Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ETs) are potent regulatory peptides that cause numerous phenotypic changes in glomerular mesangial cells including differential regulation of gene expression and mitogenesis. Although the second messengers produced by activated ET receptors are well characterized, little is known about pathways of nuclear signaling. In this report, we evaluate the role of a well-characterized effector linked to ET receptor activation, protein kinase C, in the stimulation of mitogen-activated protein kinase (p42-44mapk) and the induction of protooncogene c-fos. Stimulation of protein kinase C by phorbol ester was sufficient to increase p42-44mapk activity and induce c-fos. When ET-1 was added to mesangial cells depleted of protein kinase C, the increase in p42-44mapk was attenuated and the induction of c-fos was abolished. Taken together with previous data, these experiments suggest that protein kinase C, p42-44mapk, and c-fos constitute a pathway by which ET-1 regulates expression of mesangial cell genes. These effectors might have relevance to the role of ET-1 in cell growth and vascular remodeling.
J Cardiovasc Pharmacol 1992
PMID:Protein kinase C regulates activation of mitogen-activated protein kinase and induction of proto-oncogene c-fos by endothelin-1. 128 79

We have reported that endothelin-1 (ET-1), which is a constrictor and mitogenic peptide, can increase mitogen-activated protein kinase p42 (p42mapk) activity in rat mesangial cells. In this study, we investigate the mechanism of activation of p42mapk. Treatment of quiescent mesangial cells with 10(-7) M ET-1 biphasically stimulated p42mapk activity. The kinetics of the immunoprecipitated p42mapk activity induced by ET-1 showed a maximal 3.5- to 4.5-fold stimulation 5 min after the addition of the agonist to the cell cultures and a smaller, 2.5-fold increase of activity between 2 and 6 h after ET challenge. Neither peak of p42mapk activity induced by ET-1 was inhibited by pretreatment of the cells with either cycloheximide to inhibit protein synthesis or actinomycin D to retard transcription. Analysis by immunoblot showed that p42mapk was not affected by these pretreatments. In addition, the kinetics of phosphorylation of p42mapk showed a significant 32P incorporation into p42 at 5, 30, and 240 min after ET stimulation. Because phosphorylation on tyrosine and threonine residues of the enzyme is necessary for activation of the kinase, we believe that the phosphorylation of the p42mapk rather than transcriptional or translational induction is responsible for the activation of p42mapk in mesangial cells stimulated with ET-1.
J Cardiovasc Pharmacol 1993
PMID:Endothelin stimulates mitogen-activated protein kinase p42 activity through the phosphorylation of the kinase in rat mesangial cells. 750 33

Protein kinases play important roles in intracellular signalling pathways in probably all cells. In the heart, they are involved in the regulation of ion handling, contractility, fuel metabolism and growth. In this review, we discuss the consequences of activation of protein kinases known to be expressed in the heart. We concentrate principally on the following: cyclic AMP-dependent protein kinase, protein kinase C, mitogen-activated protein kinase, Ca2+/calmodulin-dependent protein kinases and pyruvate dehydrogenase kinase.
Cardiovasc Res 1995 Oct
PMID:Intracellular signalling through protein kinases in the heart. 857 96

In this review, the angiotensin-II-mediated signal transduction pathways involved in vascular smooth muscle cell growth are discussed. Classical pathways involving phospholipase C and protein kinase C, as well as the mitogen-activated protein kinase pathway, are common signal transduction pathways activated by a variety of growth factors to stimulate cell growth. Besides its vasoconstrictor activity, angiotensin II stimulates hypertrophy of vascular smooth muscle cells and is involved in neointimal proliferation following balloon angioplasty. Understanding angiotensin-II-stimulated signaling events, as well as the crosstalk among signaling pathways, may form the basis for the development of new therapies for hypertension and restenosis.
Cardiovasc Res 1995 Oct
PMID:Angiotensin II signal transduction and the mitogen-activated protein kinase pathway. 857 99

Ito cells play a key role in the development of liver fibrosis associated with chronic liver diseases. Both ETA (20%) and ETB (80%) receptors were identified in human Ito cells. ET-1 did not stimulate proliferation of Ito cells. In contrast, ET-1 inhibited DNA synthesis stimulated by serum or PDGF-BB, through an ETB-mediated pathway. The mechanism leading to growth inhibition involved elevation of cAMP leading to inhibition of serum-stimulated MAP kinase and selective reduction of c-jun expression. Finally, ET receptors were upregulated by cAMP, providing a positive feedback loop that would amplify ET-1-induced growth inhibition. We conclude that ET-1 is a potent growth inhibitory peptide and may exert positive or negative control of cell growth, depending on cell type. Moreover, this peptide may play a key role in the negative control of liver fibrogenesis.
J Cardiovasc Pharmacol 1995
PMID:Antiproliferative effects of ET-1 in human liver Ito cells: an ETB- and a cyclic AMP-mediated pathway. 858 42

To evaluate a possible mechanism for the chronic regulation of MAPK/ERK kinase-1 (MEK-1) and p42 mitogen-activated protein kinase (MAPK) we studied the long-term effects of the G-protein-coupled receptor agonist endothelin-1 (ET-1) and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor BB (PDGF BB) on MEK-1 and p42 MAPK in glomerular mesangial cells (GMCs). ET-1 and PDGF BB led to a time-dependent increase in MEK-1 mRNA expression without altering p42 MAPK mRNA levels. The effect of ET-1 and PDGF BB on MEK-1 mRNA expression was maximal after 24 h (3.3-fold) or 6 h (2.9-fold). Furthermore, the effect of ET-1 and PDGF BB on MEK-1 mRNA expression was additive (4.2-fold after 6 h) and was inhibited by actinomycin D (5 micrograms/ml). Cycloheximide (10 micrograms/ml) inhibited MEK-1 mRNA induction but stimulated p42 MAPK mRNA expression in both the absence and the presence of ET-1 and/or PDGF BB. The ET-1 and PDGF BB-induced increase in MEK-1 mRNA was accompanied by sustained enhancement of both p45 MEK protein expression after 12 h and by elevation of p42 MAPK activity for up to 24 h. We conclude that, in GMCs, MEK-1 acts like a delayed-early gene, whereas p42 MAPK resembles an immediate-early gene. MEK-1 mRNA and protein levels, as well as p42 MAPK activity, can be chronically regulated by both a seven-transmembrane domain receptor-coupled peptide such as ET-1 and by an agonist binding to a receptor with intrinsic protein tyrosine kinase activity, such as PDGF BB.
J Cardiovasc Pharmacol 1995
PMID:ET-1 and PDGF BB induce MEK mRNA and protein expression in mesangial cells. 858 80

We investigated the effects of YM087, a potent nonpeptide V1A and V2 vasopressin (AVP)-receptor antagonist, in binding and functional studies on rat vascular smooth-muscle cells (VSMCs). V1A AVP receptors on VSMCs were characterized by using the radioligand [3H]AVP. Specific binding of [3H]AVP was time dependent, reversible, and saturable. A single class of high-affinity binding sites with the expected V1A profile was identified. YM087 showed high affinity for V1A receptors with an inhibitory dissociation constant (Ki) value of 0.24 nM. In addition, YM087 potently and concentration-dependently inhibited AVP-induced increase in intracellular free calcium concentration and activation of mitogen-activated protein kinase. When added to growth-arrested VSMCs, AVP concentration-dependently induced hyperplasia and hypertrophy. YM087 prevented AVP-induced hyperplasia and hypertrophy of these cells in a concentration-dependent manner. YM087 had no agonistic activity in any biological assays used. These results suggest that YM087 displays high affinity for V1A receptors on VSMCs and high potency in inhibiting the AVP-induced physiological response. YM087 is a potent pharmacologic probe for investigating the physiologic and pathophysiologic roles of AVP in several diseases.
J Cardiovasc Pharmacol 1997 Dec
PMID:Effect of YM087, a potent nonpeptide vasopressin antagonist, on vasopressin-induced hyperplasia and hypertrophy of cultured vascular smooth-muscle cells. 943 15

Endothelin (ET)-1 is an endothelium-derived vasoconstrictor as well as a mitogen. We have recently described a novel role of ET-1 as a survival factor for rat endothelial cells from serum deprivation-induced apoptosis. The present study was designed to determine which receptor subtype (ETA or ETB) is responsible for and what intracellular mediators are involved in endothelial apoptosis. Apoptotic cell death was evaluated by nucleosomal ladders on agarose gel electrophoresis and immunohistochemical study using anti-single-stranded DNA antiserum. ET-1 and an ETB receptor agonist suppressed endothelial apoptosis, whose effects were abrogated by an ETB receptor antagonist but not by an ETA receptor antagonist. Addition of an ETB receptor antagonist or nonselective ETA/B receptor antagonists, but not an ETA receptor antagonist, enhanced the apoptotic events caused by serum deprivation, suggesting an autocrine/paracrine role of endogenous ET-1 in protecting against endothelial apoptosis. The effect of ET-1 in suppressing apoptosis was unaffected by any of the following reagents: a phospholipase C inhibitor (U73122), a tyrosine kinase inhibitor (ST638), an MEK inhibitor (PD98059), a phosphatidylinositol-3 kinase inhibitors (wortmannin, LY294002). Taken together, these results confirm a role for ET-1 as an autocrine/paracrine survival factor for rat endothelial cells, in which neither phospholipase C, tyrosine kinase, MAP kinase, nor phosphatidylinositol-3 kinase is involved in mediating the antiapoptotic effect of ET-1.
J Cardiovasc Pharmacol 1998
PMID:Endothelin-B receptor-mediated suppression of endothelial apoptosis. 959 22

To elucidate the molecular mechanism of the mitogenic effect of endothelin-1 (ET-1) on vascular smooth-muscle cells (VSMCs), we studied the effect of AG1478, a novel epidermal growth factor receptor (EGFR) kinase inhibitor, on p42/44 mitogen-activated protein (MAP) kinase activation, c-Fos expression, and DNA synthesis stimulated by ET-1. AG1478 dose-dependently (2.5 x 10(-8) M-2.5 x 10(-7) M) inhibited ET-1-induced MAP kinase activation. The ET-1-induced c-Fos protein expression was inhibited by AG1478 (2.5 x 10(-7) M). AG1478 also dose-dependently inhibited ET-1-stimulated [3H]thymidine incorporation. These data suggest that ET-1 induces MAP kinase activation, c-Fos expression, and promotes proliferation of VSMCs via transactivation of EGFR.
J Cardiovasc Pharmacol 1998
PMID:Endothelin-1 stimulates DNA synthesis of vascular smooth-muscle cells through transactivation of epidermal growth factor receptor. 959 33

The proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the formation of atherosclerotic lesions and restenosis after angioplasty. It has been suggested that probucol inhibits VSMCs proliferation, but this effect has not been directly demonstrated. In this study we investigated the effect of probucol on neointimal formation after balloon injury in normocholesterolemic rabbits and examined whether probucol could inhibit the proliferation of rabbit cultured VSMC stimulated by fetal bovine serum (FBS). Probucol inhibited the formation of neointima by about 63% 2 weeks after balloon injury. Probucol inhibited the increase in the number of cultured VSMCs and bromodeoxyuridine (BrdU) incorporation stimulated by 10% FBS in a dose-dependent manner. Also, 10% FBS stimulated the activities of mitogen-activated protein kinase (MAP kinase) and protein kinase C (PKC) in cultured VSMCs. Probucol inhibited these activities in a dose-dependent fashion. These results suggest that probucol may inhibit neointimal formation after balloon injury in normocholesterolemic rabbits by preventing the proliferation of VSMCs via inactivation of MAP kinase and PKC.
Cardiovasc Drugs Ther 1998 Mar
PMID:Probucol inhibits neointimal formation in carotid arteries of normocholesterolemic rabbits and the proliferation of cultured rabbit vascular smooth muscle cells. 960 29


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