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)

Fluid shear stress induces a number of morphological and functional changes in vascular endothelium, including a rapid and significant down-regulation of endothelin 1 (ET-1) mRNA and peptide release in bovine aortic endothelial cells. We show here that both the cell alignment and ET-1 down-regulation depend on on-going protein synthesis, and that the latter is the result of a decrease in transcription, as shown by nuclear run-off assay, and not the result of changes in ET-1 mRNA half-life. The treatment of endothelial cells with either phorbol 12-myristate 13-acetate (100 nM) to activate protein kinase C (PKC) or forskolin (10 microM) to stimulate adenylate cyclase sharply decreased ET-1 mRNA. However, the phorbol-induced ET-1 decrease was, unlike the shear-induced down-regulation, independent of active protein synthesis. Physiological shear stress (20 dynes/cm2) did not significantly activate PKC, as assessed by PKC translocation and enzymatic activity assay and failed to increase intracellular cAMP content. Furthermore treatment with calphostin C (1 microM) did not prevent the shear-induced down-regulation of ET-1. DNA transfection experiments suggest that the shear stress-responsive element of the ET-1 gene is contained in the sequence between -2.5 kb and -2.9 kb of the 5'-upstream region. Neither the transcription factor AP-1 binding site nor the GATA-2-factor binding site, necessary for the basal level of transcription of ET-1 gene, is sufficient to confer shear-responsiveness to the reporter gene. These results suggest that shear stress regulates the transcription of the ET-1 gene via an upstream cis element by a distinct mechanism not dependent on the PKC or cAMP pathways.
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PMID:Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP. 839 84

We tested the coupling of endothelin receptors to mitogen-activated protein kinases (MAPK) and nuclear factor c-Jun in intact canine pulmonary artery smooth muscle. Muscle rings denuded of endothelium were stimulated with 10(-7)M ET-1 and frozen during contraction. An <<in-gel>> kinase assay with myelin basic protein as substrate revealed protein kinase activities at 98, 75, 55, 50, 44 and 40 kDa. Erk1 and Erk2 MAPK were activated by ET-1 to 5.4+/-0.97 and 4.03+/-1. 54 times basal activity at 10 min. Using phospho-specific antibodies, we found increased threonine/tyrosine phosphorylation of p38 and JNK1 MAPK to 2.04+/-0.47 and 2.56+/-0.72 times basal. ET-1 increased the phosphorylation level of nuclear factor c-Jun with a time-course closely matching the activation of JNK1 and p38 MAPK. Therefore, endothelin receptors initiate intracellular signals leading to activation of Erk, p38 and JNK1 MAPK pathways and ultimately to nuclear targets. The activation of JNK1 MAPK seems closely related to the phosphorylation of nuclear transcription factor c-Jun.
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PMID:Endothelin-1 activates MAP kinases and c-Jun in pulmonary artery smooth muscle. 991 57

Immortalized rat Schwann cells (iSC) express endothelin (ET) receptors coupled to inhibition of adenylyl cyclase and stimulation of phospholipase C (PLC). These effects precede phenotypic changes and increased DNA synthesis. We have investigated the role of ETs in the regulation of arachidonic acid (AA) release and mitogen-activated protein kinases (MAPKs). Both ET-1 and ET-3 increased AA release in iSC. This effect was sensitive to the phospholipase A(2) (PLA(2)) inhibitors E:-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H:-pyran-2-one and arachidonyl-trifluoromethyl ketone but was insensitive to inhibitors of PLC or phospholipase D-dependent diacylglycerol generation. ET-1-dependent AA release was also unaffected by removal of extracellular Ca(2+) and blocking the concomitant elevation in [Ca(2+)](i), consistent with participation of a Ca(2+)-independent PLA(2). Treatment of iSC with ETs also resulted in activation of extracellular signal-regulated kinase, c-Jun-NH(2)-terminal kinase (JNK), and p38 MAPK. A cause-effect relationship between agonist-dependent AA release and stimulation of MAPKs, but not the opposite, was suggested by activation of JNK by exogenous AA and by the observation that inhibition of MAPK kinase or p38 MAPK was inconsequential to ET-1-induced AA release. Similar effects of ETs on AA release and MAPK activity were observed in cultures expanded from primary SC and in iSC. Regulation of these effectors may mediate the control of proliferation and differentiation of SC by ETs during peripheral nerve development and regeneration.
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PMID:Endothelins regulate arachidonic acid release and mitogen-activated protein kinase activity in Schwann cells. 1108 Jan 83

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 micromol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours, P<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of (3)H-phenylalanine (1.4-fold by ET and 1.5-fold by PE, P<0.01), cell size (2.3-fold and 2.5-fold, P<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold, P<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold, P<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of (3)H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.
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PMID:Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine. 1179 83

Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogenactivated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta MHC), skeletal alpha-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2 alpha (SERCA2 alpha), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, PI3K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.
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PMID:Molecular mechanisms of cardiac hypertrophy induced by toxicants. 1221 66

We previously found that human chymase cleaves big endothelins (ETs) at the Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further degradation products. In the present study, we investigated the effects of various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31) stimulated rapid and significant activation of the mitogen-activated protein (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid), inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase-induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in addition to ET-1 increased the generation of cellular reactive oxygen species (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein-1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an extent similar to that of ET-1. This ET-1 (1-31)-induced increase in [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)-induced RASMC proliferation by inhibiting ROS generation within the cells. The underlying mechanisms of the inhibition of cellular proliferation by antioxidants may be explained, in part, by the inhibition of JNK activation and the resultant inhibition of AP-1-DNA binding.
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PMID:Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1). 1241 65

Three endothelin (ET) isopeptides have been identified: ET-1, ET-2 and ET-3. These have two well-established gross effects on the cardiac myocyte. They affect the contractile properties and they stimulate myocyte growth and myofibrillogenesis. There may be other effects that are less fully characterized (e.g. increased resistance apoptosis). The changes in myocyte biology are brought about by modulation of intracellular signaling pathways. ET-1 binds to the ET(A) receptor on the cell surface and stimulates hydrolysis of phosphatidylinositol 4', 5'-bisphosphate to diacylglycerol and inositol 1', 4', 5'-trisphosphate. Diacylglycerol remains in the plane of the membrane and this causes translocation of the delta- and epsilon-isoforms of protein kinase C (PKC) to that compartment, an event thought to be indicative of PKC activation. The next events (probably associated with PKC activation) are the activation of the small G-protein Ras and of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Over a longer time course, two protein kinase cascades related to the ERK1/2 cascade, the c-Jun N-terminal kinase and p38-mitogen-activated protein kinase (p38-mitogen) cascades, also become activated. As the signals originating from the ET(A) receptor are transmitted through these protein kinase pathways, other signaling molecules become phosphorylated, thus changing their biological activity. Such molecules include nuclear transcription factors (e.g. GATA-4, c-Jun), protein kinases (e.g. 90-kDa ribosomal protein S6 kinase, MAPK-activated protein kinase 2), and ion exchangers/channels (e.g. the Na(+)/H(+) exchanger 1). These changes are responsible for the overall biological effects of ET isopeptides on the myocyte.
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PMID:An overview of endothelin signaling in the cardiac myocyte. 1287 73

Trilinolein, isolated from the traditional Chinese herb Sanchi (Panax notoginseng), has been shown to have myocardial protective effects via its antioxidant ability. However, the cellular and molecular mechanisms of the protective effect of trilinolein in the heart remain to be elucidated. Oxidative mechanisms have been implicated in neonatal cardiomyocyte hypertrophy. We previously reported that ET-1 induces ROS generation via the ET(A) receptor and ROS modulates c-fos gene expression. We have therefore examined whether trilinolein attenuates ROS production and ET-1-induced c-fos gene expression in cardiomyocytes. Cultured neonatal rat cardiomyocytes were stimulated with ET-1 (10 nM), and c-fos gene expression was examined. Trilinolein (1 and 10 microM) inhibited ET-1-induced c-fos gene expression in cardiomyocytes. We also examined the effects of trilinolein on ET-1-increased NADPH oxidase activity and superoxide formation. Trilinolein inhibited ET-1-increased NADPH oxidase activity and superoxide formation in a concentration-dependent manner. This increase in superoxide production by ET-1 was significantly inhibited by trilinolein, diphenyleneiodonium, or N-acetylcysteine. Trilinolein also decreased ET-1- or H2O2-induced extracellular signal-regulated kinase (ERK) phosphorylation, c-Jun NH2-terminal kinase (JNK) phosphorylation, and activator protein-1 activation. These data indicate that trilinolein inhibits ET-1-induced ERK phosphorylation, JNK phosphorylation, and c-fos gene expression via attenuating superoxide production in cardiomyocytes.
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PMID:Inhibitory effect of trilinolein on endothelin-1-induced c-fos gene expression in cultured neonatal rat cardiomyocytes. 1618 2

Endothelin A (ET(A)) transmembrane receptors predominate in rat cardiac myocytes. These are G protein-coupled receptors whose actions are mediated by the G(q) heterotrimeric G proteins. Through these, ET-1 binding to ET(A)-receptors stimulates the hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. Diacylglycerol remains in the membrane whereas inositol 1,4,5-trisphosphate is soluble (though its importance in the cardiac myocyte is still debated). Isoforms of the phospholipid-dependent protein kinase, protein kinase C (PKC), are intracellular receptors for diacylglycerol. Cytoplasmic nPKCdelta and nPKCepsilon detect increases in membrane diacylglycerols and translocate to the membrane. This brings about PKC activation, though modifications additional to binding to phospholipids and diacylglycerol are involved. The next event (probably associated with PKC activation) is the activation of the membrane-bound small G protein Ras by exchange of GTP for GDP. Ras.GTP loading translocates Raf family mitogen-activated protein kinase (MAPK) kinase kinases to the membrane, initiates the activation of Raf, and thus activates the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Over longer times, two analogous protein kinase cascades, the c-Jun N-terminal kinase and p38-mitogen-activated protein kinase cascades, become activated. As the signals originating from the ET(A) receptor are transmitted through these protein kinase pathways, other signalling molecules become phosphorylated, thus changing their biological activities. For example, ET-1 increases the expression of the c-jun transcription factor gene, and increases abundance and phosphorylation of c-Jun protein. These changes in c-Jun expression and phosphorylation are likely to be important in the regulation of gene transcription.
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PMID:Endothelin signalling in the cardiac myocyte and its pathophysiological relevance. 1624 77

The cardiovascular benefit of fish oil in humans and experimental animals has been reported. Endothelin (ET)-1 is a well-known cardiac hypertrophic factor. However, although many studies link a fish oil extract, eicosapentaenoic acid (EPA), to cardiac protection, the effects of EPA on cardiac hypertrophy and underlying mechanism(s) are unclear. The present study investigated whether EPA prevents ET-1-induced cardiomyocyte hypertrophy; the potential pathways likely to underlie such an effect were also investigated. Cardiomyocytes were isolated from neonatal rat heart, cultured for 3 days, and then treated for 24 h with vehicle only (control), treated with 0.1 nM ET-1 only, or pretreated with 10 microM EPA and then treated with 0.1 nM ET-1. The cells were harvested, and changes in cell surface area, protein synthesis, expression of a cytoskeletal (alpha-actinin) protein, and cell signaling were analyzed. ET-1 induced a 97% increase in cardiomyocyte surface area, a 72% increase in protein synthesis rate, and an increase in expression of alpha-actinin and signaling molecule [transforming growth factor-beta 1 (TGF-beta 1), c-Jun NH2-terminal kinase (JNK), and c-Jun]. Development of these ET-1-induced cellular changes was attenuated by EPA. Moreover, the hypertrophied cardiomyocytes showed a 1.5- and a 1.7-fold increase in mRNA expression of atrial and brain natriuretic peptides, the classical molecular markers of cardiac hypertrophy, respectively; these changes were also suppressed by EPA. Here we show that ET-1 induces cardiomyocyte hypertrophy and expression of hypertrophic markers, possibly mediated by JNK and TGF-beta 1 signaling pathways. These ET-1-induced effects were blocked by EPA, a major fish oil ingredient, suggesting that fish oil may have beneficial protective effects on cardiac hypertrophy.
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PMID:Eicosapentaenoic acid prevents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-beta 1 and phosphorylated JNK. 1650 Oct 10


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