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

The hypertrophic response is characterized by increased myofibril/sarcomere organization, induction of the cardiac specific atrial natriuretic factor (ANF) and myosin light chain-2 (MLC-2v) genes, and an increase in total cell volume. The alpha1-adrenergic agonist phenylephrine induces both the morphological and biochemical markers of hypertrophy in cultured neonatal rat ventricular cardiomyocytes. Previous studies have suggested a functional requirement for the heterotrimeric G-protein, Galphaq, for a subset of the hypertrophic phenotypes. The small GTPases Ras and Rho have also been implicated in phenylephrine-induced hypertrophy. To further delineate the role of Galphaq in hypertrophy, a constitutively active mutant of Galphaq was transiently transfected in primary rat ventricular cardiomyocytes. This molecule was sufficient to induce ANF-, AP1-, and MLC-2-driven gene expression. Co-transfection of Galphaq and dominant negative Ras or dominant negative Raf resulted in dose-dependent inhibition of ANF-driven expression. Both dominant negative Rho, and the Rho inhibitor C3-transferase, also attenuated Galphaq- and Ras-induced ANF-driven gene expression. Cells transfected with active Galphaq did not show a detectable increase in activation of the mitogen activated protein kinases ERK or SAPK. However, activity of the MAP-kinases appears to be important for Galphaq-induced gene expression since the MAP-kinase phosphatase Clone 100 and catalytically inactive SAPK strongly inhibited Galphaq-induced ANF expression. Thus, our studies indicate Galphaq-induced hypertrophic gene expression requires the small G-proteins Ras and Rho. The data also indicates that Galphaq mediated gene expression is dependent on functional MAP-kinases and that multiple signaling pathways contribute to Galphaq-mediated cardiac cell hypertrophy.
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PMID:Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytes. 951 26

Atrial natriuretic peptide (ANP) has been shown to counteract various actions of endothelin-1 (ET-1) in mesangial cells. We have reported that both extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) are activated by ET-1 and ET-1-induced activation of ERK is inhibited by ANP. To further clarify the action of ANP, we examined the effect of ANP on ET-1-induced activation of JNK. ANP inhibited ET-1-induced activation of JNK in a dose-dependent manner. This inhibitory effect of ANP was reversed by HS-142-1, an antagonist for biological receptors of ANP, while C-ANP, an analog specific to clearance receptors of ANP, failed to inhibit ET-1-induced activation of JNK. 8-Bromo-cGMP and sodium nitroprusside were also able to inhibit ET-1-induced activation of JNK, suggesting cGMP-dependent action of ANP. In contrast, ANP failed to inhibit interleukin-1 beta (IL-1 beta)-induced activation of JNK. Since an increase in intracellular calcium ([Ca2+]i) was shown to be necessary for ET-1-induced activation of JNK in mesangial cells, we measured [Ca2+]i using fura-2. ANP attenuated the ET-1-induced increase in [Ca2+]i in concentrations enough to inhibit ET-1-induced activation of JNK. Finally, ANP was able to inhibit ET-1-, but not IL-1 beta-induced increase in DNA-binding activity of AP-1 by gel shift assay. These results indicate that ANP is able to inhibit ET-1-induced activation of AP-1 by inhibiting both ERK and JNK, suggesting that ANP might be able to counteract the expression of AP-1-dependent genes induced by ET-1.
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PMID:Atrial natriuretic peptide inhibits endothelin-1-induced activation of JNK in glomerular mesangial cells. 957 27

Agonist-induced hypertrophy of cultured neonatal rat ventricular myocytes (NRVM) has been attributed to biochemical signals generated during receptor activation. However, NRVM hypertrophy can also be induced by spontaneous or electrically stimulated contractile activity in the absence of exogenous neurohormonal stimuli. Using single-cell imaging of fura 2-loaded myocytes, we found that low-density, noncontracting NRVM begin to generate intracellular Ca2+ concentration ([Ca2+]i) transients and contractile activity within minutes of exposure to the alpha 1-adrenergic agonist phenylephrine (PE; 50 microM). However, NRVM pretreated with verapamil and then stimulated with PE failed to elicit [Ca2+]i transients and beating. We therefore examined whether PE-induced [Ca2+]i transients and contractile activity were required to elicit specific aspects of the hypertrophic phenotype. PE treatment (48-72 h) increased cell size, total protein content, total protein-to-DNA ratio, and myosin heavy chain (MHC) isoenzyme content. PE also stimulated sarcomeric protein assembly and prolonged MHC half-life. However, blockade of voltage-gated L-type Ca2+ channels with verapamil, diltiazem, or nifedipine (10 microM) blocked PE-induced total protein and MHC accumulation and prevented the time-dependent assembly of myofibrillar proteins into sarcomeres. Inhibition of actin-myosin cross-bridge cycling with 2,3-butanedione monoxime (7.5 mM) also prevented PE-induced total protein and MHC accumulation, indicating that mechanical activity, rather than [Ca2+]i transients per se, was required. In contrast, blockade of [Ca2+]i transients and contractile activity did not prevent the PE-induced increase in cell surface area, activation of the mitogen-activated protein kinases ERK1 and ERK2, or upregulation of atrial natriuretic factor gene expression. Thus contractile activity is required to elicit some but not all aspects of the the hypertrophic phenotype induced by alpha 1-adrenergic receptor activation.
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PMID:Contractile activity is required for sarcomeric assembly in phenylephrine-induced cardiac myocyte hypertrophy. 961 9

We showed before that in neonatal rat cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophic growth and transcriptional regulations of genes that are markers of cardiac hypertrophy. In view of the suggested roles of Ras and p42/44 mitogen-activated protein kinases (MAPKs) as key mediators of cardiac hypertrophy, the aim of this work was to explore their roles in ouabain-initiated signal pathways regulating four growth-related genes of these myocytes, i.e. those for c-Fos, skeletal alpha-actin, atrial natriuretic factor, and the alpha3-subunit of Na+/K+-ATPase. Ouabain caused rapid activations of Ras and p42/44 MAPKs; the latter was sustained longer than 90 min. Using high efficiency adenoviral-mediated expression of a dominant-negative Ras mutant, and a specific inhibitor of MAPK kinase (MEK), activation of Ras-Raf-MEK-p42/44 MAPK cascade by ouabain was shown. The effects of the mutant Ras, an inhibitor of Ras farnesylation, and the MEK inhibitor on ouabain-induced changes in mRNAs of the four genes indicated that (a) skeletal alpha-actin induction was dependent on Ras but not on p42/44 MAPKs, (b) alpha3 repression was dependent on the Ras-p42/44 MAPK cascade, and (c) induction of c-fos or atrial natriuretic factor gene occurred partly through the Ras-p42/44 MAPK cascade, and partly through pathways independent of Ras and p42/44 MAPKs. All ouabain effects required extracellular Ca2+, and were attenuated by a Ca2+/calmodulin antagonist or a protein kinase C inhibitor. The findings show that (a) signal pathways linked to sarcolemmal Na+/K+-ATPase share early segments involving Ca2+ and protein kinase C, but diverge into multiple branches only some of which involve Ras, or p42/44 MAPKs, or both; and (b) there are significant differences between this network and the related gene regulatory pathways activated by other hypertrophic stimuli, including those whose responses involve increases in intracellular free Ca2+ through different mechanisms.
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PMID:Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. 961 40

In response to hormones and growth factors, cultured neonatal ventricular myocytes increase in profile, exhibit myofibrillogenesis, and re-express genes whose expression is normally restricted to the fetal stage of ventricular development. These include atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC), and skeletal muscle (SkM)-alpha-actin. By using luciferase reporter plasmids, we examined whether oncogenes that activate the extracellular signal-regulated kinase cascade (srcF527, Ha-rasV12, and v-raf) increased expression of "fetal" genes. Transfection of myocytes with srcF527 stimulated expression of ANF, SkM-alpha-actin, and beta-MHC by 62-, 6.7-, and 50-fold, respectively, but did not induce DNA synthesis. Stimulation of ANF expression by srcF527 was greater than by Ha-rasV12, which in turn was greater than by v-raf. General gene expression was also increased but to a lesser extent. The response to srcF527 was inhibited by dominant-negative Ha-rasN17. Myocyte area was increased by srcF527, Ha-rasV12, and v-raf, and although it altered myocyte morphology by causing a pseudopodial appearance, srcF527 did not detectably increase myofibrillogenesis either alone or in combination with Ha-rasV12. A kinase-dead src mutant increased myocyte size to a much lesser extent than srcF527 and also did not inhibit ANF-luciferase expression in response to phenylephrine. We conclude that members of the Src family of tyrosine kinases may be important in mediating the transcriptional changes occurring during cardiac myocyte hypertrophy and that Ras and Raf may be downstream effectors.
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PMID:Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes. 966 Jul 73

In various cell types certain stresses can stimulate p38 mitogen-activated protein kinase (p38 MAPK), leading to the transcriptional activation of genes that contribute to appropriate compensatory responses. In this report the mechanism of p38-activated transcription was studied in cardiac myocytes where this MAPK is a key regulator of the cell growth and the cardiac-specific gene induction that occurs in response to potentially stressful stimuli. In the cardiac atrial natriuretic factor (ANF) gene, a promoter-proximal serum response element (SRE), which binds serum response factor (SRF), was shown to be critical for ANF induction in primary cardiac myocytes transfected with the selective p38 MAPK activator, MKK6 (Glu). This ANF SRE does not possess sequences typically required for the binding of the Ets-related ternary complex factors (TCFs), such as Elk-1, indicating that p38-mediated induction through this element may take place independently of such TCFs. Although p38 did not phosphorylate SRF in vitro, it efficiently phosphorylated ATF6, a newly discovered SRF-binding protein that is believed to serve as a co-activator of SRF-inducible transcription at SREs. Expression of an ATF6 antisense RNA blocked p38-mediated ANF induction through the ANF SRE. Moreover, when fused to the Gal4 DNA-binding domain, an N-terminal 273-amino acid fragment of ATF6 was sufficient to support trans-activation of Gal4/luciferase expression in response to p38 but not the other stress kinase, N-terminal Jun kinase (JNK); p38-activating cardiac growth promoters also stimulated ATF6 trans-activation. These results indicate that through ATF6, p38 can augment SRE-mediated transcription independently of Ets-related TCFs, representing a novel mechanism of SRF-dependent transcription by MAP kinases.
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PMID:p38 Mitogen-activated protein kinase mediates the transcriptional induction of the atrial natriuretic factor gene through a serum response element. A potential role for the transcription factor ATF6. 968 22

The proto-oncogenes jun and fos are members of the AP-1 family of transcription factors, which activate transcription of target genes via the tetradecanoyl phorbol acetate response element (TRE). Both jun and fos contain activation domains, but their relative contributions to transcriptional activation of different TREs remain unclear. It is not apparent whether the cellular availability of specific AP-1 members is the major determinant for regulation of TREs or whether other factors including the TRE sequence itself contribute to selectivity. We have identified in the promoter of the rat atrial natriuretic factor (ANF) a novel AP-1 site which is unresponsive to jun homodimers and is inducible only in the presence of c-fos. This activation is potentiated by mitogen-activated protein (MAP) kinase. The jun proteins appear to be required solely to tether c-fos to the promoter, and c-fos mutants lacking putative activation domains abrogate transactivation. Unexpectedly, the oncogenic form of c-fos which diverges most significantly in the carboxy-terminal 50 amino acids is unable to mediate transactivation at this specialized AP-1 site. Mutations within the C terminus of c-fos at serine residues that are phosphorylation targets for growth factors and MAP kinase completely abrogate transactivation and block potentiation by MAP kinase. Using GAL4 fusions, we show that the 90-amino-acid C terminus of c-fos contains autonomous activation domains and that the serine residues are essential for full activity. These results suggest that phosphorylation of the C terminus of c-fos affects its transactivation properties and provide evidence for novel regulatory mechanisms that may contribute to biologic specificities of the AP-1 transcription complex.
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PMID:The C-terminal domain of c-fos is required for activation of an AP-1 site specific for jun-fos heterodimers. 971 May 91

The signal transduction pathways governing the hypertrophic response of cardiomyocytes are not well defined. Constitutive activation of the stress-activated protein kinase (SAPK) family of mitogen-activated protein (MAP) kinases or another stress-response MAP kinase, p38, by overexpression of activated mutants of various components of the pathways is sufficient to induce a hypertrophic response in cardiomyocytes, but it is not clear what role these pathways play in the response to physiologically relevant hypertrophic stimuli. To determine the role of the SAPKs in the hypertrophic response, we used adenovirus-mediated gene transfer of SAPK/ERK kinase-1 (KR) [SEK-1(KR)], a dominant inhibitory mutant of SEK-1, the immediate upstream activator of the SAPKs, to block signal transmission down the SAPK pathway in response to the potent hypertrophic agent, endothelin-1 (ET-1). SEK-1(KR) completely inhibited ET-1-induced SAPK activation without affecting activation of the other MAP kinases implicated in the hypertrophic response, p38 and extracellular signal-regulated protein kinases (ERK)-1/ERK-2. Expression of SEK-1(KR) markedly inhibited the ET-1-induced increase in protein synthesis. In contrast, the MAPK/ERK kinase inhibitor, PD98059, which blocks ERK activation, and the p38 inhibitor, SB203580, had no effect on ET-1-induced protein synthesis. ET-1 also induced a significant increase in atrial natriuretic factor mRNA expression as well as in the percentage of cells with highly organized sarcomeres, responses which were also blocked by expression of SEK-1(KR). In summary, inhibiting activation of the SAPK pathway abrogated the hypertrophic response to ET-1. These data are the first demonstration that the SAPKs are necessary for the development of agonist-induced cardiomyocyte hypertrophy, and suggest that in response to ET-1, they transduce critical signals governing the hypertrophic response.
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PMID:Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy. 976 23

In vitro cardiac myocyte hypertrophy is characterized by increased cell size, sarcomere organization, and induction of several genes including atrial natriuretic factor (ANF). The hypertrophic growth program has been associated with activation of various mitogen-activated protein kinase (MAP) kinase family members, one of which is a stress kinase, p38. In this study, we found that the p38-specific inhibitor SB-203580 failed to inhibit phenylephrine-induced ANF-driven gene expression in low-density myocyte cultures but did inhibit gene expression in higher density cultures. Dense myocyte cultures also had a higher metabolic activity and contraction rate than cells plated at low density. We found that mimicking this effect by rapid electrical pacing activated ANF-driven gene expression and that this expression was inhibited by inactivation of p38. However, addition of SB-203580 at time points ranging between 1 and 72 h suggests that the effect of p38 on the ANF promoter may be both direct and indirect. Electrical pacing induced a small, but consistent, increase in p38 phosphorylation (phospho-p38) at time points ranging from 30 min to 4 h, but at later times phospho-p38 levels were reduced. When myocytes were treated with phenylephrine or electrically paced in the presence of the p38 inhibitor, there was little discernible change in morphology or rates of protein synthesis from DMSO-treated cells at 48 or 72 h. These data indicate that cell density and myocyte contraction may modulate p38-dependent pathways for ANF gene expression, but these pathways may not be direct and have limited effects on hypertrophic morphology.
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PMID:Cell density and contraction regulate p38 MAP kinase-dependent responses in neonatal rat cardiac myocytes. 1040 13

Atrial natriuretic peptide (ANP) is present in the fetoplacental circulation of humans and sheep. The ANP-A receptor is the specific membrane receptor for ANP, which produces cGMP. The clearance receptor of natriuretic peptide (CR) is postulated to modulate local concentrations of ANP, thereby modulating cGMP production through the ANP-A receptor. Recently we reported that fetoplacental basic fibroblast growth factor (bFGF) and cGMP levels are increased dramatically during the third trimester of ovine gestation. Therefore we hypothesized that bFGF will downregulate CR expression in cultured ovine fetoplacental artery endothelial (OFPAE) cells via the mitogen-activated protein kinase (MAPK) signal cascade mechanism, thereby causing augmentation of ANP-mediated cGMP production. Western analysis and/or RT-PCR of CR expression were performed after treatment of OFPAE cells with bFGF (10 pg/ml-1 microgram/ml) with or without 50 microM PD-98059, a selective inhibitor of MAPK kinase. To investigate the possible effects of CR downregulation on the functional modulation of ANP-A receptor activation, cGMP production (20 min) by OFPAE cells was measured in response to ANP (10 pM-1 microM) with or without pretreatment (24 h) of 10 ng/ml bFGF. CR expression in OFPAE cells was dose dependently downregulated by 1-10 ng/ml bFGF treatment (maximum -69%), which was completely reversed by pretreatment with PD-98059. Treatment of OFPAE cells with 10 ng/ml bFGF (24 h) did not alter maximum ANP-A activity (cGMP production/20 min), but decreased the apparent ED(50) of ANP to stimulate cGMP production from 2.5 to 0.83 nM, suggesting the possibility that bFGF-mediated downregulation of CR may elevate ANP-mediated cGMP production responses. Thus bFGF downregulates CR mRNA and protein expressions via the MAPK cascade in OFPAE cells.
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PMID:Basic FGF decreases clearance receptor of natriuretic peptides in fetoplacental artery endothelium. 1044 62


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