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)

Mechanical forces are important modulators of cellular function in many tissues and are particularly important in the cardiovascular system. The endothelium, by virtue of its unique location in the vessel wall, responds rapidly and sensitively to the mechanical conditions created by blood flow and the cardiac cycle. In this study, we examine data which suggest that steady laminar shear stress stimulates cellular responses that are essential for endothelial cell function and are atheroprotective. We explore the ability of shear stress to modulate atherogenesis via its effects on endothelial-mediated alterations in coagulation, leukocyte and monocyte migration, smooth muscle growth, lipoprotein uptake and metabolism, and endothelial cell survival. We also propose a model of signal transduction for the endothelial cell response to shear stress including possible mechanotransducers (integrins, caveolae, ion channels, and G proteins), intermediate signaling molecules (c-Src, ras, Raf, protein kinase C) and the mitogen activated protein kinases (ERK1/2, JNK, p38, BMK-1), and effector molecules (nitric oxide). The endothelial cell response to shear stress may also provide a mechanism by which risk factors such as hypertension, diabetes, hypercholesterolemia, and sedentary lifestyle act to promote atherosclerosis.
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PMID:Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. 959 24

Interleukin-1beta (IL-1beta) is cytotoxic to rat pancreatic beta-cells by inhibiting glucose oxidation, causing DNA damage and inducing apoptosis. Nitric oxide (NO) is a necessary but not sufficient mediator of these effects. IL-1beta induced kinase activity toward Elk-1, activation transcription factor 2, c-Jun, and heat shock protein 25 in rat islets. By Western blotting with phosphospecific antibodies and by immunocomplex kinase assay, IL-1beta was shown to activate extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38) in islets and rat insulinoma cells. Specific ERK1/2 and p38 inhibitors individually reduced but in combination blocked IL-1beta-mediated islet NO synthesis, and reverse transcription-polymerase chain reaction of inducible NO synthase mRNA showed that ERK1/2 and p38 controlled IL-1beta-induced islet inducible NO synthase expression at the transcriptional level. Hyperosmolarity caused phosphorylation of Elk-1, activation transcription factor 2, and heat shock protein 25 and activation of ERK1/2 and p38 in islets comparable to that induced by IL-1beta but did not lead to NO synthesis. Inhibition of p38 but not of ERK1/2 attenuated IL-1beta-mediated inhibition of glucose-stimulated insulin release. We conclude that ERK1/2 and p38 activation is necessary but not sufficient for IL-1beta-mediated beta-cell NO synthesis and that p38 is involved in signaling of NO-independent effects of IL-1beta in beta-cells.
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PMID:Interleukin-1beta-induced rat pancreatic islet nitric oxide synthesis requires both the p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. 961 46

We measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme activity was not affected in the adventitia. The MAP kinase activation was inhibited by either the angiotensin AT1 receptor antagonist losartan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT2 receptor antagonist PD 123,319 and the endothelin ETB receptor antagonist BQ 788 did not affect the MAP kinase activation. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) caused an activation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitroprusside inhibited the MAP kinase activation induced by endothelium removal or angiotensin II. These results suggest that even in isolated arteries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media are tonically released to cause MAP kinase-stimulating effects in medial smooth muscle.
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PMID:Evidence that angiotensin II, endothelins and nitric oxide regulate mitogen-activated protein kinase activity in rat aorta. 965 1

Bacterial lipopolysaccharide (LPS) in the presence of interferon gamma (IFNgamma) stimulates the synthesis of the cationic amino acid transporter 2B (CAT-2B) and inducible nitric oxide synthetase (iNOS) in RAW264 macrophages, which are thought to underlie the increased rate of arginine uptake into these cells and its conversion to nitric oxide, respectively. Here I demonstrate that the LPS- and IFNgamma-induced increase in arginine uptake into RAW264 cells is partially suppressed in the presence of PD 98059, partially suppressed in the presence of SB 203580, and completely inhibited by both drugs. In contrast, the LPS- and IFNgamma-induced synthesis of CAT-2B mRNA and iNOS protein is unaffected by PD 98059 and SB 203580. The results indicate that the MAPK/ERK and SAPK2/p38 cascades are both rate-limiting for LPS- and IFNgamma-stimulated arginine uptake, but not for iNOS synthesis. They also suggest that PD 98059 and SB 203580 suppress CAT-2B synthesis at a post-transcriptional level.
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PMID:Role of MAP kinase cascades in inducing arginine transporters and nitric oxide synthetase in RAW264 macrophages. 966 26

This study examines intracellular signaling events associated with the activation of chondrocytes by the cytokine interleukin-17 (IL-17). Stimulation of normal human articular chondrocytes with IL-17 induced nitric oxide (NO) production, concomitant with an increase in transcripts and de novo translation products of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes. Several other genes associated with inflammation and cartilage degradation, such as IL-1beta, IL-6, and stromelysin, were also up-regulated in IL-17-treated chondrocytes. Among signaling events displaying early response to IL-17 in chondrocytes were the mitogen-activated protein (MAP) kinases ERK1, ERK2, JNK, and p38. DNA binding activity of NF-kappaB was also significantly induced. IL-17 effects on NO release, as well as iNOS, COX-2, and IL-6 protein expression, were inhibited by the anti-inflammatory drug dexamethasone. Importantly, dexamethasone blunted IL-17-dependent activation of MAP kinases, suggesting a mechanistic relationship between these activities and the aforementioned gene expression responses. Similar effects of a lesser extent were observed with the p38-specific inhibitor SB203580. These results suggest that IL-17 activation of chondrocytes is associated with and depends at least in part on the activation of MAP kinases and NF-kappaB.
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PMID:Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. 976 76

The mechanisms of exogenous nitric oxide (NO)-enhanced growth of the U937 human myeloid leukemic cells were examined using sodium nitroprusside (SNP) as a NO donor. Treatment with 0.1 mM SNP for 72 h caused a 45 +/- 2% increase in U937 cell growth with significantly increased S/G2+M-phase and decreased G0/G1-phase of the cell cycle. The growth-enhancing effect of SNP was blocked by indomethacin, a cyclooxygenase inhibitor, but not by H7, a broad spectrum kinase inhibitor, or PD98059, a mitogen-activated protein kinase inhibitor. SNP treatment resulted in a dose-dependent increase in prostaglandin E2 (PGE2) production. Furthermore, the addition of exogenous PGE2 not only enhanced U937 cell growth but restored the indomethacin-inhibited mitogenic effect of SNP. We suggest that NO can enhance cell growth through activating the cyclooxygenase pathway and that PGE2 may be an effector molecule for NO-regulated cell proliferation. Our data provide a mechanistic insight into the regulatory role of NO in myelopoiesis.
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PMID:Nitric oxide enhances the growth of U937 human leukemic cells through a cyclooxygenase-mediated pathway. 976 25

Sphingomyelin hydrolysis is induced in myeloid cell-lines by tumour necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1beta), and interferon gamma (IFN-gamma). Ceramide, a product of sphingomyelin hydrolysis, recapitulates many of the cellular responses elicited by these cytokines, and this has lead to the hypothesis that ceramide is a second messenger of cytokine signalling. Sphingomyelin hydrolysis is catalysed by an acid spingomyelinase (ASMase) and one or more neutral sphingomyelinases (NSMase); both ASMase and NSMase are activated during cytokine signalling. In the present study, the contribution of ASMase to TNF-alpha, IL-1beta, and IFN-gamma signalling in murine macrophages was addressed. Cytokine-induced responses were compared in macrophages derived from the bone marrow of AMSase null and wild-type mice. Specifically, TNF-alpha-and IFN-gamma-induced nitric oxide production and TNF-alpha- and IL-1beta-induced expression of the alpha-chemokine, KC, were intact in ASMase null macrophages. Furthermore, TNF-alpha induction of p42/p44 ERK and p38-MAPK phosphorylation, c-jun kinase activation, and IkappaBalpha degradation were normal. Also normal in ASMase null macrophages was TNF-alpha-, IL-1beta- and IFN-gamma-induced expression of a panel of early response genes. It is concluded that ASMase is non-essential for the inflammatory signals activated in murine macrophages by TNF-alpha, IL-1beta and IFN-gamma.
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PMID:Acid sphingomyelinase-derived ceramide is not required for inflammatory cytokine signalling in murine macrophages. 977 Mar 26

Reactive free radical species are known to trigger biochemical events culminating in transcription factor activation and modulation of gene expression. The cytosolic signaling events triggered by free radicals that result in nuclear responses are largely unknown. Here we identify a signaling cascade triggered immediately upon redox activation of Ras. We examined two physiologically relevant models of redox signaling: 1) nitric oxide in human T cells, and 2) advanced glycation end product in rat pheochromocytoma cells. Reactive free radical species generated by nitric oxide donors and the interaction of advanced glycation end product with its receptor led to the recruitment of p85/p110 phosphatidylinositol 3'-kinase (PI3K) to the plasma membrane, where it associated directly with the effector domain of Ras and became activated. Only the p110beta and p110delta (but not p110alpha) catalytic subunits were recruited by redox-activated Ras. Activation of downstream targets of PI3K such as protein kinase B/Akt and mitogen-activated protein kinase was found to be PI3K dependent. Our study demonstrates that nitrosative and oxidative stressors trigger Ras-dependent and PI3K-regulated events in cells and define a biochemical pathway that is triggered by redox signaling.
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PMID:A redox-triggered ras-effector interaction. Recruitment of phosphatidylinositol 3'-kinase to Ras by redox stress. 979 10

The exposure of rat mesangial cells to cytokines promoted activation of the p42/p44 mitogen-activated protein kinase (MAPK). We identified a rapid and delayed phase of MAPK activation with distinctive activity increases at 5 to 15 min and 15 to 24 h. Rapid and late MAPK activation were attenuated by the redox-modulating agent N-acetylcysteine. Specifically, late-phase activation coincided with endogenous nitric oxide (NO) generation and in turn was suppressed by the NO synthase-blocking compounds diphenyliodonium or nitroarginine methyl ester. By using NO-liberating agents such as S-nitrosoglutathione and 3-morpholinosydnonimine, we investigated intermediary signaling elements of NO in promoting MAPK activation. Early and transient activation at 5 min was suppressed by the soluble guanylyl cyclase-blocking agent 1H-(1,2,4)-oxdiazolo-(4,3-alpha)-6-bromoquinoxazin-1-one (NS 2028) and, moreover, was mimicked by the lipophilic cyclic GMP (cGMP) analogue 8-bromo-cGMP. In contrast, NO-mediated activation achieved within hours was unrelated to cGMP signaling. Late and persistent MAPK activation, induced by NO donors or endogenously generated NO, was found in association with inhibition of phosphatase activity. In vitro dephosphorylation of activated and immunoprecipitated p42/p44 by cytosolic phosphatases was sensitive to the readdition of NO and was found to be inhibited in cytosol of S-nitrosoglutathione-stimulated cells. Also, cells that had been exposed to cytokines for 24 h revealed a blocked phosphatase activity, which was successfully attenuated by the NO synthase inhibitor nitroarginine methyl ester and, therefore, was NO mediated. Conclusively, NO affects p42/p44 MAPK in rat mesangial cells twofold: rapid activation is cGMP mediated, whereas late activation is transmitted via inhibition of tyrosine dephosphorylation.
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PMID:Rapid and delayed p42/p44 mitogen-activated protein kinase activation by nitric oxide: the role of cyclic GMP and tyrosine phosphatase inhibition. 979 18

This study examined the signal transduction pathway(s) leading to phosphorylation of p38 in human neutrophils stimulated with lipopolysaccharide and formyl peptides. Blockade of the nitric oxide (NO) pathway in neutrophils with the NO synthase inhibitor N-nitro-L-arginine methyl ester or by treatment with the NO scavenger 2-phenyl-tetramethylimidazoline-1-oxyl-3-oxide attenuated phosphorylation of the mitogen-activated protein kinase p38 in response to lipopolysaccharide but not fMet-Leu-Phe. Using the NO releasing agents S-nitroso-N-acetylpenicillamine and sodium nitroprusside it was determined that nitric oxide is sufficient to cause an increase in phosphorylation of p38. Increasing cellular cGMP with phosphodiesterase inhibitors, by stimulation of soluble guanylyl cyclase with YC-1 or with exogenous dibutyryl cGMP resulted in mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 3,6 (MEK3,6) activation and phosphorylation of p38. This phenomenon was specific for MEK3,6, because these agents had no effect on the phosphorylation state of MEK1,2. A role for protein kinase G but not protein kinase A downstream of lipopolysaccharide but not formylmethionylleucylphenylalanine was shown using the specific inhibitors KT5823 and H89, respectively. These data indicate that activation of p38 by fMet-Leu-Phe and lipopolysaccharide involve different mechanisms, and that activation of protein kinase G by NO-dependent stimulation of guanylyl cyclase is necessary and sufficient for phosphorylation of p38 downstream of lipopolysaccharide.
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PMID:Activation of p38 mitogen-activated protein kinase by lipopolysaccharide in human neutrophils requires nitric oxide-dependent cGMP accumulation. 986 77


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