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)

We have previously shown that murine recombinant leptin directly stimulates catecholamine synthesis through the long form of the leptin receptor (Ob-Rb) expressed in cultured porcine chromaffin cells. Additionally, we found that leptin activates IP3 production after PLC activation. It is well established that activation of PLC elicits IP3 production as well as an increase in diacylglycerol, a compound that stimulates PKC. Therefore, we investigated the involvement of PKC in leptin-induced catecholamine synthesis. Leptin was found to induce significant increases in PKC activity in a dose-dependent manner (1, 10, and 100 nM); chelation of extracellular Ca(2+) by EDTA abolished this PKC stimulatory activity. We also confirmed by Western blot analysis that leptin (at 100 nM) induced significant increases in Ca(2+)-dependent PKC alpha, -beta(I), and -gamma expression. The activity of the rate-limiting enzyme tyrosine hydroxylase (TH) in the biosynthesis of catecholamine is regulated at the transcriptional and posttranscriptional levels. TH enzyme activity and TH mRNA levels induced by 100 nM leptin were significantly inhibited by the PKC inhibitor Ro 32-0432 as well as by EDTA. In addition, increases in TH protein and intracellular catecholamine content stimulated by leptin were completely inhibited by Ro 32-0432. Leptin markedly activated ERKs and, to a lesser extent, JNK; these stimulatory effects on ERKs and JNK were completely inhibited by Ro 32-0432 as well as EDTA. In contrast, leptin did not activate P38 MAPK. Similar to leptin, PMA activated ERK and JNK. Nicardipine and omega-conotoxin GVIA, each at 1 microM, were effective at inhibiting leptin-induced TH enzyme activity, TH mRNA accumulation, PKC activity, and ERK activity. Leptin increased activating protein-1 DNA-binding activity, and this was diminished by Ro 32-0432 as well as EDTA, similar to the reduction of TH mRNA levels. In addition, using supershift analysis, we documented the involvement of c-Fos and, to a lesser extent, c-Jun in leptin-induced activating protein-1 activity. These results indicate that leptin stimulates Ca(2+)-dependent PKC isoform-dependent catecholamine synthesis in porcine chromaffin cells. Previously, we had shown that leptin stimulated cAMP. The present study also showed that H89 (a PKA inhibitor) moderately, but significantly, inhibited leptin-induced ERK and TH mRNA. Consistent with this finding, leptin is shown here to activate novel PKC epsilon, which is assumed to stimulate Raf, upstream of ERKs, via cAMP, supporting the suggestion that Ca(2+)-independent novel PKC may also play some physiological role in regulating catecholamine synthesis.
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PMID:Leptin stimulates catecholamine synthesis in a PKC-dependent manner in cultured porcine adrenal medullary chromaffin cells. 1160 54

The activator protein 1 (AP-1) transcription factor is composed of heterodimers of the Fos/activating transcription factor (ATF) and Jun subfamilies of basic-region leucine-zipper (B-ZIP) proteins. In order to determine the identities of individual B-ZIP proteins in various AP-1 complexes we tested the effect of dominant-negative mutants to the B-ZIP proteins c-Fos, ATF2, ATF4 and CCAAT-enhancer-binding protein (C/EBP) on the activities of the collagenase and c-Jun promoters. These dominant-negative mutants inhibit DNA binding of wild-type B-ZIP proteins in a leucine-zipper-dependent fashion. Transcription of a collagenase promoter/reporter gene was induced in HepG2 hepatoma cells by expression of c-Fos and c-Jun, administration of PMA ("TPA") or by expression of a truncated form of MEK (mitogen-activated/extracellular-signal-regulated kinase kinase) kinase-1, MEKK1Delta. In all cases, the dominant-negative mutants A-Fos and A-ATF2 decreased collagenase promoter activity. However, A-ATF4 and A-C/EBP had no effect. A-Fos and A-ATF2 also reduced MEKK1Delta-induced stimulation of the c-Jun promoter. In contrast, constitutive c-Jun promoter activity was blocked solely by A-ATF2, strongly suggesting that ATF2 and/or an ATF2-dimerizing protein are of major importance for c-Jun transcription in unstimulated cells. These results demonstrate that AP-1 transcription factors of different compositions control c-jun gene transcription in resting or stimulated cells.
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PMID:Regulation and composition of activator protein 1 (AP-1) transcription factors controlling collagenase and c-Jun promoter activities. 1173 49

Bikunin (bik, also known as urinary trypsin inhibitor [UTI]), a Kunitz-type protease inhibitor, interacts with cells as a negative modulator of the invasive cells. Human ovarian cancer cell line, HRA, was treated with phorbol ester (PMA) in order to evaluate the effect on expression of urokinase-type plasminogen activator (uPA). Preincubation of the cells with bik reduced the ability of PMA to trigger the uPA expression at the gene level and at the protein level. We next asked whether the mechanism of inhibition of uPA expression by bik is due to interference with MAP kinase, since PMA could also activate a signaling pathway involving MEK/ERK/c-Jun-dependent uPA expression. When cells were preincubated with bik, we could detect suppression of phosphorylation of these proteins, demonstrating that bik markedly suppresses the cell motility possibly through negative regulation of MEK/ERK/c-Jun-dependent mechanisms, and that these changes in behavior are correlated with a coordinated down-regulation of uPA which is likely to contribute to the cell invasion processes. To clarify the role of bik on tumor metastasis, HRA cells were transfected with an expression vector harboring a cDNA encoding for human bik. Transfection of HRA with the bik cDNA resulted in five variants stably expressing functional bik and significantly reduced invasion, but not proliferation, adhesion, or migration relative to the parental cells. Animals with bik* transfectants induced reduced peritoneal dissemination and long term survival. These results suggest that transfection with the bik gene induces the suppression of tumor cell invasion and peritoneal dissemination, and can prolong survival. This pre-clinical animal model offers the possibility to explore gene therapy as a new treatment modality for ovarian cancer.
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PMID:Suppression of urokinase expression and tumor metastasis by bikunin overexpression [mini-review]. 1177 42

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anticancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptor-alpha and CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptor-alpha relieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms.
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PMID:Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms. 1198 Jun 44

The 92-kDa type IV collagenase (MMP-9) contributes to tumor invasion and metastases and strategies to down-regulate its expression could ultimately be of clinical utility. Although the expression of this collagenase is regulated by numerous growth factors, the signaling pathways that transduce these signals are fewer in number and therefore represent pharmacological targets. In this regard, we previously reported that MMP-9 expression was regulated by the c-jun amino terminal kinase (JNK) signaling cascade. Therefore, we undertook a study to determine the efficacy of a novel compound (SP600125), which binds to the ATP binding site of all known JNKs, in repressing MMP-9 expression. In OVCAR-3 cells, SP600125 inhibited the PMA-dependent secretion of MMP-9 in a time-dependent manner and over a dose range that blocked c-Jun phosphorylation and AP-1 binding. SP600125 repressed the activity of a PMA-stimulated MMP-9 promoter-driven luciferase reporter, suggesting that diminished secretion of this collagenase reflected reduced transcription. Further, the activity of a GAL4-driven reporter in PMA-treated cells, co-transfected with an expression construct encoding the trans-activation domain of c-Jun fused to the DNA binding domain of GAL4, was repressed by SP600125. These findings indicate the efficacy of SP600125 in inhibiting c-Jun activation, DNA-binding and the PMA-dependent induction of MMP-9 expression.
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PMID:An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression. 1203 98

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are drugs very effective to decrease low-density lipoprotein (LDL) cholesterol. In addition, a number of studies suggest that statins have other beneficial clinical effects beyond cholesterol lowering. We recently reported that statins decrease nuclear factor kappa B (NF-kappaB) binding activity in monocytes and vascular smooth muscle cells. We now explored the effect of two different statins, simvastatin and atorvastatin, in the activation of the octamer transcription factor Oct-1 on the monocytic cell line THP-1. Oct-1 is a nuclear factor that represses the transcription of proinflammatory genes such as interleukin-8, CD11c/CD18, vascular cell adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1). Low concentrations of both statins increased Oct-1 DNA binding activity (electrophoretic mobility shift assay) that was resolved into two specific bands. The upper one was supershifted by preincubation of nuclear extracts with anti-Oct-1 antibody. The lower one was supershifted by preincubation of nuclear extracts with an anti-Oct-2 antibody, also partially competed with 100 mol/l excess of cold activator protein-1 (AP-1) and attenuated by anti-c-Jun antibody. Both statins increased Oct-1 and Oct-2 nuclear protein levels (Western blot). In contrast, neither had any effect on PMA-differentiated cells, suggesting a distinct sensitivity between circulating monocytes and resident tissular macrophages. In addition, statins did not increase Oct-lipoprotein lipase binding activity that contains an Oct-1 binding element. The mRNA expression of interleukin-8, a chemokine containing Oct sites in its promoter, was diminished by statin pretreatment. Our results indicate that simvastatin and atorvastatin increase the activity of the transcriptional repressor Oct-1 in mononuclear cells, and could thus contribute to decrease the activation of these cells. These data suggest a possible novel mechanism supporting a certain anti-inflammatory effect of these two 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors.
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PMID:3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the binding activity and nuclear level of Oct-1 in mononuclear cells. 1214 30

Cardiac hypertrophy, an important adaptational response, is associated with up-regulation of the immediate early gene, c- jun, which encodes the c-Jun transcription factor. c-Jun may feed back to up-regulate its own transcription and, since the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) phosphorylate c-Jun(Ser-63/73) to increase its transactivating activity, JNKs are thought to be the principal factors involved in c- jun up-regulation. Hypertrophy in primary cultures of cardiac myocytes is induced by endothelin-1, phenylephrine or PMA, probably through activation of one or more of the MAPK family. These three agonists increased c- jun mRNA with the rank order of potency of PMA approximately endothelin-1>phenylephrine. Up-regulation of c- jun mRNA by endothelin-1 was attenuated by inhibitors of protein kinase C (GF109203X) and the extracellular signal-regulated kinase (ERK) cascade (PD98059 or U0126), but not by inhibitors of the JNK (SP600125) or p38-MAPK (SB203580) cascades. Hyperosmotic shock (0.5 M sorbitol) powerfully activates JNKs, but did not increase c- jun mRNA. These data suggest that ERKs, rather than JNKs, are required for c- jun up-regulation. However, endothelin-1 and phenylephrine induced greater up-regulation of c-Jun protein than PMA and phosphorylation of c-Jun(Ser-63/73) correlated with the level of c-Jun protein. Up-regulation of c-Jun protein by endothelin-1 was attenuated by inhibitors of protein kinase C and the ERK cascade, probably correlating with a primary input of ERKs into transcription. In addition, SP600125 inhibited the phosphorylation of c-Jun(Ser-63/73), attenuated the increase in c-Jun protein induced by endothelin-1 and increased the rate of c-Jun degradation. Thus whereas ERKs are the principal MAPKs required for c- jun transcription, JNKs are necessary to stabilize c-Jun for efficient up-regulation of the protein.
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PMID:Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein. 1216 99

Human N -acetyltransferase Type I (NAT1) catalyses the acetylation of many aromatic amine and hydrazine compounds and it has been implicated in the catabolism of folic acid. The enzyme is widely expressed in the body, although there are considerable differences in the level of activity between tissues. A search of the mRNA databases revealed the presence of several NAT1 transcripts in human tissue that appear to be derived from different promoters. Because little is known about NAT1 gene regulation, the present study was undertaken to characterize one of the putative promoter sequences of the NAT1 gene located just upstream of the coding region. We show with reverse-transcriptase PCR that mRNA transcribed from this promoter (Promoter I) is present in a variety of human cell-lines, but not in quiescent peripheral blood mononuclear cells. Using deletion mutant constructs, we identified a 20 bp sequence located 245 bases upstream of the translation start site which was sufficient for basal NAT1 expression. It comprised an AP-1 (activator protein 1)-binding site, flanked on either side by a TCATT motif. Mutational analysis showed that the AP-1 site and the 3' TCATT sequence were necessary for gene expression, whereas the 5' TCATT appeared to attenuate promoter activity. Electromobility shift assays revealed two specific bands made up by complexes of c-Fos/Fra, c-Jun, YY-1 (Yin and Yang 1) and possibly Oct-1. PMA treatment enhanced expression from the NAT1 promoter via the AP-1-binding site. Furthermore, in peripheral blood mononuclear cells, PMA increased endogenous NAT1 activity and induced mRNA expression from Promoter I, suggesting that it is functional in vivo.
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PMID:Identification of a minimal promoter sequence for the human N-acetyltransferase Type I gene that binds AP-1 (activator protein 1) and YY-1 (Yin and Yang 1). 1294 72

Human 12(S)-lipoxygenase is a platelet-type 12(S)-lipoxyenase. Its expression is detected in human erythroleukemia cells, human skin epidermal cells and human epidermoid carcinoma A431 cells. Treatment of A431 cells with EGF or PMA induces the gene expression of human 12(S)-lipoxygenase. The induction of gene expression is mediated through the cell signaling of MAPK activation, followed by the induction of c-Jun expression. The transcription factor Sp1 binding to the two Sp1 recognition motifs residing at -158 to 150 bp and -123 to 114 bp in the gene promoter is found to be essential for both EGF- and PMA-induced gene expression of human 12(S)-lipoxygenase. However, no change of Sp1 binding to GC-rich sequence was observed while no AP-1-binding site can be found in the responsive region of the promoter in EGF- and PMA-induced promoter activation of the human 12(S)-lipoxygenase gene. Since both of the transcription factors c-Jun and Sp1 are prerequisite for EGF and PMA response, interaction between c-Jun and Sp1 may account for the functional regulation of human 12(S)-lipoxygenase gene regulation. The direct and cooperative interaction between c-Jun and Sp1 induced by EGF or PMA activates the expression of the human 12(S)-lipoxygenase gene. Therefore, Sp1 may serve at least in part as a carrier to bring c-Jun to the promoter, thu's transactivating the transcriptional activity of the human 12(S)-lipoxygenase gene.
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PMID:Cell signaling and gene regulation of human 12(S)-lipoxygenase expression. 1451 67

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

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