Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.
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PMID:Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA. 784 46

Endothelins are paracrine or autocrine peptides that regulate diverse aspects of renal function. In addition to their potent vasoconstrictor activity, recent evidence suggests that endothelin-1 is a growth factor for renal cells. Different forms of renal injury markedly upregulate endothelin-1 secretion, which is postulated to contribute to compensatory renal growth. Similar roles have been hypothesized for other vasoactive peptides, such as angiotensin II and arginine vasopressin. New information has recently emerged regarding pathways of mitogenic signaling linking activation of endothelin receptors to changes in gene expression. ETA receptor subtypes activate downstream effectors, such as protein kinase C, protein tyrosine kinases of the src gene family, and mitogen-activated protein kinases. These cytosolic effectors in turn lead to altered programs of gene expression by activating, among others, AP-1 and serum response factor transcription factors. In addition, recent studies in organisms amenable to genetic analysis, such as Drosophila, Dictyostelium, and yeast, are providing important clues to effector mechanisms employed by vasoactive peptide receptors in higher organisms. Information on the molecular mechanisms for mitogenic signaling by endothelin receptors might be used to gain insight into the pathogenesis of compensatory renal growth and the development of novel therapeutic strategies.
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PMID:Endothelin peptides and compensatory growth of renal cells. 785 Apr 15

The vasoactive peptides endothelin-1 (ET-1) and angiotensin-II (AII) have been implicated in chronic hypertension and may play important roles in related vascular diseases such as restenosis and atherosclerosis. Using a rat aortic smooth muscle (RASM) cell model, both ET-1 and AII induced concentration-dependent delayed increases in DNA synthesis relative to that in the serum-deprived controls. Stimulation of DNA synthesis was maximal at 100 nM for each peptide. All treatment of RASM cells resulted in a greater mitogenic effect (4- to 7-fold) than that observed for ET-1 (3-fold). When added in the presence of AII, ET-1 had a supplemental effect on DNA synthesis (5- to 10-fold above control). Although RASM cells expressed both ETA and AT1 receptors, radioligand binding experiments indicated that approximately 10-fold as many AT1 receptors as ETA receptors were present. In signal transduction studies, ET-1 and AII each elicited concentration-dependent increases in the intracellular Ca2+ concentration. ET-1 and AII also stimulated phosphoinositide metabolism and phosphorylation of a specific substrate for protein kinase-C. The release of total inositol phosphates in response to ET-1 and AII was concentration dependent and inhibited by the ETA receptor-selective antagonist BQ-123 and the AT1 receptor-selective antagonist losartan, respectively. In addition, tyrosine phosphorylation of 120- and 75-kilodalton proteins as well as the mitogen-activated protein kinases p44mapk and p42mapk was observed within 5 min of the addition of either ET-1 or AII. Taken together, these data indicate that ET-1 and AII may promote smooth muscle cell growth through common intracellular signaling mechanisms.
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PMID:Endothelin-1 and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for common signaling mechanisms. 817 Apr 71

Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. ET-1 has been shown to activate p42 and p44 mitogen-activated protein kinases (MAPKs), also known as extracellular signal regulated kinases (ERKs), through both protein kinase C (PKC) and protein tyrosine kinase (PTK)-dependent pathways. However, an involvement of c-Jun NH2-terminal kinase (JNK), one of members of the MAPK family, in ET-1 signaling in mesangial cells has not yet been elucidated. To clarify this point, we examined whether ET-1 could activate JNK and the mechanism of activation in cultured mesangial cells. ET-1 enhanced the activities of JNK in a dose-dependent (10(-8) M maximum) and time-dependent manner, with a peak at 15 minutes. ET-1-induced activation of JNK was blocked by BQ-123, an antagonist for the ETA receptor. The depletion of PKC by prolonged treatment with phorbol 12,13 dibutyrate or the inhibition of PKC by GF 109203X failed to inhibit ET-1-induced activation of JNK. In contrast, ET-1-induced activation of JNK was significantly reduced by calcium chelation (with BAPTA/AM and EGTA). In addition, ionomycin, a calcium ionophore, and thapsigargin, an intracellular calcium-rising agent, were able to induce the activation of JNK. ET-1-induced activation of JNK was also inhibited by PTK inhibitors (herbimycin A and genistein). Furthermore, ET-1 increased the DNA-binding activity of AP-1 containing c-Jun and c-Fos proteins. These results indicate that ET-1 is able to activate JNK in glomerular mesangial cells through PKC-independent and PTK-dependent pathways and intracellular calcium is necessary to the activation of JNK.
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PMID:Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells. 906 93

We have previously shown that in NIH 3T3 fibroblasts phosphocholine (PCho) potentiates sphingosine-1-phosphate (S1P)-induced mitogenesis. Here we report that PCho and S1P also synergistically stimulate DNA synthesis in mouse Swiss 3T3 fibroblasts and in mouse JB6 epidermal cells. The combined actions of PCho and S1P on DNA synthesis were associated with synergistic activation of the p42/p44 mitogen-activated protein (MAP) kinases. Ethanolamine (50-100 microM) further enhanced the synergistic effects of PCho and SIP on DNA synthesis but not on MAP kinase activity. The results indicate that the synergistic mitogenic effects of PCho and S1P (i) are not restricted to NIH 3T3 fibroblasts, (ii) are predominantly mediated by the MAP kinase-dependent signal transduction pathway, and (iii) are enhanced by ethanolamine via a MAP kinase-independent mechanism.
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PMID:Phosphocholine and sphingosine-1-phosphate synergistically stimulate DNA synthesis by a MAP kinase-dependent mechanism. 925 19

In this work, we determined the effects of sphingosine 1-phosphate (S1P) on phospholipase D (PLD)-mediated hydrolysis of phosphatidylethanolamine (PtdEtn), and evaluated the effects of the water-soluble product ethanolamine on S1P-induced DNA synthesis in NIH 3T3 cells. In [14C]ethanolamine-labelled cells, S1P (0.5-5 microM) stimulated PLD-mediated hydrolysis of PtdEtn 1.5-2.1-fold. Down-regulation of protein kinase C by chronic (24 h) treatment of cells with 300 nM PMA, or pretreatments (10 min) with the cell-permeant calcium chelator 1,2-bis-(O-aminophenoxy)-ethane-N,N, N',N'-tetra-acetic acid tetra-acetoxymethyl ester led to the inhibition of S1P-induced PtdEtn hydrolysis. S1P alone was a weak inducer of DNA synthesis, but its effects were enhanced by phosphocholine (PCho), insulin, ATP or PMA. Ethanolamine (5-100 microM) did not modify the mitogenic effect of S1P alone, whereas at 50-100 microM concentrations it actually enhanced the mitogenic effect of PCho via a mitogen-activated protein (MAP) kinase-independent mechanism. In contrast, 5-20 microM concentrations of ethanolamine, which correspond to normal blood ethanolamine levels in humans, strongly inhibited DNA synthesis induced by S1P plus PCho via a MAP kinase-dependent mechanism; importantly, less or no inhibition was observed with 50-100 microM concentrations of ethanolamine. At 5-50 microM concentrations, ethanolamine also inhibited the synergistic mitogenic effects of both S1P plus insulin (22-27% inhibition) and PCho plus ATP (45-73% inhibition) but not those of S1P plus PMA or S1P plus ATP. The results indicate that S1P stimulates PLD-mediated hydrolysis of PtdEtn by a mechanism that may involve a regulatory protein kinase C isoform. Increased formation of ethanolamine by PLD-mediated PtdEtn hydrolysis or by other means may be required for maximal stimulation of DNA synthesis by S1P in the presence of insulin, and particularly PCho.
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PMID:Extracellular sphingosine 1-phosphate stimulates formation of ethanolamine from phosphatidylethanolamine: modulation of sphingosine 1-phosphate-induced mitogenesis by ethanolamine. 937 92

Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, exerts a growth-promoting effect on vascular smooth muscle cells, implicating its pathogenic role in vascular remodeling. To gain insight into the cellular and molecular mechanism whereby ET-1 induces vascular growth, we studied whether transactivation of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, are required for activation of p42/p44 mitogen-activated protein (MAP) kinase and p70 S6 kinase (p70S6K), and subsequent growth-promotion by ET-1 in cultured rat vascular smooth muscle cells. Immunoblotting with antiphosphotyrosine antibody revealed that ET-1 rapidly (within 2 min) and transiently induced tyrosine phosphorylation of several proteins, among which 180-kDa protein was shown to be EGFR. ET-1 rapidly increased association of EGFR and Shc with glutathione-S-transferase-Grb2 fusion protein. The ET-1-induced activation of MAP kinase was reduced by an EGFR kinase inhibitor (AG1478) but not by a platelet-derived growth factor receptor kinase inhibitor (AG1296). AG1478 dose-dependently decreased ET-1-stimulated MAP kinase activity as well as [3H]leucine and [3H]thymidine uptake. The ET-1-induced tyrosine phosphorylation of EGFR, as well as MAP kinase activation, was inhibited by an ETA receptor antagonist and intracellular Ca2+ antagonists but not by an ETB receptor antagonist, pertussis toxin, or protein kinase C inhibitors. In addition, dominant negative mutant of H-Ras and a MAP kinase kinase (MEK-1) inhibitor (PD98059) completely blocked ET-1-induced MAP kinase activation as well as [3H]leucine and [3H]thymidine uptake. Both AG1478 and PD98059 inhibited ET-1-induced phosphorylation and activation of p70S6K. Furthermore, rapamycin, a selective inhibitor of mammalian target of rapamycin, completely blocked ET-1-stimulated [3H]leucine and [3H]thymidine uptake. These results suggest that ETA receptor-mediated vascular growth by ET-1 requires both MAP kinase and p70S6K cascades mediated partly via Ca2+-dependent EGFR transactivation.
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PMID:Endothelin-mediated vascular growth requires p42/p44 mitogen-activated protein kinase and p70 S6 kinase cascades via transactivation of epidermal growth factor receptor. 1049 23

Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ETA receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.
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PMID:Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. 1266 84

This study examines the importance of mitogen-activated protein kinases (MAPKs) in upregulation of endothelin type B (ETB) receptors. Rat middle cerebral arteries (MCAs) were incubated for 24 h with or without kinase inhibitors. Vessel segments were mounted in myographs and the contractile responses to endothelin-1 (ET-1; ETA and ETB receptor agonist) and sarafotoxin 6c (S6c; ETB receptor agonist) were studied. We used real-time PCR to measure the receptor mRNA levels. An ELISA assay showed the activation of ERK1/2 kinases after 3 h. Immunohistochemistry revealed the presence of ETB receptors on the vessels. After organ culture, S6c induced vasoconstriction. Incubation with the MEK/ERK inhibitors U0126 and SB386023 diminished the contractile response to S6c. The p38 MAPK inhibitor SB239063 did not affect the S6c-induced contraction. The ET-1-induced vasoconstriction was increased after incubation with SB386023 or SB239063, while unaffected by U0126. The ETB receptor mRNA levels were diminished by SB386023 and U0126. The ETA receptor mRNA levels were unaffected. The levels of activated ERK1/2 kinases were significantly higher after 3 h of organ culture as compared to fresh vessels. The level of ETB receptor protein on the smooth muscle cells of the MCA, visualised by immunohistochemistry, was somewhat diminished by SB386023. Our results show that the ERK1/2 MAPK is important in the upregulation of contractile ETB receptors in MCA after organ culture. Since there is a similar upregulation in models of focal ischaemia and subarachnoid haemorrhage, this may be an important pathophysiological event.
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PMID:Importance of ERK1/2 in upregulation of endothelin type B receptors in cerebral arteries. 1523 95

Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.
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PMID:MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia. 1709 Dec 94


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