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)

The regulation of amphiregulin, an epidermal growth factor (EGF) family member, and its effect on vascular smooth muscle cells (VSMC) were examined. Amphiregulin mRNA was upregulated by amphiregulin itself as well as alpha-thrombin. Amphiregulin caused an approximate 3-fold increase in DNA synthesis. Its effect on growth was compared with those of other mitogens, and was found to be approximately 3.5-, 2.4-, and 1.0-fold greater than those of endothelin-I (ET-I), alpha-thrombin, and platelet-derived growth factor-AB (PDGF-AB), respectively. As evidenced by Western blot analysis, amphiregulin stimulated the phosphorylation of p42/p44-mitogen-activated protein kinase (MAPK), p38-MAPK, c-Jun NH2-terminal protein kinase (JNK), and Akt/protein kinase B (PKB), respectively. By statistical analysis, the amphiregulin-induced growth effect was significantly decreased by the MAP kinase/ extracellular regulated kinase kinase-1 (MEK-1) inhibitor PD98059, p38-MAPK inhibitor SB203580, and phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor wortmannin, respectively, but was not decreased by JNK inhibitor SP600125. These results suggest that amphiregulin is the most potent mitogen of the mitogens tested, and its growth effect is mediated at least in part through the p42/p44-MAPK, p38-MAPK, and PI-3 kinase-Akt/PKB pathways in VSMC.
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PMID:Amphiregulin is a potent mitogen for the vascular smooth muscle cell line, A7r5. 1258 27

Alphavbeta3-integrin antagonists reduced neointimal formation following vascular injury in eight different animal models. Because alpha-thrombin contributes to neointimal formation, we examined the hypothesis that alphavbeta3-integrins influence alpha-thrombin-induced signaling. Cultured rat aortic smooth muscle cells (RASMC) expressed alphavbeta3-integrins as demonstrated by immunofluorescence microscopy and fluorescence-activated cell sorting analysis. Proliferative responses to alpha-thrombin were partially inhibited by anti-beta3-integrin monoclonal antibody F11 and by cyclic RGD peptides. Immunofluorescence microscopy showed that alpha-thrombin stimulated a rapid increase in the formation of focal adhesions as identified by vinculin staining and that this effect was partially inhibited by alphavbeta3 antagonists. Beta3-integrin staining was diffuse in quiescent RASMC and did not concentrate at sites of focal adhesions following thrombin treatment. Alpha-thrombin elicited a time-dependent increase in activation of c-Jun NH2-terminal kinase-1 (JNK1) and in tyrosine phosphorylation of focal adhesion kinase (FAK). Alphavbeta3-integrin antagonists partially inhibited increases in JNK1 activity but had no effect on FAK phosphorylation. In SMC isolated from beta3-integrin-deficient mice, focal adhesion formation was impaired in response to thrombin but not sphingosine-1-phosphate, a potent activator of Rho. In summary, alphavbeta3-integrins play an important role in alpha-thrombin-induced proliferation and focal adhesion formation in RASMC.
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PMID:Alphavbeta3-integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells. 1287 90

The beta3-integrin family consists of alphaIIbbeta3 (also known as glycoprotein IIb/IIIa) and alpha(v)beta3. alphaIIbbeta3 is found on platelets and megakaryocytes and has an essential role in hemostasis. alpha(v)beta3 has a broader distribution, and it functions in angiogenesis, neointimal formation after vascular injury, and leukocyte trafficking. There are important interactions between thrombin and beta3-integrins relative to both "inside-out" (integrin activation) and "outside-in" (modification of cellular events by ligand binding to integrins) signaling. Thrombin, by binding to G protein-coupled, protease-activated receptors, is a potent activator of alphaIIbbeta3. Conversely, outside-in signaling through alphaIIbbeta3 amplifies events initiated by thrombin and is necessary for full platelet spreading, platelet aggregation, granule secretion, and the formation of a stable platelet thrombus. In smooth muscle cells, alpha(v)beta3-integrins influence various responses to thrombin, including proliferation, c-Jun NH2-terminal kinase-1 activation, and focal adhesion formation. Other interactions between beta3-integrins and thrombin include beta3-integrin promotion of the generation of thrombin by localizing prothrombin to cellular surfaces and/or enhancing the formation of procoagulant microparticles and the requirement of beta3-integrin function for platelet-dependent clot retraction. In summary, there is increasing evidence that interactions between beta3-integrins and thrombin play important roles in the regulation of hemostatic and vascular functions.
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PMID:Effects of thrombin on interactions between beta3-integrins and extracellular matrix in platelets and vascular cells. 1294 18

Although the ability of G protein-coupled receptors to stimulate normal and aberrant cell growth has been intensely investigated, the precise nature of the molecular mechanisms underlying their transforming potential are still not fully understood. In this study, we have taken advantage of the potent mitogenic effect of thrombin and the focus-forming activity of one of its receptors, protease-activated receptor-1, to dissect how this receptor coupled to Galphai, Galphaq/11, and Galpha12/13 transduces signals from the membrane to the nucleus to initiate transcriptional events involved in cell transformation. Using endogenous and transfected thrombin receptors in NIH 3T3 cells, ectopic expression of muscarinic receptors coupled to Galphaq and Galphai, and chimeric G protein alpha subunits and murine fibroblasts deficient in Galphaq/11, and Galpha12/13, we show here that, although coupling to Galphai is sufficient to induce ERK activation, the ability to couple to Galphaq and/or Galpha13 is necessary to induce c-jun expression and cell transformation. Furthermore, we show that Galphaq and Galpha13 can initiate the activation of MAPK cascades, including JNK, p38, and ERK5, which in turn regulate the activity of transcription factors controlling expression from the c-jun promoter. We also present evidence that c-Jun and the kinases regulating its expression are integral components of the transforming pathway initiated by protease-activated receptor-1.
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PMID:Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation. 1295 41

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

The activation and function of c-Jun N-terminal kinases (JNKs) were investigated in primary microglia cultures from neonatal rat brain, which express all three JNK isoforms. Lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and thrombin preparations induced a rapid and lasting activation of JNKs in the cytoplasm. In the nucleus, the activation patterns were rather complex. In untreated microglia, the small pool of nuclear JNKs was strongly activated, while the high-affinity JNK substrate c-Jun was only weakly phosphorylated. Stimulation with LPS increased the total amount of nuclear JNKs and the phosphorylation of the transcription factor c-Jun. Levels of activated JNKs in the nucleus, however, rapidly decreased. Analysis of the nuclear JNK isoforms revealed that the amount of JNK1 declined, while JNK2 increased, and the weakly expressed JNK3 did not vary. This observation suggests that JNK2 is mainly responsible for the activation of c-Jun in this context. Upstream of JNKs, LPS induced a lasting activation of the constitutively present JNK kinase MKK4. The function of JNKs in LPS-triggered cellular reactions was investigated using SP600125 (0.5-5 microM), a direct inhibitor of JNKs. Inhibition of JNKs reduced the LPS-induced metabolic activity and induction of the AP-1 target genes cyclooxygenase-2 (Cox-2), TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in response to LPS, while ERK1/2 and p38 alpha had a more pronounced effect on LPS-induced cellular enlargement than JNKs. In summary, JNKs are essential mediators of relevant pro-inflammatory functions in microglia with different contributions of the JNK isoforms.
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PMID:c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. 1573 88

Thrombin-activated Factor XIII (FXIIIa), a plasma transglutaminase, stabilizes fibrin clots by crosslinking fibrin chains. FXIIIa was previously shown by us to exhibit proangiogenic activity associated with downregulation of thrombospondin-1, phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2), and upregulation of c-Jun. In the current study, we evaluated the proangiogenic effect of FXIIIa in two murine models: a neonatal heterotopic cardiac allograft model in normal mice, and a Matrigel plug model in FXIII-deficient mice. In the neonatal cardiac allograft model, the number of new vessels as well as graft viability (contractile performance) was significantly higher in FXIIIa-injected animals than in controls. A significant increase in the level of c-Jun mRNA and a significant decrease in the level of TSP-1 mRNA were observed in heart allografts treated with FXIIIa. A marked decrease in TSP-1 protein expression was observed within the endothelial cells of hearts treated with FXIIIa. In the Matrigel plug model, FXIII-deficient mice showed a significantly decreased number of new vessels compared to that of the control mice, and the number of vessels almost reached normal levels following addition of FXIIIa. The results of this study provide substantial in vivo evidence for the proangiogenic activity of FXIIIa.
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PMID:Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. 1652 85

Heparin is used clinically for the prevention of pregnancy complications associated with prothrombotic disorders, especially antiphospholipid antibody syndrome. Recent studies have suggested that heparin may exert direct effects on placental trophoblast, independently of its anticoagulant activity. We now demonstrate that heparin abrogates apoptosis of primary first trimester villous trophoblast in response to treatment with the pro-inflammatory cytokines interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. This multifunctional glycosaminoglycan also inhibited apoptosis induced by other agents, including staurosporin, broad-spectrum kinase inhibitor and thrombin. Furthermore, heparin attenuated caspase-3 activity, a hallmark of apoptosis, in human first trimester villous and extravillous trophoblast cell lines treated with peptidoglycan, a Toll-like receptor-2 agonist isolated from Staphylococcus aureus. The ability of heparin to antagonize cell death induced by such diverse apoptotic signals suggested that it acts as a survival factor for human trophoblast. We demonstrate that heparin, like epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), elicits phosphorylation of the EGF receptor and activation of the phosphatidyl inositol 3-kinase (PI3K)-, the extracellular signal-related kinase 1/2 (ERK1/2)- and the c-Jun NH2 terminal kinase (JNK)-signal transduction pathways in primary villous trophoblast. In summary, we have demonstrated that heparin activates multiple anti-apoptotic pathways in human trophoblast. Our results suggest that heparin may be useful in the management of at-risk patients, even in the absence of an identifiable thrombophilic disorder.
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PMID:Heparin prevents programmed cell death in human trophoblast. 1655 79

Paclitaxel is used on drug-eluting stents because it inhibits proliferation of vascular cells. Stent thrombosis remains a concern with this compound, particularly with higher dosages. This study investigates the effect of paclitaxel on tissue factor (TF) expression in human endothelial cells. Paclitaxel enhanced thrombin-induced endothelial TF protein expression in a concentration- and time-dependent manner. A concentration of 10(-5) mol/L elicited a 2.1-fold increase in TF protein and a 1.6-fold increase in TF surface activity. The effect was similar after a 1 hour as compared with a 25-hour pretreatment period. Real-time polymerase chain reaction revealed that paclitaxel increased thrombin-induced TF mRNA expression. Paclitaxel potently activated c-Jun terminal NH2 kinase (JNK) as compared with thrombin alone, whereas the thrombin-mediated phosphorylation of p38 and extracellular signal-regulated kinase remained unaffected. Similar to paclitaxel, docetaxel enhanced both TF expression and JNK activation as compared with thrombin alone. The JNK inhibitor SP600125 reduced thrombin-induced TF expression by 35%. Moreover, SP600125 blunted the effect of paclitaxel and docetaxel on thrombin-induced TF expression. Paclitaxel increases endothelial TF expression via its stabilizing effect on microtubules and selective activation of JNK. This observation provides novel insights into the pathogenesis of thrombus formation after paclitaxel-eluting stent deployment and may have an impact on drug-eluting stent design.
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PMID:Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2 kinase activation. 1679 85

Berberine (BBR) is a novel natural hypolipidemic agent. This study investigates whether BBR, similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. BBR enhanced tumor necrosis factor-alpha (TNF-alpha) and thrombin induced TF expression in human endothelial cells by 3.5-fold. These effects were paralleled by an enhanced TF surface activity. In contrast, expression of TF pathway inhibitor was impaired. BBR enhanced TNF-alpha induced TF mRNA expression; however, TF promoter activity was inhibited. Activation of ERK and p38 remained unaffected, while c-Jun terminal NH(2) kinase was inhibited. BBR reduced TF mRNA degradation rates, prolonging its half-life from 1.1 to 4.3 h. The HMG-CoA reductase inhibitor simvastatin impaired thrombin induced TF expression, and BBR blunted this inhibition. Simvastatin did not affect TNF-alpha induced TF expression, and BBR enhanced TF under these conditions. Administration of BBR (100 mg/kg/d) increased TF activity and impaired TFPI expression in carotid artery of ApoE(-/-) mice. BBR enhances TF via mRNA stabilization at clinically relevant concentrations. Clinical application of BBR, either as an alternative to or in combination with statins, should be considered with caution.
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PMID:Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells. 1901 47


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