UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to study the role played by known and novel genes in growth control and neoplasia, we here compare the pEX and pGEX bacterial expression systems for recombinant oncoprotein production and for generation of specific antisera. The results of five pEX (MS2-c-Fos, MS2-Fra-1, MS2-JunD, bgal-c-Jun and bgal-JunB) and two pGEX [glutathione S-transferase (GSH)-JE/MCP-1 and GST-JunD] fusion-protein productions are presented. Higher (15-43-fold) yields are obtained with the pEX system, but only the pGEX system allows separation of the protein of interest from the fusion moiety by digestion with specific proteases. The degree of fusion-protein purification, as assessed by SDS/PAGE, is similar for both systems. Proteins produced by both systems were successfully used in the generation of specific antisera. The choice between the pEX and pGEX systems is dependent upon the specific recombinant protein produced.
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PMID:Use of pEX and pGEX bacterial heterologous protein expression systems for recombinant oncoprotein production and antisera generation. 919 74

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

Chemokine expression is associated with reperfusion of infarcted myocardium in the setting of tissue necrosis, intense inflammation, and inflammatory cytokine release. The specific synthesis of monocyte chemotactic protein (MCP)-1 mRNA by cardiac venules in reperfused infarcts corresponded to the region where leukocytes normally localize. MCP-1 could be induced by exogenous tumor necrosis factor (TNF)-alpha or by postischemic cardiac lymph containing TNF-alpha. However, the release of TNF-alpha during early reperfusion did not explain the venular localization of MCP-1 induction. To better understand the factors mediating MCP-1 induction, we examined the role of ischemia/reperfusion in a model of brief coronary occlusion in which no necrosis or inflammatory response is seen. Adult mongrel dogs were subjected to 15 minutes of coronary occlusion and 5 hours of reperfusion. Ribonuclease protection assay revealed up-regulation of MCP-1 mRNA only in ischemic segments of reperfused canine myocardium. Pretreatment with the reactive oxygen scavenger N-(2-mercaptopropionyl)-glycine completely inhibited MCP-1 induction. In situ hybridization localized MCP-1 message to small venular endothelium in ischemic areas without myocyte necrosis. Gel shift analysis of nuclear extracts from the ischemic area showed enhanced DNA binding of the transcription factors AP-1 and nuclear factor (NF)-kappaB, crucial for MCP-1 expression, in ischemic myocardial regions. Immunohistochemical staining demonstrated reperfusion-dependent nuclear translocation of c-Jun and NF-kappaB (p65) in small venular endothelium, only in the ischemic regions of the myocardium, that was inhibited by N-(2-mercaptopropionyl)-glycine. In vitro, treatment of cultured canine jugular vein endothelial cells with the reactive oxygen intermediate H2O2 induced a concentration-dependent increase in MCP-1 mRNA levels, which was inhibited by the antioxidant N-acetyl-L-cysteine, a precursor of glutathione, but not pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and activator of AP-1. In contrast to our studies with infarction, incubation of canine jugular vein endothelial cells with postischemic cardiac lymph did not induce MCP-1 mRNA expression suggesting the absence of cytokine-mediated MCP-1 induction after a sublethal ischemic period. These results suggest that reactive oxygen intermediate generation, after a brief ischemic episode, is capable of inducing MCP-1 expression in venular endothelium through AP-1 and NF-kappaB. Short periods of ischemia/reperfusion, insufficient to produce a myocardial infarction, induce MCP-1 expression, potentially mediating angiogenesis in the ischemic noninfarcted heart.
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PMID:Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. 1158 58

IL-8 is an important mediator of leukocyte trafficking and activation, participating in tumor angiogenesis, inflammatory processes and coronary atherosclerosis. Under flow conditions IL-8, in conjunction with MCP-1, triggers the firm adhesion of monocytes to the vascular endothelium. While previous studies have suggested the requirement of NF-kappaB for IL-8 secretion by endothelial cells, we investigated the possibility of IL-8 transactivation under conditions of NF-kappaB suppression. Inhibition of the proteasome by MG-132 or lactacystin completely blocked TNF-alpha-induced IkappaBalpha degradation as well as NF-kappaB activity in human arterial endothelial cells. Surprisingly, basal secretion of IL-8 protein was eight- to tenfold induced by proteasome inhibitors, while MCP-1 expression was, as expected, completely down-regulated. IL-8 was up-regulated at the transcriptional level, and promoter studies proved a more than ninefold induction of transcription factor AP-1 activity to be the cause of increased IL-8 transcription. Mutation of the AP-1 binding site in an IL-8 promoter construct completely abrogated this effect, while mutation of the NF-kappaB motif did not influence IL-8 transactivation by proteasome inhibitors. With DNA binding assays we found a seven- to eightfold induction of phosphorylated c-Jun and hence JNK kinase activity under MG-132 treatment. Induction of JNK kinase appeared independent of the cell type, even in tumor cell lines not responding to proteasome inhibitors. Since neither inactivation of p53 in wild-type p53 cells nor reintroduction of functional p53 into p53(-/-) cells affected MG-132-inducible IL-8 secretion, a direct influence of p53 on IL-8 regulation could be excluded. These results show that proteasome inhibitors can not only lead to functional AP-1 induction by enhanced c-Jun phosphorylation, but also transactivate the IL-8 gene in human endothelial cells despite complete suppression of NF-kappaB activity.
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PMID:Proteasome inhibition leads to NF-kappaB-independent IL-8 transactivation in human endothelial cells through induction of AP-1. 1220 33

Transforming growth factor (TGF)-beta(1) is a pleiotropic growth factor with known inhibitory effects on immune cell activation. However, the specific mechanism(s) and in vivo significance of the effectors of TGF-beta(1) modulation in the context of vascular inflammation are not well characterized. The chemokine monocyte chemoattractant protein (MCP)-1 is critical for the recruitment of macrophages in inflammatory disease states. In this study, we provide definitive evidence that the ability of TGF-beta(1) to inhibit MCP-1 expression is mediated via its effector Smad3. Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous MCP-1. Conversely, TGF-beta(1) inhibition of cytokine-mediated induction of MCP-1 expression was completely blocked in Smad3-deficient macrophages. Consistent with this impaired response, cardiac allografts in Smad3-deficient mice developed accelerated intimal hyperplasia with increased infiltration of adventitial macrophages expressing MCP-1. Previous studies show that MCP-1 inducibility is regulated by an AP-1 complex composed of c-Jun/c-Fos heterodimers. We demonstrate that the inhibitory effect of Smad3 occurs via a novel antagonistic effect of Smad3 on AP-1 DNA-protein binding and activity. Thus, Smad3 plays an essential role in modulating vascular inflammation characteristic of transplant-associated arteriopathy, is important in regulating MCP-1 expression, and plays a critical role in the ability of TGF-beta(1) to repress stimuli from a major inflammatory signaling pathway.
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PMID:Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. 1475 27

Expression profiling has previously revealed that acute exposure to the common foodborne mycotoxin deoxynivalenol (DON) induces a large number of immediate early genes in murine lymphoid tissues that potentially affect immune function. The purpose of this study was to test the hypothesis that consumption of (n-3) polyunsaturated fatty acids (PUFAs) found in fish oil interferes with DON-induced immediate early gene expression. Mice were fed AIN-93G diet containing 1% corn oil (CO) plus 6% oleic acid (control) or a diet containing 1% CO, 2% fish oil enriched in the (n-3)-PUFAs docosahexaenoic and eicosapentaenoic acid and 4% oleic acid. After 12 weeks, the mice were gavaged orally with 25 mg/kg DON and the kinetics of immediate early gene expression in spleen monitored over 8 h by real-time polymerase chain reaction (PCR). Deoxynivalenol was found to readily induce expression of cytokines (IL-1alpha, IL-1beta, and IL-6 and IL-11), chemokines (MCP-1, MCP-3, CINC-1 and MIP-2), components of the activator protein-1 (AP-1) transcription factor complex (c-Fos, Fra-2, c-Jun and JunB), as well as two hydrolases (MKP1, CnAbeta). Expression of these genes was transient, peaking within 2-4 h and declining thereafter, with the single exception being IL-11 that was elevated at 8 h. (n-3)-PUFA consumption significantly suppressed DON-induced expression of IL-1alpha, IL-6, IL-11, MCP-1, MCP-3, MIP-2 and Fra-2 at 8 h. In contrast, mice fed (n-3)-PUFA exhibited significant increases in MKP1 and CnAbeta expression. Taken together, these data suggest that dietary supplementation with (n-3)-PUFAs prematurely truncated cytokine, chemokine and transcription factor expression responses to DON that may impact its previously described capacity to disrupt immune function including immunoglobulin A (IgA) production. Since expression of many of these genes has been linked to mitogen-activated protein kinase (MAPK) activation, enhanced expression of MKP1, a negative MAPK regulator in (n-3)-PUFA-fed mice might contribute to this suppression.
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PMID:Truncated deoxynivalenol-induced splenic immediate early gene response in mice consuming (n-3) polyunsaturated fatty acids. 1568 Nov 67

The approximately 20-kDa heat-labile toxin produced by enterotoxigenic Bacteroides fragilis is known to be associated with the development of enteritis. However, the molecular mechanism involved is not yet fully understood. In this study, we assessed whether B. fragilis enterotoxin (BFT)-induced enteritis is related to mitogen-activated protein kinase (MAPK) signaling pathways. In human colon epithelial cells, BFT activated three major MAPK cascades. The activation of p38 was sustained for a relatively long period, while the stimulation of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) was transient. BFT stimulation also activated AP-1 signals composed of c-Jun/c-Fos heterodimers. The p38 inhibitor SB203580 and the ERK inhibitor U0126 reduced not only AP-1 activity, but also decreased IL-8 and MCP-1 expression. In addition, the overexpression of superrepressors for c-Jun and Ras induced by BFT stimulation decreased the levels of IL-8 and MCP-1 production. Furthermore, SB203580 prevented BFT-induced colitis in the mouse ileum, as evidenced by significant decreases in villous destruction, neutrophil infiltration, and mucosal congestion. These results suggest that a pathway, including Ras, MAPK, and subsequent AP-1 activation, is required for IL-8 and MCP-1 expression in intestinal epithelial cells exposed to BFT, and can be involved in the development of enteritis.
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PMID:Mitogen-activated protein kinase and activator protein-1 dependent signals are essential for Bacteroides fragilis enterotoxin-induced enteritis. 1611 10

Biochemical evidence indicates that TGF-beta-activated kinase 1 (TAK1), a key modulator of the inflammatory response, exists in a complex with various adaptor proteins including the TAK1 binding protein 1 (TAB1). However, the physiological importance of TAB1 in TAK1 activation, and in the subsequent induction of proinflammatory mediators, remains unclear. In this study, a critical role for TAK1 in IL-1alpha or TNFalpha stimulated MAPK and NFkappaB activation was confirmed by inhibition of the nuclear accumulation of NFkappaB p65 and phosphorylated forms of c-Jun and p38 following siRNA mediated TAK1 silencing. These effects were associated with significant reductions in IL-1alpha stimulated levels of secreted IL-6, IL-8, MCP-1 and GM-CSF. In contrast, IL-1alpha or TNFalpha dependent cellular redistribution of NFkappaB p65 and phosphorylated c-Jun and p38 was not affected by 80% siRNA mediated knockdown of TAB1 protein levels. Interestingly, IL-6, IL-8 and GM-CSF release from TAB1 siRNA transfected cells was significantly reduced following IL-1alpha treatment, but was unchanged after TNFalpha stimulation, suggesting differential roles for TAB1 in IL-1alpha and TNFalpha signalling pathways. These findings may imply an as yet unidentified role for TAB1 in the inflammatory response, which is independent of the activation of classical TAK1 associated signalling cascades.
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PMID:TAB1 modulates IL-1alpha mediated cytokine secretion but is dispensable for TAK1 activation. 1705 91

The contribution of nutrient overload and associated inflammation to insulin resistance has highlighted several therapeutic targets including c-Jun N-terminal kinase (JNK) and S6 kinase (S6K). To investigate how a lipopolysaccharide (LPS)-mediated inflammatory response may modulate pathways implicated in insulin resistance, we characterized the LPS-induced changes in key biomarkers. Administration of 0.06-4 mg/kg LPS to C57BL/6 mice stimulated increases in plasma levels of TNFalpha, IL-12p40, IL-6 and MCP-1 and in JNK activity as measured by phosphorylated c-Jun in fat. For the first time, we show that LPS induces S6K activity by up to 6.1-fold, as measured by the phosphorylation of S6 ribosomal protein in liver, and increases by up to 1.8-fold, plasma levels of the novel pro-inflammatory cytokine osteopontin which is implicated in the pathogenesis of insulin resistance. These novel findings suggest that LPS administration may form the basis of an acute in vivo pharmacodynamic model for therapies targeting multiple pathways implicated in insulin resistance.
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PMID:LPS-induced biomarkers in mice: a potential model for identifying insulin sensitizers. 1765 59

The transcription factor c-Jun regulates the expression of genes involved in proliferation and inflammation in many cell types but its role in human renal disease is largely unclear. In the current study we investigated whether c-Jun activation is associated with human renal disease and if c-Jun activation regulates pro-inflammatory and pro-fibrotic genes in renal cells. Activation of c-Jun was quantified by scoring renal expression of phosphorylated c-Jun (pc-Jun) in control human renal tissue and in biopsies from patients with various renal diseases (diabetic nephropathy, focal glomerulosclerosis, hypertension, IgA nephropathy, membranous glomerulopathy, minimal change disease, membranoproliferative glomerulonephritis, systemic lupus erythematosus, acute rejection, and Wegener's granulomatosis); this was correlated with parameters of renal damage. Furthermore, we studied the functional role of c-Jun activation in human tubular epithelial cells (HK-2) stimulated with TGF-beta. Activated c-Jun was present in nuclei of glomerular and tubular cells in all human renal diseases, but only sporadically in controls. Across the diseases, the extent of pc-Jun expression correlated with the degree of focal glomerulosclerosis, interstitial fibrosis, cell proliferation, kidney injury molecule-1 (Kim-1) expression, macrophage accumulation, and impairment of renal function. In HK-2 cells, TGF-beta induced c-Jun activation after 1 h (+40%, p < 0.001) and 24 h (+160%, p < 0.001). The specific c-Jun N-terminal kinase (JNK) inhibitor SP600125 abolished c-Jun phosphorylation at all time points and blunted TGF-beta- or BSA-induced procollagen-1alpha 1 and MCP-1 gene expression in HK-2 cells. We conclude that in human renal disease, the transcription factor c-Jun is activated in glomerular and tubular cells. Activation of c-Jun may be involved in the regulation of inflammation and/or fibrosis in human renal disease.
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PMID:Glomerular and tubular induction of the transcription factor c-Jun in human renal disease. 1789 46

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