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)

Various Gq protein-coupled receptor agonists such as the alpha1 adrenoceptor agonist phenylephrine, angiotensin II, and endothelin-1 are potent hypertrophic factors. There is evidence of potential cross talk between these agents, particularly in terms of endothelin-1 as playing a central role in mediating the actions of other hypertrophic factors. Using cultured rat neonatal ventricular myocytes, we assessed the potential cross talk between these factors and sought to examine the potential underlying mechanisms. Twenty-four-hour exposure to either agent produced significant hypertrophy as determined by cell size and molecular markers. Although the hypertrophic effects of phenylephrine and angiotensin II were expectedly prevented by alpha1 and AT1 receptor antagonists, respectively, these effects were also blocked by the ETA receptor antagonist BQ123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] but not by the ETB antagonist BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine). Both phenylephrine and angiotensin II significantly increased protein expression of both endothelin receptor subtypes. Both phenylephrine and angiotensin II produced significant activation of p38 as well as extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase, although this was unaffected by endothelin receptor blockade. Further studies revealed that the effects of phenylephrine and angiotensin II were mediated by stimulated endothelin-1 production occurring via two separate mechanisms: angiotensin II by increasing the levels of the endothelin-1 precursor prepro endothelin-1 and phenylephrine by upregulating endothelin-converting enzyme 1. Our results indicate that the endothelin-1 system plays an obligatory role in the hypertrophic response to both phenylephrine and angiotensin II in cultured myocytes through a mechanism independent of mitogenactivated protein kinase activation.
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PMID:Obligatory role for endogenous endothelin in mediating the hypertrophic effects of phenylephrine and angiotensin II in neonatal rat ventricular myocytes: evidence for two distinct mechanisms for endothelin regulation. 1500 6

Serum response factor (SRF) is activated by contractile and hypertrophic agonists, such as endothelin-1 (ET1) to stimulate expression of cytoskeletal proteins in vascular smooth muscle cells (VSMCs). While studying the regulation of smooth muscle alpha-actin (SMA) expression at the level of protein stability, we discovered that inhibition of proteasome-dependent protein degradation by N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) or lactacystin (LC) did not enhance the levels of SMA, but, unexpectedly, attenuated SMA expression in response to ET1, without affecting the viability of VSMCs. Down-regulation of SMA protein by MG132 or LC occurred at the level of SMA transcription and via the inhibition of SRF activity. By contrast, MG132 and LC potentiated the activity of activator protein-1 transcription factor. Regulation of SRF by MG132 was not related to inhibition of nuclear factor-kappaB, an established target of proteasome inhibitors, and was not mediated by protein kinase A, a powerful regulator of SRF activity. Signaling studies indicate that inhibition of ET1-induced SRF activity by MG132 occurs at the level downstream of heterotrimeric G proteins Gq/11 and G13, of small GTPase RhoA, and of actin dynamics but at the level of SRF-DNA binding. MG132 treatment did not result in ubiquitination or accumulation of SRF. By contrast, the levels of c-Jun were rapidly increased upon incubation of cells with MG132, and ectopic overexpression of c-Jun mimicked the effect of MG132 on SRF activity. Together, these data suggest that inhibition of proteasome results in down-regulation of SMA expression via up-regulation of c-Jun and repression of SRF activity at the level of DNA binding.
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PMID:Regulation of serum response factor-dependent gene expression by proteasome inhibitors. 1555 Jun 77

Plasminogen activator inhibitor-1 (PAI-1) has been implicated as a contributing risk factor for cardiovascular disease. However, little is known about molecular mechanisms of cardiac PAI-1 gene expression. To elucidate these mechanisms, dominant negative mutants of c-Jun NH(2)-terminal kinase (JNK), p38MAPK, apoptosis signal-regulating kinase-1 (ASK-1) and c-Jun were overexpressed in rat neonatal ventricular cardiac myocytes and fibroblasts by adenovirus vector to abrogate the activation of the corresponding endogenous proteins. One hundred nmol/l of angiotensin II significantly enhanced the JNK and p38MAPK activities of cardiomyocytes (2.3-fold and 1.9-fold, P < 0.05) and fibroblasts (3.2-fold and 2.5-fold, P < 0.05). At 3 h after stimulation, angiotensin II was found to have significantly increased PAI-1 mRNA, by 5.2-fold in cardiomyocytes and by 9.7-fold in fibroblasts. Dominant negative mutants of JNK, ASK-1 and c-Jun significantly inhibited PAI-1 mRNA expression and protein synthesis in both cardiomyocytes and fibroblasts, whereas a dominant negative mutant of p38MAPK did not change this expression. Moreover, a dominant negative mutant of JNK also significantly prevented the induction of PAI-1 mRNA expression by 100 nmol/l endothelin-1 and 10 micromol/l phenylephrine. In conclusion, G-protein-coupled receptor agonist-induced PAI-1 expression is partially mediated through JNK activation.
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PMID:Role of c-Jun NH2-terminal kinase in G-protein-coupled receptor agonist-induced cardiac plasminogen activator inhibitor-1 expression. 1580 35

The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some of the molecular mechanisms involved. Starting at 8 weeks of diabetes, pioglitazone (10 mg/kg) was administered to STZ-induced diabetic rats for 4 weeks. In untreated STZ rats (vs age-matched control rats): (1) ACh-induced relaxation, cGMP accumulation, phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein at Ser-239 [an established biochemical end-point of nitric oxide (NO)/cGMP signaling], and Cu/Zn-superoxide dismutase (SOD) expression and SOD activity were all reduced; (2) aortic superoxide generation, nitrotyrosine expression, and NAD(P)H oxidase activity were increased; (3) plasma endothelin-1 (ET-1) and aortic c-Jun (AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. Collectively, these results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P)H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway.
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PMID:Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats. 1734 27

Although estrogen replacement therapy may improve dampened endothelial function in postmenopausal women, the associated risk of breast and ovarian cancer has limited its long-term use. Identifying effective alternative remedy with less carcinogenicity is in serious demand. This study was designed to examine the effect of the phytoestrogen alpha-zearalanol (alpha-ZAL) on homocysteine-induced endothelin-1 (ET-1) induction, reactive oxygen species (ROS) production and transcription pathways in human umbilical vein endothelial cells (HUVECs). ROS was measured by DCF fluorescent microscopy. Homocysteine-induced expression of ET-1 mRNA, ERK, pERK and c-jun/AP-1 protein was measured using RT-PCR and Western blot analysis, respectively. ET-1 secretion was determined by the enzymatic immunoassay. Transcriptional factor AP-1 expression in response to alpha-ZAL, homocysteine or both was evaluated by transient transfection assay. Our data revealed that alpha-ZAL ablated homocysteine-elicited ET-1 secretion, upregulated ET-1 mRNA and homocysteine-induced ROS accumulation without any effects by itself. alpha-ZAL also nullified homocysteine-induced increase in c-Jun/AP-1 expression/activity without eliciting any effect by itself. Collectively, our data indicated that alpha-ZAL may antagonize homocysteine-induced ET-1 gene induction, ROS accumulation, activation of ERK signaling pathway and AP-1 transcriptional factor, all of which may contribute to alpha-ZAL-induced beneficial effect on endothelial function.
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PMID:Phytoestrogen alpha-zearalanol inhibits homocysteine-induced endothelin-1 expression and oxidative stress in human umbilical vein endothelial cells. 1790 May 92

Reactive gliosis is characterized by enhanced glial fibrillary acidic protein (GFAP) expression, cellular hypertrophy, and astrocyte proliferation. The cellular and molecular mechanisms underlying this process are still largely undefined. We investigated the role of endothelin-1 (ET-1) in reactive gliosis in corpus callosum after lysolecithin (LPC)-induced focal demyelination and in cultured astrocytes. We show that ET-1 levels are upregulated in demyelinated lesions within 5 d after LPC injection, together with enhanced astrocyte proliferation, GFAP expression, and JNK phosphorylation. Infusion of the pan-ET-receptor (ET-R) antagonist Bosentan or the selective ET(B)-R antagonist BQ788 into the corpus callosum prevented postlesion astrocyte proliferation and JNK phosphorylation. In cultured astrocytes, ET-1-induced activation of ET(B)-Rs promotes a reactive phenotype by enhancing both GFAP expression and astrocyte proliferation. In the same cells, ET-1 activates both JNK and p38MAPK pathways, and induces c-Jun expression at the mRNA and protein levels. By using selective pharmacological inhibitors, we also provide evidence that ET-1 induces astrocyte proliferation and GFAP expression through activation of ERK- and JNK-dependent pathways, consistent with the previous observation of ET-1-induced activation of ERK (Schinelli et al., 2001). Finally, we show by gain and loss of function that increased c-Jun expression enhances the proliferative response of astrocytes to ET-1, whereas c-jun siRNA prevents ET-1-induced cell proliferation. Our results indicate that the effects of ET-1 on astrocyte proliferation depend on c-Jun induction and activation through ERK- and JNK-dependent pathways, and suggest that ET-R-associated pathways might represent important targets to control reactive gliosis.
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PMID:Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. 1832 86

In vivo, endothelial cells are constantly exposed to shear stress by flowing blood. Short-term exposure of endothelial cells to shear stress has been shown to induce endothelin-1 release. It is currently unknown, however, whether this shear stress-dependent endothelin-1 release affects the expression and activity of transcription factors. In this study, primary cultures of human endothelial cells from the umbilical vein were exposed to laminar shear stress in a cone-and-plate viscometer. Laminar shear stress for 30 min induced a 2-fold increase in mRNA expression of c-jun , but not c-fos, in human endothelial cells. Blockade of endothelin receptor subtype B (ET B) with BQ788 prevented this shear stress-dependent induction of c-jun expression. The induction of c-jun by shear stress involved protein kinase C and endothelial NO synthase. In addition, exposure of endothelial cells to arterial laminar shear stress for 1 h increased the binding of transcription factor AP-1 to its consensus sequence by 1.7-fold in electrophoretic mobility shift assays. This induction was also mediated by an ET B-dependent pathway. Supershift analysis supports an AP-1 complex containing c-jun, but not c-fos, in human endothelial cells. In conclusion, our data suggest endothelin-1-mediated induction of c-jun expression and activation of AP-1 (possibly as a c-jun homodimer) by laminar shear stress in human endothelial cells.
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PMID:Endothelin receptor B-mediated induction of c-jun and AP-1 in response to shear stress in human endothelial cells. 1875 96

Angiotensin II was reported to induce insulin-like growth factor-I and endothelin-1 gene expression and peptide release by ventricular cardiomyocytes. However, the progression from cardiac hypertrophy to failure in humans is characterized by a reduced myocyte expression of insulin-like growth factor-I and endothelin-1, notwithstanding the enhanced cardiac generation of angiotensin II. In the present study we investigated the functional status of the signaling pathways responsible for angiotensin II-induced endothelin-1 and insulin-like growth factor-I formation in human ventricular myocytes isolated from patients with dilated (n = 19) or ischemic (n = 14) cardiomyopathy and nonfailing donor hearts (n = 6).In human nonfailing ventricular myocytes, angiotensin II (100 nmol/l) induced insulin-like growth factor-I and endothelin-1 gene expression, and peptide release was mediated by extracellular signal-regulated kinase activation and inhibited by extracellular signal-regulated kinase antagonism (PD98059, 30 micromol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 micromol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 micromol/l) and Janus tyrosine kinase 2 (AG490, 10 micromol/l). In failing myocytes, angiotensin II failed to induce insulin-like growth factor-I and endothelin-1 formation; angiotensin II-induced extracellular signal-regulated kinase activation was significantly impaired (-88% vs. controls) although c-Jun NH2-terminal kinase activation was preserved. The impaired extracellular signal-regulated kinase phosphorylation in failing myocytes was associated with increased myocyte levels of mitogen-activated protein kinase phosphatases.Therefore, the altered growth factor production in failing myocytes is associated with a significant derangement in intracellular signaling.
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PMID:Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes. 1880 28

Endothelin-1 is considered to be an important mediator in the pathophysiology of asthma because it induces contraction, hypertrophy, and proliferation in airway smooth muscle cells as well as inflammatory responses in the airway. Airway smooth muscle cells have been suggested to contribute to airway inflammation in asthma by producing cytokines. Nevertheless, the role of intracellular Ca(2+) signal in cytokine production in human airway smooth muscle cells is still unclear. We investigated the mechanisms by which endothelin-1 induces production of interleukin (IL)-6, a pleiotropic cytokine, in primary cultured human airway smooth muscle cells. Levels of IL-6 protein and mRNA were significantly increased by endothelin-1 in dose- and time-dependent manners. Endothelin-1-induced IL-6 production was markedly attenuated by EGTA and various Ca(2+) channel inhibitors such as 3,5-bis(trifluoromethyl)-1H-pyrazole derivative (BTP-2), 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF96365), and nifedipine. Endothelin-1-induced increases in intracellular Ca(2+) concentrations were significantly inhibited in Ca(2+)-free solution and by BTP-2, SKF96365, and nifedipine. The IL-6 synthesis was also inhibited by the extracellular signal-regulated kinase (ERK)1/2 inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)-butadiene ethanolate (U0126) and the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), but not by the c-Jun NH2-terminal kinase inhibitor anthra[1,9-cd]-pyrazol-6-(2H)-one (SP600125). Endothelin-1 significantly upregulated phosphorylation of ERK1/2 and p38 but blocking Ca(2+) influx pathways did not inhibit either upregulation. These findings demonstrate that endothelin-1-induced IL-6 synthesis in airway smooth muscle cells occurs via two parallel but independent events that include Ca(2+) influx and activation of ERK1/2 and p38.
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PMID:Regulation of endothelin-1-induced interleukin-6 production by Ca2+ influx in human airway smooth muscle cells. 1917 Nov 35

The bioactivity of endothelin-1 (ET-1) has been suggested in the development of CNS diseases, including disturbance of water homeostasis and blood-brain barrier integrity. Recent studies suggest that hypoxic/ischemic injury of the brain induces release of ET-1, behaving through a G-protein coupled ET receptor family. The deleterious effects of ET-1 on astrocytes may aggravate brain inflammation. Increased plasma levels of matrix metalloproteinases (MMPs), in particular MMP-9, have been observed in patients with neuroinflammatory disorders. However, the detailed mechanisms underlying ET-1-induced MMP-9 expression remain unknown. In this study, the data obtained with zymographic, western blotting, real-time PCR, and immunofluorescent staining analyses showed that ET-1-induced MMP-9 expression was mediated through an ET(B)-dependent transcriptional activation. Engagement of G(i/o)- and G(q)-coupled ET(B) receptor by ET-1 led to activation of p42/p44 MAPK and then activated transcription factors including Ets-like kinase, nuclear factor-kappa B, and activator protein-1 (c-Jun/c-Fos). These activated transcription factors translocated into nucleus and bound to their corresponding binding sites in MMP-9 promoter, thereby turning on MMP-9 gene transcription. Eventually, up-regulation of MMP-9 by ET-1 enhanced the migration of astrocytes. Taken together, these results suggested that in astrocytes, activation of Ets-like kinase, nuclear factor-kappa B, and activator protein-1 by ET(B)-dependent p42/p44 MAPK signaling is necessary for ET-1-induced MMP-9 gene up-regulation. Understanding the mechanisms of MMP-9 expression and functional changes regulated by ET-1/ET(B) system on astrocytes may provide rational therapeutic interventions for brain injury associated with increased MMP-9 expression.
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PMID:Endothelin-1 enhances cell migration via matrix metalloproteinase-9 up-regulation in brain astrocytes. 2034 68

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