Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These studies examine the molecular basis for increased transcription of tissue factor (TF) in THP-1 cells stimulated with lipopolysaccharide (LPS). DNase I footprinting identified six sites of protein-DNA interaction between -383 and the cap site that varied between control and induced extracts. Four footprints show qualitative differences in nuclease sensitivity. Footprints I (-85 to -52) and V (-197 to -175) are induction-specific and localize to regions of the promoter that mediate serum, phorbol ester, partial LPS response (-111 to +14), and the major LPS-inducible element (-231 to -172). Electrophoretic mobility shift assays with the -231 to -172 probe demonstrate JunD and Fos binding in both control and induced nuclear extracts; however, binding of c-Jun is only detected following LPS stimulation. Antibody inhibition studies implicate binding of Ets-1 or Ets-2 to the consensus site between -192 and -177, a region that contains an induction-specific footprint. The proximal region (-85 to -52), containing the second inducible footprint, binds Egr-1 following induction. These data suggest that LPS stimulation of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the TF promoter and implicates these factors in the transcriptional activation of TF mRNA synthesis.
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PMID:Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the tissue factor promoter. 864 47

Tissue factor (TF) expression by peripheral blood monocytes during sepsis initiates intravascular thrombosis. Bacterial lipopolysaccharide (LPS) rapidly induces TF gene transcription in monocytes. The human TF promoter contains binding sites for the transcription factors AP-1, c-Rel/p65, Egr-1, and Sp1. NF-kappa B/Rel proteins have been shown to physically interact with both AP-1 and Sp1 proteins. In this study, we investigated the role of these transcription factors in uninduced and LPS-induced TF gene expression in human monocytic THP-1 cells. Deletional analysis indicated that five Sp1 sites mediated basal expression in uninduced cells. The two AP-1 sites bound c-Fos/c-Jun heterodimers in both unstimulated and LPS-stimulated cells. Maximal LPS induction of the TF promoter required the two AP-1 sites and the kappa B site within the LPS response element. Disruption of the conserved spacing between the proximal AP-1 site and the kappa B site abolished LPS induction. Replacement of the two AP-1 sites with intrinsically bent DNA partially restored LPS induction, suggesting an additional structural role for the AP-1 sites. Synergistic transactivation of the LPS response element in Drosophila Schneider cells by coexpression of c-Fos, c-Jun, c-Rel, and p65 or c-Jun and p65 required the transactivation domains of c-Jun and p65. These data indicated that c-Fos/c-Jun, c-Rel/p65, and Sp1 regulate TF gene expression in human monocytic cells.
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PMID:Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. 908 93

Expression of tissue factor (TF) by activated monocytes in several diseases leads to disseminated intravascular coagulation. Lipopolysaccharide (LPS)-induced monocyte TF expression is downregulated by the nuclear hormone all-trans retinoic acid (ATRA). In this study, we examined the mechanism by which ATRA inhibits monocyte TF expression. We show that ATRA selectively inhibited LPS induction of TF expression in human monocytes and monocytic THP-1 cells without affecting LPS induction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). Inhibition of TF expression occurred at the level of transcription as determined by nuclear run-on. ATRA did not significantly alter the binding or functional activity of the transcription factors c-Fos/c-Jun and c-Rel/p65, which are required for LPS induction of the TF promoter in monocytic cells. In contrast to the ATRA inhibition of the endogenous TF gene, LPS induction of the cloned TF promoter was not inhibited by ATRA in transiently transfected THP-1 cells. Our results demonstrate that ATRA selectively inhibited LPS-induced TF gene transcription in human monocytic cells by a mechanism that does not involve repression of AP-1- or NF-kappaB-mediated transcription.
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PMID:Retinoic acid selectively inhibits lipopolysaccharide induction of tissue factor gene expression in human monocytes. 953 96

A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease mortality. The phytochemical resveratrol found in wine, derived from grapes, has been thought to be responsible for cardiovascular benefits associated with wine consumption because it was shown to have antioxidant and antiplatelet activities. In the present investigation, we examined the effect of resveratrol on induction of tissue factor (TF) expression in vascular cells that were exposed to pathophysiological stimuli. The data presented herein show that resveratrol, in a dose-dependent manner, inhibited the expression of TF in endothelial cells stimulated with a variety of agonists, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha) and lipopolysaccharide (LPS). A similar inhibition of TF induction was also seen in LPS stimulated monocytes that were pretreated with resveratrol before their stimulation with LPS. In addition, resveratrol was shown to inhibit the LPS-induced expression of TNFalpha mRNA in endothelial cells and of TNFalpha and IL-1beta mRNA in monocytes. Nuclear run-on analysis in endothelial cells showed that resveratrol inhibited TF expression at the level of transcription. However, resveratrol did not significantly alter the binding of the transcription factors c-Fos/c-Jun and c-Rel/p65, the transcription factors required for the induction of TF promoter in both endothelial cells and monocytes. Similarly, resveratrol had no significant effect on the binding of NF-kappaB in endothelial cells stimulated with IL-1beta, TNFalpha, and LPS. Overall, our data show that resveratrol could effectively suppress the aberrant expression of TF and cytokines in vascular cells, but it requires further investigation to understand how resveratrol exerts its inhibitory effect.
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PMID:Resveratrol, a polyphenolic compound found in wine, inhibits tissue factor expression in vascular cells : A possible mechanism for the cardiovascular benefits associated with moderate consumption of wine. 997 27

A role of membrane microparticles (MP) released by vascular cells in endothelial cell (EC) activation was investigated. Flow cytofluorimetric analysis of blood samples from normal volunteers revealed the presence of an heterogeneous MP population, which increased by approximately 2-fold after inflammatory stimulation with the chemotactic peptide, N-formyl-Met-Leu-Phe (2,799 +/- 360 versus 5241 +/- 640, p < 0.001). Blood-derived MP stimulated release of EC cytokines interleukin (IL)-6 (377 +/- 68 pg/ml) and MCP-1 (1, 282 +/- 79) and up-regulated de novo expression of tissue factor on the EC surface. This was associated with generation of a factor Xa-dependent procoagulant response (2.28 +/- 0.56 nM factor Xa/min/10(4) cells), in a reaction inhibited by a monoclonal antibody to tissue factor. Fluorescent labeling with antibodies to platelet GPIbalpha or leukocyte lactoferrin demonstrated that circulating MP originated from both platelets and leukocytes. However, depletion of platelet MP with an antibody to GPIbalpha did not reduce EC IL-6 release, and, similarly, MP from thrombin-stimulated platelets did not induce IL-6 release from endothelium. EC stimulation with leukocyte MP did not result in activation of the transcription factor NF-kappaB and was not associated with tyrosine phosphorylation of extracellular signal-regulated protein kinase, ERK1. In contrast, leukocyte MP stimulated a sustained, time-dependent increased tyrosine phosphorylation of approximately 46-kDa c-Jun NH(2)-terminal kinase (JNK1) in EC. These findings demonstrate that circulating leukocyte MP are up-regulated by inflammatory stimulation in vivo and activate a stress signaling pathway in EC, leading to increased procoagulant and proinflammatory activity. This may provide an alternative mechanism of EC activation, potentially contributing to dysregulation of endothelial functions during vascular injury.
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PMID:Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. 1043 80

This study examined the effect of verotoxin-1 (VT-1), which is released from Escherichia coli O157:H7, on endothelial expression of tissue factor (TF), a cofactor required to initiate blood coagulation. In order to elucidate the molecular basis for development of hemolytic uremic syndrome (HUS) in patients infected with E. coli O157:H7, human umbilical vein endothelial cells (HUVECs) were exposed to purified VT-1. VT-1 increased both TF activity and TF mRNA in HUVECs without loss of cell viability in a time- and dose-dependent manner from 0.1 to 10 ng/ml VT-1. Nuclear proteins extracted from VT-1-stimulated HUVECs bound to the consensus NF-kappaB/Rel and AP-1 binding oligonucleotides in a dose-dependent manner within 2 h after the stimulation in electrophoretic mobility shift assays (EMSA). Nuclear proteins from VT-1-stimulated HUVECs formed two complexes with the NF-kappaB/Rel binding motif in the human TF promoter (TF-kappaB motif). The supershift assays, using antibodies for human p65, p50 or c-Rel, indicated that the lower complex was composed of p65/p50 and the higher complex was a p65 homo- or hetero-dimer with the Rel family, except c-Rel. The human TF promoter contains two AP-1 binding sites, the proximal and distal AP-1 binding sites. The supershift assays indicated that AP-1 containing mainly c-Jun and JunD, positively bound to the proximal AP-1 motif of TF (TF-AP-1). The distal TF-AP-1 motif did not show positive binding with nuclear proteins from VT-1-stimulated HUVECs. Pretreatment of HUVECs with curcumin, an inhibitor of NF-kappaB/Rel activation, synthesis of c-Jun mRNA and binding of activated AP- I with AP-binding oligonucleotide, prevented the VT-1 induced increase in TF mRNA and activity in VT-1-stimulated HUVECs. Curcumin also inhibited NF-kappaB and AP-1 binding to TF-kappaB and proximal TF-AP-1 oligonucleotides, respectively, in a dose-dependent manner. The present work suggests that both the NF-kappaB/Rel and AP-1 activated in endothelial cells by stimulation with VT-1 binds to the TF-kappaB and proximal AP-1 binding sites, respectively, of the TF promoter.
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PMID:Verotoxin-1 induces tissue factor expression in human umbilical vein endothelial cells through activation of NF-kappaB/Rel and AP-1. 1105 75

Atherosclerosis is an inflammatory disease of large arteries that is initiated through the activation of endothelium by proinflammatory mediators. CD40 receptor stimulation has been implicated in the pathogenesis of atherosclerosis. One of the most important atheroprotective stimuli is the viscous drag (shear stress) generated by the streaming blood acting on the endothelial monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-induced endothelial cell activation, and we identify upregulation of TNF receptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. Shear stress specifically upregulates TRAF-3 in cultured endothelial cells. Moreover, in the endothelial cells overlying human atherosclerotic plaques, TRAF-3 expression is upregulated in areas with high shear stress. Overexpression of TRAF-3 inhibits endothelial expression of proinflammatory cytokines and tissue factor and blocks DNA-binding activity of the transcription factor AP-1; it thereby prevents CD40-induced endothelial activation. Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer.
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PMID:Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation. 1171 36

Tissue factor (TF), which is expressed in atherosclerotic plaques and colocalizes with oxidized lipids, initiates the thrombogenic process. We have analyzed the effect of aldehydes derived from peroxidation of polyunsaturated fatty acids on TF expression in human vascular smooth muscle cells (HVSMC). Our results demonstrate that hexanal and 2,4-decadienal (2,4-DDE), two apolar aldehydes, increase TF expression. Exposure of HVSMC to hexanal for 2 h led to TF protein levels up to seven times higher than untreated cells whereas 2,4-DDE for 30 min led to them being up to 2.2 times higher. This induction of TF antigen by aldehydes correlates with an increase in TF mRNA levels. Electrophoretic mobility shift assays (EMSAs) showed that the binding activity of the transcription factor AP-1 (c-Fos/c-Jun) to TF promoter was elevated in response to these oxidation products. This enhancement was associated to an increase of c-fos transcriptional activity, which was reversible by pretreatment with simvastatin. We conclude that the induction of TF by aldehydes might contribute to the severity of atherogenesis.
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PMID:Aldehydes mediate tissue factor induction: a possible mechanism linking lipid peroxidation to thrombotic events. 1460 25

Tissue factor (TF) is expressed rapidly by human monocytes exposed to a variety of agonists such as lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Activation of both activator protein-1 (AP-1; c-Jun/c-Fos) and nuclear factor-kappaB (NF-kappaB) pathways is necessary for maximal induction of the TF gene. It has been demonstrated that activation of both AP-1 and NF-kappaB is correlated with the degradation of both phosphorylated c-Jun and inhibitor kappaB (IkappaB) by proteasome. The present study was designed to investigate whether various protease inhibitors, including proteasome inhibitors, affect TF expression in monocytic cells. Protease inhibitors, 3,4-dichloroisocoumarin (DCI), N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), and N-acetyl-Leu-Leu-norleucinal (ALLN) induced TF activity in monocytic cells in a dose- and time-dependent manner at the level of the transcription of the TF gene, which was mediated through inducing phosphorylation of both Jun-N-terminal kinase and p38. The early growth response-1 (Egr-1) pathway was not affected. The NF-kappaB pathway was not activated; rather it was inhibited. These results were distinct from the findings previously reported for LPS-stimulated cells. The present study demonstrated that some protease inhibitors might act as stress and induced TF expression with direct phosphorylation of JNK and p38, followed by phosphorylation and activation of AP-1 in monocytic cells. This evidence may help elucidate further regulatory mechanisms of TF induction, and might have physiological significance for the clinically challenged use of proteasome inhibitors. In addition to phosphorylation of JNK and p38, an unknown signal pathway needs to be clarified for TF induction.
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PMID:Induction of tissue factor expression in human monocytic cells by protease inhibitors through activating activator protein-1 (AP-1) with phosphorylation of Jun-N-terminal kinase and p38. 1504 Dec 76

Tissue factor is critically important for initiating the activation of coagulation zymogens leading to the generation of thrombin. Quiescent endothelial cells do not express tissue factor on their surface, but many stimuli including cytokines and coagulation proteases can elicit tissue factor synthesis. We challenged human endothelial cells simultaneously with tumor necrosis factor alpha (TNFalpha) and thrombin because many pathophysiological conditions, such as sepsis, diabetes, and coronary artery disease, result in the concurrent presence of circulating inflammatory mediators and activated thrombin. We observed a remarkable synergy in the expression of tissue factor by thrombin plus TNFalpha. This was due to altered regulation of the transcription factors c-Jun and c-Fos. The activation of c-Jun was greater and more sustained than that obtained with either thrombin or TNFalpha alone. Thrombin-stimulated expression of c-Fos was both enhanced and prolonged by the concurrent presence of TNFalpha. These changes support the increased availability of c-Jun/c-Fos AP-1 complexes for mediating transcription at the tissue factor promoter. Transcription factors downstream of the extracellular signal-regulated kinases as well as changes in NFkappaB regulation were not involved in the synergistic increase in tissue factor expression by thrombin and TNFalpha. Thus, concurrent exposure of vascular endothelial cells to cytokines and procoagulant proteases such as thrombin can result in greatly enhanced tissue factor expression on the endothelium, thereby perpetuating the prothrombotic phenotype of the endothelium.
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PMID:Thrombin and tumor necrosis factor alpha synergistically stimulate tissue factor expression in human endothelial cells: regulation through c-Fos and c-Jun. 1520 Dec 77


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