of the human B-lymphocyte cell cycle , whereas <protein>E2F1 and -3</protein> are first detected in late G1 , and their expression levels increase towards S phase .


Intriguingly , the major E2F complex that we detected in quiescent human B-lymphocytes is consisted of pRB , E2F4 , and DP1 .

Intriguingly , the <protein>major E2F complex</protein> that we detected in <cell_type>quiescent human B-lymphocytes</cell_type> is consisted of <protein>pRB</protein> , <protein>E2F4</protein> , and <protein>DP1</protein> .


Though the levels of DP1 and -2 increase when cells progress from G0 to S , the proportion of DP1 to DP2 remains relatively constant during the cell cycle .

Though the levels of <protein>DP1 and -2</protein> increase when cells progress from G0 to S , the proportion of <protein>DP1</protein> to <protein>DP2</protein> remains relatively constant during the cell cycle .


We also observed an increase in electrophoretic mobility of the predominant E2F components , DP1 and E2F4 , as B-lymphocytes progressed from G0 into early G1 .

We also observed an increase in electrophoretic mobility of the predominant <protein>E2F components</protein> , <protein>DP1</protein> and <protein>E2F4</protein> , as <cell_type>B-lymphocytes</cell_type> progressed from G0 into early G1 .


This increase in mobility was attributable to dephosphorylation , as lambda phosphatase treatment could convert the slower migrating forms into the corresponding faster mobility forms .

This increase in mobility was attributable to dephosphorylation , as lambda phosphatase treatment could convert the <protein>slower migrating forms</protein> into the <protein>corresponding faster mobility forms</protein> .


We further demonstrated that this change in phosphorylation status correlates with a decrease in DNA binding activity .


This modulation of DNA binding activity mediated through the dephosphorylation of DP1 and E2F4 could help to explain the lack of in vivo DNA footprinting in late G1 and S phases of gene promoters negatively regulated through E2F sites and suggests a novel mechanism for controlling E2F transcriptional activity during the transition from quiescence to proliferation .

This modulation of DNA binding activity mediated through the dephosphorylation of <protein>DP1</protein> and <protein>E2F4</protein> could help to explain the lack of in vivo DNA footprinting in late G1 and S phases of <dna>gene promoters</dna> negatively regulated through <dna>E2F sites</dna> and suggests a novel mechanism for controlling <protein>E2F</protein> transcriptional activity during the transition from quiescence to proliferation .


Engagement of natural cytotoxicity programs regulates AP-1 expression in the NKL human NK cell line .

Engagement of natural cytotoxicity programs regulates <protein>AP-1</protein> expression in the <cell_line>NKL human NK cell line</cell_line> .


NK cell cytotoxicity is a fast and efficient mechanism of target cell lysis .


Using transcription analysis , such as multiplex messenger assays , we show here that natural cytotoxicity exerted by the human NKL cell line correlates with mRNA accumulation of very early activator protein ( AP ) -1 transcription factor genes such as JunB , FosB and c-Fos .

Using transcription analysis , such as multiplex messenger assays , we show here that natural cytotoxicity exerted by the <cell_line>human NKL cell line</cell_line> correlates with mRNA accumulation of <protein>very early activator protein ( AP ) -1</protein> <dna>transcription factor genes</dna> such as <dna>JunB</dna> , <dna>FosB</dna> and <dna>c-Fos</dna> .


In addition , DNA-binding activities of Jun-Fos heterodimers were observed by electrophoretic mobility shift assays during the course of natural cytotoxicity .

In addition , DNA-binding activities of <protein>Jun-Fos heterodimers</protein> were observed by electrophoretic mobility shift assays during the course of natural cytotoxicity .


Interaction between immunoglobulin-like transcript-2/leukocyte Ig-like receptor 1 on NKL cells and HLA-B27 on target cells leads to an impairment of NKL natural cytotoxicity , which correlates with an absence of JunB , FosB , and c-Fos transcription , as well as an absence of their DNA-binding activity .

Interaction between <protein>immunoglobulin-like transcript-2/leukocyte Ig-like receptor 1</protein> on <cell_type>NKL cells</cell_type> and <protein>HLA-B27</protein> on <cell_type>target cells</cell_type> leads to an impairment of NKL natural cytotoxicity , which correlates with an absence of JunB , FosB , and c-Fos transcription , as well as an absence of their DNA-binding activity .


Our studies thus indicate that , despite the rapidity of NK cell-mediated lysis , AP-1 transcription factor is activated during the early stage of NK cell cytolytic programs and that engagement of NK cell inhibitory receptors for MHC class I molecules impairs the very early activation of AP-1 .

Our studies thus indicate that , despite the rapidity of NK cell-mediated lysis , <protein>AP-1 transcription factor</protein> is activated during the early stage of NK cell cytolytic programs and that engagement of <protein>NK cell inhibitory receptors</protein> for <protein>MHC class I molecules</protein> impairs the very early activation of <protein>AP-1</protein> .


Evidence for a polyclonal etiology of palmar fibromatosis .


X chromosome inactivation patterns at the androgen receptor locus were evaluated to determine clonality in microdissected lesional tissue and in leukocytes from 2 women with Dupuytren 's disease .

<dna>X chromosome</dna> inactivation patterns at the androgen receptor locus were evaluated to determine clonality in microdissected lesional tissue and in <cell_type>leukocytes</cell_type> from 2 women with Dupuytren 's disease .


The tissue from both patients generated a polyclonal pattern of X chromosome inactivation of the human androgen receptor gene .

The tissue from both patients generated a polyclonal pattern of <dna>X chromosome</dna> inactivation of the <dna>human androgen receptor gene</dna> .


This finding supports a polyclonal reactive process as the underlying etiology for palmar fibromatosis .


Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate , triflusal , and its deacetylated metabolite , 2-hydroxy-4-trifluoromethylbenzoic acid .

Inhibition of <protein>cyclooxygenase-2</protein> expression by 4-trifluoromethyl derivatives of salicylate , triflusal , and its deacetylated metabolite , 2-hydroxy-4-trifluoromethylbenzoic acid .


The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized .

The therapeutic potential of drugs that block the induction of <protein>cyclooxygenase-2</protein> has been emphasized .


When two 4-trifluoromethyl salicylate derivatives [ 2-acetoxy-4-trifluoromethyl-benzoic acid ( triflusal ) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid ( HTB ) ] were compared with aspirin and sodium salicylate as cyclooxygenase-2 ( COX-2 ) inhibitors , we observed that in bacterial lipopolysaccharide-activated human blood , triflusal , aspirin , and HTB , but not sodium salicylate , inhibited COX-2-mediated prostaglandin E2 ( PGE2 ) production ( IC50 = 0.16 , 0.18 , 0.39 , and > 10 mM , respectively ) .

When two 4-trifluoromethyl salicylate derivatives [ 2-acetoxy-4-trifluoromethyl-benzoic acid ( triflusal ) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid ( HTB ) ] were compared with aspirin and sodium salicylate as <protein>cyclooxygenase-2</protein> ( COX-2 ) inhibitors , we observed that in bacterial lipopolysaccharide-activated human blood , triflusal , aspirin , and HTB , but not sodium salicylate , inhibited COX-2-mediated prostaglandin E2 ( PGE2 ) production ( IC50 = 0.16 , 0.18 , 0.39 , and > 10 mM , respectively ) .


However , only triflusal and aspirin inhibited purified COX-2 enzyme .

However , only triflusal and aspirin inhibited <protein>purified COX-2 enzyme</protein> .


To test this apparent discrepancy , we realized that HTB and triflusal ( but neither aspirin nor salicylate ) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells .

To test this apparent discrepancy , we realized that HTB and triflusal ( but neither aspirin nor salicylate ) produced a concentration-dependent inhibition of <protein>COX-2</protein> protein expression in <cell_type>peripheral human mononuclear cells</cell_type> .


This observation was further confirmed in a rat air pouch model in vivo , in which both aspirin and triflusal inhibited PGE2 production ( ID50 = 18.9 and 11.4 mg/kg p.o. , respectively ) but only triflusal-treated animals showed a decrease in COX-2 expression .

This observation was further confirmed in a rat air pouch model in vivo , in which both aspirin and triflusal inhibited PGE2 production ( ID50 = 18.9 and 11.4 mg/kg p.o. , respectively ) but only triflusal-treated animals showed a decrease in <protein>COX-2</protein> expression .


This different behavior may be , at least in part , due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate .

This different behavior may be , at least in part , due to the ability of HTB and triflusal to block the activation of the transcription factor <protein>nuclear factor-kappaB</protein> to a higher extent than aspirin and sodium salicylate .


Thus , in addition to inhibiting the COX-2 activity at therapeutic concentrations , triflusal is able to block through its metabolite HTB the expression of new enzyme , and hence the resumption of PGE2 synthesis .


Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and , in a broader sense , in pathological situations in which genes under nuclear factor-kappaB control are up-regulated .

Triflusal and HTB may exert beneficial effects in processes in which de novo <protein>COX-2</protein> expression is involved and , in a broader sense , in pathological situations in which genes under <protein>nuclear factor-kappaB</protein> control are up-regulated .


Evidence for distinct intracellular signaling pathways in CD34+ progenitor to dendritic cell differentiation from a human cell line model .

Evidence for distinct intracellular signaling pathways in <cell_type>CD34+ progenitor</cell_type> to dendritic cell differentiation from a human cell line model .


Intracellular signals that mediate differentiation of pluripotent hemopoietic progenitors to dendritic cells ( DC ) are largely undefined .

Intracellular signals that mediate differentiation of <cell_type>pluripotent hemopoietic progenitors</cell_type> to <cell_type>dendritic cells</cell_type> ( <cell_type>DC</cell_type> ) are largely undefined .


We have previously shown that protein kinase C ( PKC ) activation ( with phorbol ester ( PMA ) alone ) specifically induces differentiation of primary human CD34+ hemopoietic progenitor cells ( HPC ) to mature DC .

We have previously shown that <protein>protein kinase C</protein> ( <protein>PKC</protein> ) activation ( with phorbol ester ( PMA ) alone ) specifically induces differentiation of <cell_line>primary human CD34+ hemopoietic progenitor cells</cell_line> ( <cell_line>HPC</cell_line> ) to <cell_type>mature DC</cell_type> .


We now find that cytokine-driven ( granulocyte-macrophage CSF and TNF-alpha ) CD34+ HPC -- > DC differentiation is preferentially blocked by inhibitors of PKC activation .

We now find that cytokine-driven ( granulocyte-macrophage CSF and TNF-alpha ) CD34+ <cell_line>HPC</cell_line> -- > DC differentiation is preferentially blocked by inhibitors of <protein>PKC</protein> activation .


To further identify intracellular signals and downstream events important in CD34+ HPC -- > DC differentiation we have characterized a human leukemic cell line model of this process .

To further identify intracellular signals and downstream events important in <cell_line>CD34+ HPC</cell_line> -- > <cell_type>DC</cell_type> differentiation we have characterized a human leukemic cell line model of this process .


The CD34+ myelomonocytic cell line KG1 differentiates into dendritic-like cells in response to granulocyte-macrophage CSF plus TNF-alpha , or PMA ( with or without the calcium ionophore ionomycin , or TNF-alpha ) , with different stimuli mediating different aspects of the process .

The <cell_line>CD34+ myelomonocytic cell line</cell_line> <cell_line>KG1</cell_line> differentiates into dendritic-like cells in response to <protein>granulocyte-macrophage CSF</protein> plus <protein>TNF-alpha</protein> , or PMA ( with or without the calcium ionophore ionomycin , or <protein>TNF-alpha</protein> ) , with different stimuli mediating different aspects of the process .


Phenotypic DC characteristics of KG1 dendritic-like cells include morphology ( loosely adherent cells with long neurite processes ) , MHC I+/ MHC IIbright/CD83+/CD86+/ CD14 - surface Ag expression , and RelB and DC -CK1 gene expression .

Phenotypic <cell_type>DC</cell_type> characteristics of <cell_line>KG1 dendritic-like cells</cell_line> include morphology ( <cell_type>loosely adherent cells</cell_type> with long neurite processes ) , <protein>MHC</protein> I+/ <protein>MHC</protein> IIbright/CD83+/CD86+/ <protein>CD14</protein> - surface Ag expression , and <protein>RelB</protein> and <cell_type>DC</cell_type> -CK1 gene expression .


Functional DC characteristics include fluid phase macromolecule uptake ( FITC-dextran ) and activation of resting T cells .

Functional <cell_type>DC</cell_type> characteristics include fluid phase macromolecule uptake ( FITC-dextran ) and activation of <cell_type>resting T cells</cell_type> .


Comparison of KG1 to the PMA-unresponsive subline KG1a reveals differences in expression of TNF receptors 1 and 2 ; PKC isoforms alpha , beta I , beta II , and mu ; and RelB , suggesting that these components/pathways are important for DC differentiation .

Comparison of <cell_line>KG1</cell_line> to the <cell_line>PMA-unresponsive subline KG1a</cell_line> reveals differences in expression of <protein>TNF receptors 1 and 2</protein> ; <protein>PKC isoforms alpha , beta I , beta II , and mu</protein> ; and <protein>RelB</protein> , suggesting that these components/pathways are important for <cell_type>DC</cell_type> differentiation .


Together , these findings demonstrate that cytokine or phorbol ester stimulation of KG1 is a model of human CD34+ HPC to DC differentiation and suggest that specific intracellular signaling pathways mediate specific events in DC lineage commitment .

Together , these findings demonstrate that cytokine or phorbol ester stimulation of <cell_line>KG1</cell_line> is a model of <cell_line>human CD34+ HPC</cell_line> to <cell_type>DC</cell_type> differentiation and suggest that specific intracellular signaling pathways mediate specific events in <cell_type>DC</cell_type> lineage commitment .


Involvement of adenylate cyclase and p70 ( S6 ) -kinase activation in IL-10 up-regulation in human monocytes by gp41 envelope protein of human immunodeficiency virus type 1 .

Involvement of <protein>adenylate cyclase</protein> and <protein>p70 ( S6 ) -kinase</protein> activation in <protein>IL-10</protein> up-regulation in <cell_type>human monocytes</cell_type> by <protein>gp41 envelope protein</protein> of human immunodeficiency virus type 1 .


Our previous results show that recombinant gp41 ( aa565-647 ) , the extracellular domain of HIV-1 transmembrane glycoprotein , stimulates interleukin-10 ( IL-10 ) production in human monocytes .

Our previous results show that <protein>recombinant gp41</protein> ( <protein>aa565-647</protein> ) , the <protein>extracellular domain</protein> of <protein>HIV-1 transmembrane glycoprotein</protein> , stimulates <protein>interleukin-10</protein> ( <protein>IL-10</protein> ) production in <cell_type>human monocytes</cell_type> .


The signal cascade transducing this effect is not yet clear .


In this study , we examined whether gp41 -induced IL-10 up-regulation is mediated by the previously described synergistic activation of cAMP and NF-kappaB pathways .

In this study , we examined whether <protein>gp41</protein> -induced <protein>IL-10</protein> up-regulation is mediated by the previously described synergistic activation of cAMP and <protein>NF-kappaB</protein> pathways .


gp41 induced cAMP accumulation in monocytes in a time- and concentration-dependent manner and the adenylate cyclase inhibitor SQ 22536 suppressed gp41 -induced IL-10 production in monocytes .

<protein>gp41</protein> induced cAMP accumulation in <cell_type>monocytes</cell_type> in a time- and concentration-dependent manner and the <protein>adenylate cyclase</protein> inhibitor SQ 22536 suppressed <protein>gp41</protein> -induced <protein>IL-10</protein> production in <cell_type>monocytes</cell_type> .


In contrast , gp41 failed to stimulate NF-kappaB binding activity in as much as no NF-kappaB bound to the main NF-kappaB-binding site 2 of the IL-10 promoter after addition of gp41 .

In contrast , <protein>gp41</protein> failed to stimulate <protein>NF-kappaB</protein> binding activity in as much as no <protein>NF-kappaB</protein> bound to the <dna>main NF-kappaB-binding site</dna> 2 of the <dna>IL-10 promoter</dna> after addition of <protein>gp41</protein> .


We also examined the involvement of other signal transduction pathways .


Specific inhibitors of p70 ( S6 ) -kinase ( rapamycin ) , and Gi protein ( pertussis toxin ) , prevented induction of IL-10 production by gp41 in monocytes , while inhibitors of the phosphatidylinositol 3-kinase ( PI 3-kinase ) ( wortmannin ) and mitogen-activated protein kinase ( MAPK ) pathway ( PD 98059 ) did not .

Specific inhibitors of <protein>p70 ( S6 ) -kinase</protein> ( rapamycin ) , and <protein>Gi protein</protein> ( <protein>pertussis toxin</protein> ) , prevented induction of <protein>IL-10</protein> production by <protein>gp41</protein> in <cell_type>monocytes</cell_type> , while inhibitors of the <protein>phosphatidylinositol 3-kinase</protein> ( <protein>PI 3-kinase</protein> ) ( wortmannin ) and mitogen-activated protein kinase ( <protein>MAPK</protein> ) pathway ( PD 98059 ) did not .


Thus HIV-1 gp41 -induced IL-10 up-regulation in monocytes may not involve NF-kappaB , MAPK , or PI 3-kinase activation , but rather may operate through activation of adenylate cyclase and pertussis-toxin-sensitive Gi/Go protein to effect p70 ( S6 ) -kinase activation .

Thus HIV-1 <protein>gp41</protein> -induced <protein>IL-10</protein> up-regulation in <cell_type>monocytes</cell_type> may not involve <protein>NF-kappaB</protein> , <protein>MAPK</protein> , or <protein>PI 3-kinase</protein> activation , but rather may operate through activation of <protein>adenylate cyclase</protein> and <protein>pertussis-toxin-sensitive Gi/Go protein</protein> to effect <protein>p70 ( S6 ) -kinase</protein> activation .


Analysis of the modulation of transcriptional activity in myelopoiesis and leukemogenesis .


Acute myeloid leukemia ( AML ) is still associated with a mortality of 60 to 80 % .


AML is characterized by a block in myeloid differentiation .


The transcription factors PU.1 and C/EBPalpha are responsible for normal myeloid differentiation from stem cells to monocytes or granulocytes .

The <protein>transcription factors</protein> <protein>PU.1</protein> and <protein>C/EBPalpha</protein> are responsible for normal myeloid differentiation from <cell_type>stem cells</cell_type> to <cell_type>monocytes</cell_type> or granulocytes .


In particular , PU.1 induces expression of the macrophage colony-stimulating factor ( M-CSF ) receptor and the development of monocytes , whereas C/EBPalpha increases the expression of the granulocyte colony-stimulating factor ( G-CSF ) receptor and leads to mature granulocytes .

In particular , <protein>PU.1</protein> induces expression of the <protein>macrophage colony-stimulating factor ( M-CSF ) receptor</protein> and the development of <cell_type>monocytes</cell_type> , whereas <protein>C/EBPalpha</protein> increases the expression of the <protein>granulocyte colony-stimulating factor ( G-CSF ) receptor</protein> and leads to mature <cell_type>granulocytes</cell_type> .


In AML , chromosomal aberrations result in oncoproteins such as AML1/ETO , PML/RARalpha , or activated Ras , which can deregulate genes important for normal myelopoiesis .

In AML , chromosomal aberrations result in <protein>oncoproteins</protein> such as <protein>AML1/ETO</protein> , <protein>PML/RARalpha</protein> , or <protein>activated Ras</protein> , which can deregulate genes important for normal myelopoiesis .


Thus , AML1/ETO can bind to the transcription factor C/EBPalpha , inhibit C/EBPalpha -dependent transcription , and block granulocytic differentiation .

Thus , <protein>AML1/ETO</protein> can bind to the <protein>transcription factor</protein> <protein>C/EBPalpha</protein> , inhibit <protein>C/EBPalpha</protein> -dependent transcription , and block granulocytic differentiation .


However , AML1/ETO can also synergize with the transcription factor AML1 to enhance the activity of the M-CSF receptor promoter .

However , <protein>AML1/ETO</protein> can also synergize with the <protein>transcription factor</protein> <protein>AML1</protein> to enhance the activity of the <dna>M-CSF receptor promoter</dna> .


On the other hand , the PML/RARalpha fusion protein causes transcriptional repression by recruiting the nuclear corepressor ( N-CoR ) histone deacetylase complex to the DNA , which results in decreased histone acetylation and a repressive chromatin organization .

On the other hand , the <protein>PML/RARalpha fusion protein</protein> causes transcriptional repression by recruiting the <protein>nuclear corepressor ( N-CoR ) histone deacetylase complex</protein> to the DNA , which results in decreased <protein>histone</protein> acetylation and a repressive <dna>chromatin</dna> organization .


Here we describe methods to investigate whether and how signaling agonists induce myeloid differentiation and how oncoproteins might cause AML by modulating the activity of transcription factors that are pivotal for normal myeloid development .

Here we describe methods to investigate whether and how signaling agonists induce myeloid differentiation and how <protein>oncoproteins</protein> might cause AML by modulating the activity of <protein>transcription factors</protein> that are pivotal for normal myeloid development .


Copyright 1999 Academic Press .


NF-ATc isoforms are differentially expressed and regulated in murine T and mast cells .

<protein>NF-ATc isoforms</protein> are differentially expressed and regulated in <cell_type>murine T and mast cells</cell_type> .


NF of activated T cells ( NF-AT ) denotes a family of transcription factors that regulate the activation-dependent expression of many immunologically important proteins .

<protein>NF of activated T cells</protein> ( <protein>NF-AT</protein> ) denotes a family of <protein>transcription factors</protein> that regulate the activation-dependent expression of many <protein>immunologically important proteins</protein> .


At least four distinct genes encode the various family members , and several isoforms of these have been identified as well .


The overlapping expression patterns and similar in vitro binding and trans-activation activities on various promoter elements of NF-AT-regulated genes suggest some redundancy in the function of these proteins .

The overlapping expression patterns and similar in vitro binding and trans-activation activities on various <dna>promoter elements</dna> of <dna>NF-AT-regulated genes</dna> suggest some redundancy in the function of these proteins .


However , the phenotypic analysis of NF-AT -deficient mice supports the idea that there are tissue- and gene- specific functions as well .

However , the phenotypic analysis of <protein>NF-AT</protein> -deficient mice supports the idea that there are tissue- and gene- specific functions as well .


In this study we have characterized the expression of NF-AT cDNAs in murine mast cells .

In this study we have characterized the expression of <dna>NF-AT cDNAs</dna> in murine <cell_type>mast cells</cell_type> .


The majority of clones identified correspond to two NF-ATc isoforms that differ only in their amino-terminal sequence .

The majority of clones identified correspond to two <protein>NF-ATc isoforms</protein> that differ only in their <protein>amino-terminal sequence</protein> .


Despite minimal discrepancies in the coding region , there are striking tissue- and cell type-specific differences in isoform expression patterns .

Despite minimal discrepancies in the <dna>coding region</dna> , there are striking tissue- and cell type-specific differences in isoform expression patterns .


Detection of NF-ATc.alpha mRNA is strictly dependent on cell activation signals in both T and mast cell lines .

Detection of <rna>NF-ATc.alpha mRNA</rna> is strictly dependent on cell activation signals in both <cell_line>T and mast cell lines</cell_line> .


In contrast , the beta isoform is expressed at very low constitutive levels in both cell types but is only up-regulated in response to mast cell activation signals delivered through the FcepsilonRI or via calcium ionophores .

In contrast , the <protein>beta isoform</protein> is expressed at very low constitutive levels in both cell types but is only up-regulated in response to mast cell activation signals delivered through the <protein>FcepsilonRI</protein> or via calcium ionophores .


These results demonstrate another level of regulation within the NF-AT family that can contribute to cell type-specific gene expression .

These results demonstrate another level of regulation within the <protein>NF-AT family</protein> that can contribute to cell type-specific gene expression .


Crossreactive recognition of viral , self , and bacterial peptide ligands by human class I-restricted cytotoxic T lymphocyte clonotypes : implications for molecular mimicry in autoimmune disease .

Crossreactive recognition of viral , self , and bacterial peptide ligands by <cell_type>human class I-restricted cytotoxic T lymphocyte clonotypes :</cell_type> implications for molecular mimicry in autoimmune disease .


The immunodominant , CD8 ( + ) cytotoxic T lymphocyte ( CTL ) response to the HLA-B8-restricted peptide , RAKFKQLL , located in the Epstein-Barr virus immediate-early antigen , BZLF1 , is characterized by a diverse T cell receptor ( TCR ) repertoire .

The immunodominant , <cell_type>CD8 ( + ) cytotoxic T lymphocyte</cell_type> ( CTL ) response to the HLA-B8-restricted peptide , RAKFKQLL , located in the <protein>Epstein-Barr virus immediate-early antigen</protein> , <protein>BZLF1</protein> , is characterized by a diverse <protein>T cell receptor ( TCR ) repertoire</protein> .


Here , we show that this diversity can be partitioned on the basis of crossreactive cytotoxicity patterns involving the recognition of a self peptide-RSKFRQIV-located in a serine/threonine kinase and a bacterial peptide-RRKYKQII-located in Staphylococcus aureus replication initiation protein .

Here , we show that this diversity can be partitioned on the basis of crossreactive cytotoxicity patterns involving the recognition of a self peptide-RSKFRQIV-located in a <protein>serine/threonine kinase</protein> and a bacterial peptide-RRKYKQII-located in <protein>Staphylococcus aureus replication initiation protein</protein> .


Thus CTL clones that recognized the viral , self , and bacterial peptides expressed a highly restricted alphabeta TCR phenotype .

Thus <cell_line>CTL clones</cell_line> that recognized the viral , self , and bacterial peptides expressed a highly restricted alphabeta <protein>TCR</protein> phenotype .


The CTL clones that recognized viral and self peptides were more oligoclonal , whereas clones that strictly recognized the viral peptide displayed a diverse TCR profile .

The <cell_line>CTL clones</cell_line> that recognized viral and self peptides were more oligoclonal , whereas clones that strictly recognized the viral peptide displayed a diverse <protein>TCR</protein> profile .


Interestingly , the self and bacterial peptides equally were substantially less effective than the cognate viral peptide in sensitizing target cell lysis , and also resulted only in a weak reactivation of memory CTLs in limiting dilution assays , whereas the cognate peptide was highly immunogenic .

Interestingly , the self and bacterial peptides equally were substantially less effective than the cognate viral peptide in sensitizing target cell lysis , and also resulted only in a weak reactivation of <cell_type>memory CTLs</cell_type> in limiting dilution assays , whereas the cognate peptide was highly immunogenic .


The described crossreactions show that human antiviral , CD8 ( + ) CTL responses can be shaped by peptide ligands derived from autoantigens and environmental bacterial antigens , thereby providing a firm structural basis for molecular mimicry involving class I-restricted CTLs in the pathogenesis of autoimmune disease .

The described crossreactions show that human antiviral , CD8 ( + ) CTL responses can be shaped by peptide ligands derived from autoantigens and environmental bacterial antigens , thereby providing a firm structural basis for molecular mimicry involving class <cell_line>I-restricted CTLs</cell_line> in the pathogenesis of autoimmune disease .


RFLAT-1 : a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes .

<protein>RFLAT-1</protein> : a new <protein>zinc finger transcription factor</protein> that activates <dna>RANTES gene</dna> expression in <cell_type>T lymphocytes</cell_type> .


RANTES ( Regulated upon Activation , Normal T cell Expressed and Secreted ) is a chemoattractant cytokine ( chemokine ) important in the generation of inflammatory infiltrate and human immunodeficiency virus entry into immune cells .

<protein>RANTES</protein> ( <protein>Regulated upon Activation , Normal T cell Expressed and Secreted</protein> ) is a <protein>chemoattractant cytokine</protein> ( <protein>chemokine</protein> ) important in the generation of inflammatory infiltrate and human immunodeficiency virus entry into <cell_type>immune cells</cell_type> .


RANTES is expressed late ( 3-5 days ) after activation in T lymphocytes .

<protein>RANTES</protein> is expressed late ( 3-5 days ) after activation in <cell_type>T lymphocytes</cell_type> .


Using expression cloning , we identified the first `` late '' T lymphocyte associated transcription factor and named it `` RANTES Factor of Late Activated T Lymphocytes-1 `` ( RFLAT-1 ) .

Using expression cloning , we identified the first `` late '' <protein>T lymphocyte associated transcription factor</protein> and named it `` <protein>RANTES Factor of Late Activated T Lymphocytes-1</protein> `` ( <protein>RFLAT-1</protein> ) .


RFLAT-1 is a novel , phosphorylated , zinc finger transcription factor that is expressed in T cells 3 days after activation , coincident with RANTES expression .

<protein>RFLAT-1</protein> is a novel , phosphorylated , <protein>zinc finger transcription factor</protein> that is expressed in <cell_type>T cells</cell_type> 3 days after activation , coincident with <protein>RANTES</protein> expression .


While Rel proteins play the dominant role in RANTES gene expression in fibroblasts , RFLAT-1 is a strong transactivator for RANTES in T cells .

While <protein>Rel proteins</protein> play the dominant role in <dna>RANTES gene</dna> expression in fibroblasts , <protein>RFLAT-1</protein> is a strong transactivator for <protein>RANTES</protein> in <cell_type>T cells</cell_type> .


Fas ligand induction in human NK cells is regulated by redox through a calcineurin-nuclear factors of activated T cell-dependent pathway .

<protein>Fas ligand</protein> induction in <cell_type>human NK cells</cell_type> is regulated by redox through a <protein>calcineurin-nuclear factors</protein> of activated T cell-dependent pathway .


Fas ligand ( FasL ) on cytotoxic lymphocytes is important for mediating apoptosis of activated lymphocytes and other target cells .

<protein>Fas ligand</protein> ( <protein>FasL</protein> ) on cytotoxic lymphocytes is important for mediating apoptosis of activated lymphocytes and other target cells .


We have reported that NK cell functions , such as proliferation , cell death , and killing activity , are subject to regulation by cellular redox status .


Here , we report that expression of FasL protein and mRNA in activated NK cells is also regulated by redox .

Here , we report that expression of <protein>FasL protein</protein> and <rna>mRNA</rna> in <cell_type>activated NK cells</cell_type> is also regulated by redox .


Ligation of CD16 on IL-2-preactivated NK cells resulted in reduction of intracellular peroxide level as well as induction of FasL expression .

Ligation of <protein>CD16</protein> on <cell_type>IL-2-preactivated NK cells</cell_type> resulted in reduction of intracellular peroxide level as well as induction of <protein>FasL</protein> expression .


This CD16 -induced FasL expression was suppressed by oxidative stress , including thiol deprivation or treatment with hydrogen peroxide ( H2O2 ) .

This <protein>CD16</protein> -induced <protein>FasL</protein> expression was suppressed by oxidative stress , including thiol deprivation or treatment with hydrogen peroxide ( H2O2 ) .


Addition of thiol-reducing compounds , such as L-cystine , 2-ME , or N-acetyl cysteine , restored FasL expression .

Addition of thiol-reducing compounds , such as L-cystine , 2-ME , or N-acetyl cysteine , restored <protein>FasL</protein> expression .


These data suggest that CD16 stimulation requires cellular reducing status for FasL induction in NK cells .

These data suggest that <protein>CD16</protein> stimulation requires cellular reducing status for <protein>FasL</protein> induction in <cell_type>NK cells</cell_type> .


Because FasL gene activation following CD16 cross-linking is regulated by the NF of activated T cells ( NFAT ) , we examined the effect of oxidative stresses on NFAT activation .

Because FasL gene activation following <protein>CD16</protein> cross-linking is regulated by the <protein>NF of activated T cells</protein> ( <protein>NFAT</protein> ) , we examined the effect of oxidative stresses on <protein>NFAT</protein> activation .


Electrophoretic mobility shift assays revealed that both thiol insufficiency and H2O2 treatment suppressed DNA-binding activity of NFAT and that addition of thiol-reducing compounds reversed or even enhanced it .

Electrophoretic mobility shift assays revealed that both thiol insufficiency and H2O2 treatment suppressed DNA-binding activity of <protein>NFAT</protein> and that addition of thiol-reducing compounds reversed or even enhanced it .


Furthermore , these oxidative stresses inhibited activity of calcineurin , a serine/ threonine phosphatase that regulates NFAT activation .

Furthermore , these oxidative stresses inhibited activity of calcineurin , a serine/ <protein>threonine phosphatase</protein> that regulates <protein>NFAT</protein> activation .


These results suggest that suppression of calcineurin and NFAT activation is a mechanism by which oxidative stress inhibits FasL induction in activated NK cells and further support the hypothesis that thiol-reducing compounds might be required for maintenance of optimal NK functions under physiologic oxidative conditions .

These results suggest that suppression of <protein>calcineurin</protein> and <protein>NFAT</protein> activation is a mechanism by which oxidative stress inhibits <protein>FasL</protein> induction in <cell_type>activated NK cells</cell_type> and further support the hypothesis that thiol-reducing compounds might be required for maintenance of optimal NK functions under physiologic oxidative conditions .


Heterogeneity of clonal development in chronic myeloproliferative disorders .

Heterogeneity of clonal development in <dna>chronic myeloproliferative disorders</dna> .


Recent reports have suggested a previously unexpected variability in the expression of the dominant neoplastic clone in myeloproliferative disorders ( MPD ) .

Recent reports have suggested a previously unexpected variability in the expression of the <cell_line>dominant neoplastic clone</cell_line> in myeloproliferative disorders ( MPD ) .


We evaluated 49 female patients with MPD and informative at the X-linked androgen receptor ( AR ) locus to establish the X chromosome inactivation pattern of hemopoietic cells .

We evaluated 49 female patients with MPD and informative at the <dna>X-linked androgen receptor ( AR ) locus</dna> to establish the <dna>X chromosome</dna> inactivation pattern of <cell_type>hemopoietic cells</cell_type> .


Whereas in chronic myelogenous leukemia ( CML ) the granulocytes ( PMN ) were uniformly of monoclonal origin , a striking heterogeneity of clonal development was found in PMN from patients with other MPD , with up to 50 % of them expressing a polyclonal pattern of X inactivation .

Whereas in chronic myelogenous leukemia ( CML ) the <cell_type>granulocytes</cell_type> ( <cell_type>PMN</cell_type> ) were uniformly of monoclonal origin , a striking heterogeneity of clonal development was found in <cell_type>PMN</cell_type> from patients with other MPD , with up to 50 % of them expressing a polyclonal pattern of X inactivation .


CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28 .

<protein>CD80</protein> and <protein>CD86</protein> are not equivalent in their ability to induce the tyrosine phosphorylation of <protein>CD28</protein> .


Ligation of either CD80 ( B7-1 ) or CD86 ( B7-2 ) , two principal ligands for CD28 , is thought to skew the immune response toward Th1 or Th2 differentiation .

Ligation of either <protein>CD80</protein> ( <protein>B7-1</protein> ) or <protein>CD86</protein> ( <protein>B7-2</protein> ) , two principal ligands for <protein>CD28</protein> , is thought to skew the immune response toward Th1 or Th2 differentiation .


We have examined early signal transduction pathways recruited following T cell stimulation with either CD80 or CD86 .

We have examined early signal transduction pathways recruited following T cell stimulation with either <protein>CD80</protein> or <protein>CD86</protein> .