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)

Dystrophin is a cytoskeletal protein found at the inner surface of skeletal and cardiac muscle fibers. We hypothesize that deficiency of dystrophin increases muscle compliance and causes an aberrant mechanotransduction in muscle fibers. To test this hypothesis, we measured the length-tension relationships and determined intracellular signaling leading to the activation of mitogen-activated protein (MAP) kinases in diaphragm muscle fibers from dystrophin-deficient mdx mice. Compared with controls, length-tension curves of the mdx mice were shifted to the right. A higher level of activation of extracellular signal-regulated kinase 1/2 (ERK1/2) but not c-Jun N-terminal kinase-1 or p38 MAP kinase was observed in the mdx muscle compared with the normal muscle in response to mechanical stretch. Removal of Ca2+ from the medium inhibited stretch-induced ERK1/2 activation only in mdx muscle fibers but not in the normal fibers. Conversely, pretreatment with TMB-8 (an antagonist of intracellular Ca2+ blocked the mechanical stretch-induced ERK1/2 activation in normal but not in mdx muscle fibers. Pretreatment of muscle with nifedipine (L-type calcium channel antagonist) marginally decreased the activation of ERK1/2 in normal or mdx muscle whereas pretreatment with gadolinium (III) chloride (an inhibitor of stretch-activated channels) only blocked the activation of ERK1/2 in mdx muscle, with no significant effect on normal muscle. A higher basal level of activation of activator protein-1 (AP-1) transcription factor was observed in dystrophin-deficient diaphragm, which was further augmented by mechanical stretch. Mechanical stretch-induced activation of AP-1 was decreased by pretreatment of muscle fibers with PD98059 (ERK1/2 inhibitor) and removal of Ca2+ ions from incubation medium. Our results show that dystrophin is a load-bearing element and its deficiency leads to loss of muscle stiffness and aberrant mechanotransduction in skeletal muscle fibers.
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PMID:Loss of dystrophin causes aberrant mechanotransduction in skeletal muscle fibers. 1471 91

It is recognized that heat shock protein 27 (HSP27) is highly expressed in heart. In the present study, we investigated whether platelet-derived growth factor (PDGF) phosphorylates HSP27 in mouse myocytes, and the mechanism underlying the HSP27 phosphorylation. Administration of PDGF-BB induced the phosphorylation of HSP27 at Ser-15 and -85 in mouse cardiac muscle in vivo. In primary cultured myocytes, PDGF-BB time dependently phosphorylated HSP27 at Ser-15 and -85. PDGF-BB stimulated the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) among the MAP kinase superfamily. SB203580, a specific inhibitor of p38 MAP kinase, reduced the PDGF-BB-stimulated phosphorylation of HSP27 at both Ser-15 and -85, and phosphorylation of p38 MAP kinase. However, PD98059, a specific inhibitor of MEK, or SP600125, a specific inhibitor of SAPK/JNK, failed to affect the HSP27 phosphorylation. These results strongly suggest that PDGF-BB phosphorylates HSP27 at Ser-15 and -85 via p38 MAP kinase in cardiac myocytes.
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PMID:Platelet-derived growth factor-BB phosphorylates heat shock protein 27 in cardiac myocytes. 1474 91

Hypertrophic growth of cardiac muscle is dependent on activation of the PKC-epsilon isoform. To define the effectors of PKC-epsilon involved in growth regulation, recombinant adenoviruses were used to overexpress either wild-type PKC-epsilon (PKC-epsilon/WT) or dominant negative PKC-epsilon (PKC-epsilon/DN) in neonatal rat cardiocytes. PKC-epsilon/DN inhibited acute activation of PKC-epsilon produced in response to phorbol ester and reduced ERK1/2 activity as measured by the phosphorylation of p42 and p44 isoforms. The inhibitory effects were specific to PKC-epsilon because PKC-epsilon/DN did not prevent translocation of either PKC-alpha or PKC-delta. Overexpression of PKC-epsilon/DN blunted the acute increase in ERK1/2 phorphorylation induced by the alpha(1)-adrenergic agonist phenylephrine (PE ). Inhibition of PKC-delta with rottlerin potentiated the effects of PE on ERK1/2 phosphorylation. PKC-epsilon/DN adenovirus also blocked cardiocyte growth as measured after 48 h of PE treatment, although the multiplicity of infection was lower than that required to block acute ERK1/2 activation. PE activated p38 mitogen-activated protein kinase as measured by its phosphorylation, but the response was not blocked by PKC inhibitors or by overexpression of PKC-epsilon/DN. Taken together, these studies show that the hypertrophic agonist PE regulates ERK1/2 activity in cardiocytes by a pathway dependent on PKC-epsilon and that PE-induced growth is mediated by PKC-epsilon.
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PMID:PKC-epsilon regulation of extracellular signal-regulated kinase: a potential role in phenylephrine-induced cardiocyte growth. 1497 26

Cyclic adenosine monophosphate (cAMP) modulates various agent-induced apoptosis. In this study, we observed that cAMP had a significantly protective effect on nitric oxide (NO)-induced cytotoxicity in H9c2 cardiac muscle cells. Pretreatment with DBcAMP (cAMP analogue) or forskolin (adenylyl cyclase activator) also significantly prevented the SNP-induced apoptosis in H9c2 cells. In contrast, H-89 or KT5720 (PKA inhibitor) reversed the protective effects of DBcAMP. In this study, DBcAMP or forskolin reduced SNP-induced JNK/SAPK activation to the basal level, but KT5720 reversed the inhibitory effects of these two agents. In contrast to JNK/SAPK activation, DBcAMP and forskolin significantly enhanced SNP-activated p38 MAPK phosphorylation and did not affect SNP-mediated ERK activation. KT5720 reversed the effects of DBcAMP and forskolin on p38 MAPK phosphorylation. The inhibition of the JNK pathway by transfection of a dominant negative mutant of JNK/SAPK markedly reduced the extent of SNP-induced cell death. Taken together, we suggest that JNK/SAPK is related to cAMP-protective effect in SNP-induced apoptosis. In addition, c-AMP relating agents protected SNP-induced cell death in neonatal rat ventricular cardiomyocytes. The cAMP-relating agent-induced protective effect is not restricted in H9c2 cardiac muscle cells.
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PMID:Cyclic adenosine monophosphate inhibits nitric oxide-induced apoptosis of cardiac muscle cells in a c-Jun N-terminal kinase-dependent manner. 1520 61

We detected a protein in rabbit skeletal muscle extracts that was phosphorylated rapidly by PKBa (protein kinase Ba), but not by SGK1 (serum- and glucocorticoid-induced kinase 1), and identified it as the cytoskeletal protein FLNc (filamin C). PKBa phosphorylated FLNc at Ser2213 in vitro, which lies in an insert not present in the FLNa and FLNb isoforms. Ser2213 became phosphorylated when C2C12 myoblasts were stimulated with insulin or epidermal growth factor, and phosphorylation was prevented by low concentrations of wortmannin, at which it is a relatively specific inhibitor of phosphoinositide 3-kinase. PD 184352 [an inhibitor of the classical MAPK (mitogen-activated protein kinase) cascade] and/or rapamycin [an inhibitor of mTOR (mammalian target of rapamycin)] had no effect. Insulin also induced the phosphorylation of FLNc at Ser2213 in cardiac muscle in vivo, but not in cardiac muscle that does not express PDK1 (3-phosphoinositide-dependent kinase 1), the upstream activator of PKB. These results identify the muscle-specific isoform FLNc as a new physiological substrate for PKB.
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PMID:Identification of filamin C as a new physiological substrate of PKBalpha using KESTREL. 1546 88

The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle-specific Raf-1-knockout (Raf CKO) mice with Cre-loxP-mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal-regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism.
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PMID:Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. 1546 32

Dystrophin, a product of the Duchenne muscular dystrophy gene, is a cytoskeletal protein of skeletal and cardiac muscle fibers. Dystrophin-deficient muscle fibers are abnormally vulnerable to mechanical stress including physical exercise, which is a powerful stimulator of mitogen-activated protein kinases (MAPKs). To examine how treadmill exercise affects MAPK family members in dystrophin-deficient skeletal muscle, we subjected both mdx mice, an animal model for Duchenne muscular dystrophy, and C57BL/10 mice to treadmill exercise and examined the phosphorylated protein levels of extracellular-signal regulated kinase (ERK1/2), p38 MAPK and c-Jun N terminal kinase 1 and 2 (JNK1 and JNK2) in the gastrocnemius muscle. Phosphorylation of ERK1/2, p38 MAPK and JNK2, but not JNK1, increased more in the muscles of exercise trained mdx mice than in muscles of trained C57BL/10 or untrained mdx mice. These results show that physical exercise aberrantly up-regulates the phosphorylated form of ERK1/2, p38 MAPK and JNK2 in dystrophin-deficient skeletal muscle and that their up-regulation might play a role in the degeneration and regeneration process of dystrophic features.
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PMID:Up-regulation of mitogen activated protein kinases in mdx skeletal muscle following chronic treadmill exercise. 1594 99

Chronic pressure overload (PO) and volume overload (VO) result in morphologically and functionally distinct forms of myocardial hypertrophy. However, the molecular mechanism initiating these two types of hypertrophy is not yet understood. Data obtained from different cell types have indicated that the mitogen-activated protein kinases (MAPKs) comprising c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 play an important role in transmitting signals of stress stimuli to elicit the cellular response. We tested the hypothesis that early induction of MAPKs differs in two types of overload on the heart and associates with distinct expression of hypertrophic marker genes, namely ANF, alpha-myosin heavy chain (alpha-MHC), and beta-MHC. In rats, VO was induced by aortocaval shunt and PO by constriction of the abdominal aorta. The PO animals were further divided into two groups depending on the severity of the constriction, mild (MPO) and severe pressure overload (SPO), having 35 and 85% aortic constriction, respectively. Early changes in MAPK activity (2-120 min and 1 to 2 d) were analyzed by the in vitro kinase assay using kinase-specific antibodies for p38, JNK, and ERK2. The change in expression of hypertrophy marker genes was examined by Northern blot analysis. In VO hypertrophy, the activity of p38 was markedly increased (10-fold), without changing the activity of ERK and JNK. However, during PO hypertrophy, the activity of JNK was significantly increased (two- to sixfold) and depended on the severity of the load. The activity of p38 was not changed in MPO hypertrophy, whereas it was slightly elevated (50%) in hearts with SPO. Similarly, ERK activity was not changed in hearts with MPO, but a transient rise in activity was observed in hearts with SPO. The expression of ANF and beta-MHC genes was elevated in both PO and VO hypertrophy; however, this change was much greater in hearts subjected to PO than VO hypertrophy. Alpha-MHC expression was downregulated in PO but remained unchanged in VO hypertrophy hearts. Thus, these results demonstrate differential activation of MAPKs in two types of cardiac hypertrophy and this, in part, may contribute to differential expression of cardiac muscle gene expression, giving rise to unique cardiac phenotype associated with different hemodynamic overloads.
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PMID:Mitogen-activated protein kinases (p38 and c-Jun NH2-terminal kinase) are differentially regulated during cardiac volume and pressure overload hypertrophy. 1604 84

Rosmarinic acid (RA) is a naturally occurring polyphenolic and is found in several herbs in the Lamiaceae family, such as, Perilla frutescens. ADR is a potent anti-tumor drug, but is unfortunately potently cardiotoxic. This study was undertaken to investigate the inhibitory effect of RA on ADR-induced apoptosis in H9c2 cardiac muscle cells at a mechanistic level. In vitro, ADR significantly decreased the viabilities of H9c2 cells, and this was accompanied by apoptotic features, such as a change in nuclear morphology and caspase protease activation. RA was found to markedly inhibit these apoptotic characteristics by reducing intracellular ROS generation and by recovering the mitochondria membrane potential (delta psi). In addition, RA reversed the downregulations of GSH, SOD and Bcl-2 by ADR. In the present study, ADR was found to activate c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), transcriptional factor-activator-protein (AP)-1. We found that c-fos, Jun-B, Jun-D and p-c-Jun were super shifted by ADR, indicating that these proteins have an important role in the ADR-induced AP-1 activation. The inhibitions of JNK and ERK using appropriate inhibitors or dominant negative cell lines reduced ADR-induced apoptosis in H9c2 cardiac muscle cells. Taken together, these results suggest that RA can inhibit ADR-induced apoptosis in H9C2 cardiac muscle cells by inhibiting ROS generation and JNK and ERK activation. Thus, we propose that RA should be viewed as a potential chemotherapeutic that inhibits cardiotoxicity in ADR-exposed patients.
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PMID:Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase. 1610 32

The importance of interleukin 6 (IL-6)-related cytokines in cardiac homeostasis has been studied extensively; however, little is known about their biological significance in cardiac stem cells. Here we describe that leukemia inhibitory factor (LIF), a member of IL-6-related cytokines, activated STAT3 and ERK1/2 in cardiac Sca-1+ stem cells. LIF stimulation resulted in the induction of endothelial cell-specific genes, including VE-cadherin, Flk-1, and CD31, whereas neither smooth muscle nor cardiac muscle marker genes such as GATA4, GATA6, Nkx-2.5, and calponin were up-regulated. Immunocytochemical examination showed that about 25% of total cells were positively stained with anti-CD31 antibody 14 days after LIF stimulation. Immunofluorescent microscopic analyses identified the Sca-1+ cells that were also positively stained with anti-von Willebrand factor antibody, indicating the differentiating process of Sca-1+ cells into the endothelial cells. IL-6, which did not activate STAT3 and ERK1/2, failed to induce the differentiation of cardiac stem cells into the endothelial cells. In cardiac stem cells, the transduction with dominant negative STAT3 abrogated the LIF-induced endothelial differentiation. And the inhibition of ERK1/2 with the MEK1/2 inhibitor U0126 also prevented the differentiation of Sca-1+ cells into endothelial cells. Thus, both STAT3 and ERK1/2 are required for LIF-mediated endothelial differentiation in cardiac stem cells. Collectively, it is proposed that LIF regulates the commitment of cardiac stem cells into the endothelial cell lineage, contributing to neovascularization in the process of tissue remodeling and/or regeneration.
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PMID:Leukemia inhibitory factor induces endothelial differentiation in cardiac stem cells. 1640 99


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