Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Endothelin-1 (ET-1), a 21-amino acid vasoactive peptide mainly produced by vascular endothelial cells, is involved in the regulation of vascular tone and smooth muscle cell proliferation. Peroxisome proliferator-activated receptors (PPARs), key players in lipid and glucose metabolism, have been implicated in metabolic disorders that are predisposing to atherosclerosis. Because of the potential role of ET-1 in vascular disorders such as hypertension and atherosclerosis, we investigated the regulation of ET-1 expression by PPAR activators. Western blot and reverse transcription-polymerase chain reaction analyses demonstrated that both PPARalpha and PPARgamma are expressed in human coronary artery endothelial cells as well as in endothelial cell lines such as HMEC-1 and ECV304. In bovine aortic endothelial cells and HMEC-1 cells, both PPARalpha and PPARgamma ligands inhibited thrombin-induced ET-1 secretion, whereas basal ET-1 secretion was only slightly suppressed. Reverse transcription-polymerase chain reaction experiments showed that this inhibition of ET-1 production occurs at the gene expression level. Using transient transfection assays, we demonstrated that PPARs downregulate thrombin-activated transcription of the human ET-1 promoter. Transactivation studies with c-Jun and c-Fos expression plasmids indicated that PPARs negatively interfere with the activator protein-1 signaling pathway, which mediates thrombin activation of ET-1 gene transcription. Furthermore, electrophoretic mobility shift assays demonstrated that PPAR activators reduce the thrombin-stimulated binding activity of bovine aortic endothelial cell nuclear extracts as well as c-Jun binding to an activator protein-1 consensus site. Taken together, these data indicate that (1) both PPARalpha and PPARgamma are expressed in human vascular endothelial cells and (2) PPAR activators inhibit thrombin-induced ET-1 biosynthesis, indicating a novel role for PPARs in vascular endothelial function.
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PMID:Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. 1047 69

We investigated whether peroxisome proliferator-activated receptor gamma (PPARgamma) ligands (ciglitazone, troglitazone, and 15-deoxy-Delta(12,14) prostaglandin J(2)) inhibited cyclooxygenase-2 (COX-2) induction in human epithelial cells. Ligands of PPARgamma inhibited phorbol ester (phorbol 12-myristate 13-acetate, PMA)-mediated induction of COX-2 and prostaglandin E(2) synthesis. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by PPARgamma ligands. PMA-mediated induction of COX-2 promoter activity was inhibited by PPARgamma ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPARgamma or a PPAR response element decoy oligonucleotide. The stimulatory effects of PMA were mediated by a cyclic AMP response element in the COX-2 promoter. Treatment with PMA increased activator protein-1 (AP-1) activity and the binding of c-Jun, c-Fos, and ATF-2 to the cyclic AMP response element, effects that were blocked by PPARgamma ligands. These findings raised questions about the mechanism underlying the anti-AP-1 effect of PPARgamma ligands. The induction of c-Jun by PMA was blocked by PPARgamma ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPARgamma ligands. When CREB-binding protein and c-Jun were overexpressed together, the ability of PPARgamma ligands to suppress PMA-mediated induction of COX-2 promoter activity was essentially abrogated. Bisphenol A diglycidyl ether, a compound that binds to PPARgamma but lacks the ability to activate transcription, also inhibited PMA-mediated induction of AP-1 activity and COX-2. Taken together, these findings are likely to be important for understanding the anti-inflammatory and anti-cancer properties of PPARgamma ligands.
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PMID:Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. 3190 Mar 73

The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.
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PMID:Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. 1128 55

Our previous work has shown that troglitazone (an antidiabetic, thiazolidione drug and a synthetic ligand for peroxisome proliferator-activated receptor gamma, PPARgamma) stimulated basal level of intercellular adhesion molecule-1 (ICAM-1) protein expression in the absence of cytokine stimulation in human vascular endothelial cells. In this study, we examine the molecular mechanism of troglitazone on the basal and TNFalpha-induced ICAM-1 gene expression. Activation of transcription factors, NF-kappaB and AP-1 proteins, known to regulate ICAM-1 gene expression upon external stimulators, was examined. In human vascular endothelial cells (ECV304 cells), troglitazone inhibited TNFalpha-induced ICAM-1 gene expression by suppressing NF-kappaB/DNA binding activity, NF-kappaB transcriptional responses, c-Fos mRNA and protein levels via a ligand-dependent, PPARgamma-activated manner. In contrast, both troglitazone (at 10 microM) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2), at 15 microM), a natural ligand for PPARgamma, induce c-Jun phosphorylation by activation of c-Jun N-terminal kinase (JNK) through a posttranslational regulation of c-Jun activity, therefore increasing AP-1/DNA binding activity and transcriptional responses as results of increasing basal ICAM-1 gene expression. These findings suggest dual function of troglitazone in the modulation of both basal and stimulated ICAM-1gene expression in human vascular endothelial cells.
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PMID:Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium. 1140 21

Transforming growth factor beta (TGF beta) and peroxisome proliferator-activated receptor gamma (PPAR gamma) play major roles in the development of vascular diseases. It has been documented that PPAR gamma activation inhibits the TGF beta signal pathway in vascular smooth muscle cells (VSMC). Here we examined whether TGF beta can regulate PPAR gamma expression. Northern blot analyses revealed that both TGF beta 1 and 2 exert a biphasic effect (early stimulation and late repression) on PPAR gamma gene expression in VSMC. TGF beta rapidly and transiently induced early growth-response factor-1 (Egr-1) expression through the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEK1)/ERK-mediated pathway. Inhibition of MEK1/ERK by PD98059 not only abrogated the induction of Egr-1 but also abolished the rapid and transient induction of PPAR gamma by TGF beta. Furthermore, overexpression of NAB2, a repressor of Egr-1 activation, also blocked the induction of PPAR gamma by TGF beta in VSMC, suggesting that Egr-1 mediates the rapid and transient induction of PPAR gamma by TGF beta. With regard to the TGF beta repression of PPAR gamma expression, activator protein 1 (AP1) and Smad3/4 dramatically inhibited the PPAR gamma promoter activity in transient-transfection studies. In contrast, adenovirus-mediated overexpression of a dominant-negative form of c-Jun partially rescued the TGF beta-induced PPAR gamma repression in VSMC. Taken together, our data demonstrate that Egr-1, AP1 and Smad are part components of the TGF beta signal transduction pathway that regulates PPAR gamma expression.
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PMID:Early stimulation and late inhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression by transforming growth factor beta in human aortic smooth muscle cells: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads. 1245 61

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been the focus of studies assessing its potential neuroprotective role. These studies have shown either neuroprotection or neurotoxicity by PPARgamma ligands. Comparison of these studies is complicated by the use of different PPARgamma ligands, mechanisms of neurotoxicity induction, and neuronal cell type. In this study, we compared the effects of the synthetic PPARgamma ligand ciglitazone with an endogenous PPARgamma ligand, 15-deoxy-delta(12,14)-prostaglandin J(2) (15-deoxy PGJ(2)), on inherent neurotoxicity and neuroprotection using a reduction in extracellular KCl in rat cultured cerebellar granule neurons (CGN). We also assessed the effects of these ligands on c-Jun protein expression, which is up-regulated on induction of low-KCl-mediated neuronal apoptosis as well as being associated with PPAR in other cell types. We showed that PPARgamma mRNA is expressed in CGN cultures and observed ciglitazone- and 15-deoxy PGJ(2)-mediated inherent neurotoxicity that was concentration and time dependent. c-Jun was only modestly increased in the presence of ciglitazone but was markedly up-regulated by 15-deoxy PGJ(2) after 12 hr. Treatment of CGN cultures with ciglitazone simultaneous with KCl withdrawal resulted in a modest, time-dependent neuroprotection. Such neuroprotection after KCl withdrawal was not observed with 15-deoxy PGJ(2). Despite the absence of neuroprotection, 15-deoxy PGJ(2) markedly inhibited the early up-regulation of c-Jun during KCl withdrawal. These studies suggest that ciglitazone and 15-deoxy PGJ(2) have markedly different effects on inherent and low-KCl-induced toxicity and c-Jun expression in CGN, indicating potential non-PPARgamma mechanisms.
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PMID:Effects of peroxisome proliferator-activated receptor gamma ligands ciglitazone and 15-deoxy-delta 12,14-prostaglandin J2 on rat cultured cerebellar granule neuronal viability. 1277 15

Monocyte infiltration followed by differentiation into macrophages and accumulation of oxidised LDL (oxLDL) comprise early stages of atherosclerosis. Vascular endothelial growth factor (VEGF), which is upregulated by oxLDL, may contribute to atherogenesis through monocyte recruitment, increased vascular permeability and promotion of intraplaque vessels. The VEGF receptor-1 (VEGFR-1/Flt-1) mediates monocyte migration towards VEGF and regulates the levels of available VEGF through ligand-entrapment. In this study we investigated the effect of oxLDL on VEGFR-1 expression in human monocyte-derived macrophages. mRNA expression was estimated using RT-PCR, protein secretion was measured with ELISA and the amount of membrane-bound VEGFR-1 was analysed using flow cytometry analysis. Binding of transcription factors to the promoter was studied with EMSA. Incubation with oxLDL decreased VEGFR-1 mRNA expression in a time- and dose-dependent manner, followed by a subsequent decrease in protein secretion of VEGFR-1 and a reduction of the amount of receptor expressed on the cell surface. Furthermore, the PPARgamma agonists 9-hydroxy-(S)-10,12-octadecadienoic acid (9-HODE) and darglitazone also decreased VEGFR-1 mRNA expression. Incubation of macrophages with oxLDL or 9-HODE decreased binding of the transcription factor AP-1 (c-jun/ATF-2) to the VEGFR-1 promoter. Together, these data suggest that oxLDL decreases VEGFR-1 expression in macrophages, probably through a PPARgamma-dependent reduction in the AP-1 transcriptional activity. This implies that oxLDL has effects on the biological availability of VEGF, besides its direct effect on VEGF expression.
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PMID:Oxidised LDL decreases VEGFR-1 expression in human monocyte-derived macrophages. 1292 77

The mechanisms that control the precisely regulated switch from gene repression to gene activation represent a central question in mammalian development. Here, we report that transcriptional activation mediated by liganded nuclear receptors unexpectedly requires the actions of two highly related F box/WD-40-containing factors, TBL1 and TBLR1, initially identified as components of an N-CoR corepressor complex. TBL1/TBLR1 serve as specific adaptors for the recruitment of the ubiquitin conjugating/19S proteasome complex, with TBLR1 selectively serving to mediate a required exchange of the nuclear receptor corepressors, N-CoR and SMRT, for coactivators upon ligand binding. Tbl1 gene deletion in embryonic stem cells severely impairs PPARgamma-induced adipogenic differentiation, indicating that TBL1 function is also biologically indispensable for specific nuclear receptor-mediated gene activation events. The role of TBLR1 and TBL1 in cofactor exchange appears to also operate for c-Jun and NFkappaB and is therefore likely to be prototypic of similar mechanisms for other signal-dependent transcription factors.
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PMID:A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. 1498 Feb 19

Interleukin-1beta (IL-1beta) induces degradation via hyperexpression of an array of genes, including metalloproteinases (MMP), in cartilage cells during articular degenerative diseases. In contrast, natural ligands for peroxisome proliferator-activated receptors (PPARs) display protective anti-cytokine effects in these cells. We used the PPAR agonist rosiglitazone (Rtz) to investigate PPAR-gamma isotype on IL-1beta-target genes. Immunocytochemistry, electrophoretic mobility shift, and transient transfection assays revealed a functional PPAR-gamma in chondrocytes in vitro. Rtz displayed significant inhibition of IL-1beta effects in chondrocytes. Low Rtz concentrations (close to K(d) values for PPAR-gamma, 0.1 to 1 microm) inhibited the effects of IL-1beta on (35)S-sulfated proteoglycan production and gelatinolytic activities and downregulated MMP1 expression at mRNA and protein levels. We have investigated the mechanism of action of Rtz against IL-1beta-mediated MMP1 gene hyperexpression. Rtz effect occurs at the transcriptional level of the MMP1 promoter, as observed in transiently transfected cells with pMMP1-luciferase vector. Transient expression of wild type PPAR-gamma enhanced Rtz inhibitory effect in chondrocytes, whereas a mutated dominant negative PPAR-gamma abolished it, supporting the role of PPAR-gamma in this effect. MMP1 gene promoter analysis revealed the involvement of a cis-acting element located at -83 to -77, shown to be a composite PPRE/AP1 site. Gel mobility and supershift assays demonstrated that PPAR-gamma and c-Fos/c-Jun proteins bind this cis-acting element in a mutually exclusive way. Our data highlight a new PPAR-gamma-dependent inhibitory mechanism on IL-1beta-mediated cartilage degradation occurring through DNA binding competition on the composite PPRE/AP1 site in the MMP1 promoter.
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PMID:Peroxisome proliferator-activated receptor-gamma down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element. 1509 May 44

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in a wide variety of cells. Our studies and others have demonstrated that both human and murine T cells express PPARgamma and that expression can be augmented over time in mitogen-activated splenocytes. PPARgamma ligands decrease proliferation and IL-2 production, and induce apoptosis in both B and T cells. PPARgamma ligands have also been shown to be anti-inflammatory in multiple models of inflammatory disease. In the following study, we demonstrate for the first time that PPARgamma is expressed in both murine CD4 and CD8 cells and that PPARgamma ligands directly decrease IFN-gamma expression by murine and transformed T cell lines. Unexpectedly, GW9662, a PPARgamma antagonist, increases lymphocyte IFN-gamma expression. Transient transfection studies reveal that PPARgamma ligands, in a PPARgamma-dependent manner, potently repress an IFN-gamma promoter construct. Repression localizes to the distal conserved sequence of the IFN-gamma promoter. Our studies also demonstrate that PPARgamma acts on the IFN-gamma promoter by interfering with c-Jun activation. These studies suggest that many of the observed anti-inflammatory effects of PPARgamma ligands may be related to direct inhibition of IFN-gamma by PPARgamma.
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PMID:Repression of IFN-gamma expression by peroxisome proliferator-activated receptor gamma. 1518 32


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