Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When a heart responds to increased workload it does so by hypertrophy. This is characterized by an increase in cell size in the absence of cell division, and is accompanied by distinct qualitative and quantitative changes in gene expression. The use of cardiomyocytes in cell culture has identified, besides mechanical loading, a range of substances, such as cytokines, growth factors, catecholamines, vasoactive peptides and hormones, involved in mediating cardiac myocyte hypertrophy, and has enabled the molecular dissection of the pathways involved in signal transduction. Many different pathways are activated in response to different hypertrophic stimuli, and a growing number of crosslinks are being characterized between these pathways. Recent evidence suggests a central role for Ras in transmitting signals from G-protein coupled receptors, from growth factor receptors and from cytokine receptors not only down the Raf-MEK-ERK pathway to the nucleus, but also to various other cytosolic effectors. The evaluation of distinct morphological phenotypes, together with biochemical data on gene regulation, suggests that interactions between different signaling pathways take place. Each stimulus provokes a typical cellular phenotype and different stimuli may act alone or in concert in a synergistic, antagonistic or permissive manner. Consequently, hypertrophy of cultured cardiomyocytes cannot simply be characterized as the reversal to the fetal gene expression program. Thus, hypertrophic growth of the heart may similarly be the result of a complex combinatorial action of various stimuli, which may also lead to different morphological and biochemical phenotypes with distinct physiological properties.
J Mol Cell Cardiol 1997 Nov
PMID:Signaling pathways in cardiac myocyte hypertrophy. 940 63

The present study tested the hypothesis that one or more tyrosine kinase(s) are downstream of protein kinase C (PKC) in the signal transduction pathway responsible for the cardioprotective effect of ischemic preconditioning (PC). Isolated rabbit hearts were subjected to 30 min of regional ischemia followed by 2 h of reperfusion. Infarct size was measured by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Infarction in control hearts was 32.9+/-1.8%. Ischemic PC with 5-min ischemia/10-min reperfusion reduced infarct size to 11.5+/-1.5% (P<0.05). Infusion of the tyrosine kinase inhibitors, genistein (50 microM) or lavendustin A (0.5 microM), alone did not affect the level of infarction. When infused around the 5-min PC ischemia genistein failed to block protection (13.7+/-1.0%). However, when present at the onset of the 30-min ischemia both genistein and lavendustin A completely aborted protection (31.4+/-2.0 and 28.1+/-1.5%, respectively). Activation of PKC by phorbol 12-myristate 13-acetate (PMA, 0.05 nmol) was as protective is ischemic PC (14.9+/-3.0%; P<0. 05). Similar to PC, PMA-induced protection was completely prevented by both genistein and lavendustin A. Conversely, anisomycin (50 ng/ml), an activator of MAP kinase kinases (dual tyrosine and threonine kinases), was very protective (7.5+/-1.6%; P<0.05) and this protection was still present when PKC was inhibited by 5 microM chelerythrine (12.1+/-1.6%; P<0.05). In conclusion, activation of a tyrosine kinase during the long ischemia appears to be required for cardioprotection in the rabbit heart. Furthermore, the ability of tyrosine kinase inhibitors to block PMA-induced protection in conjunction with the failure of PKC inhibition to prevent anisomycin-induced protection suggests that the tyrosine kinase is downstream of PKC and that the tyrosine kinase may be a MAP kinase kinase.
J Mol Cell Cardiol 1998 Feb
PMID:Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning's anti-infarct effect in the rabbit heart. 951 15

The current study focuses on the role of p38 MAP kinase in response to acute preconditioning stimuli and ischemia. Exposure of the rat myoblast cell line H9C2 to preconditioning stimuli, viz. brief duration of ischemia (metabolic inhibition) and adenosine, led to activation of p38 MAP kinase. The protective preconditioning effect of these stimuli against lethal ischemic insult was abolished in the presence or p38 MAP kinase inhibitor SB 203580 but not in the presence of MEK inhibitor PD 98509. Phorbol myristate acetate, PMA, which activates protein kinase C, PKC, activates p38 MAP kinase. and this activation is inhibited by PKC inhibitor G. 6850. The preconditioning effect of PMA was abolished by SB 203580 and also by protein kinase C inhibitor Go 6850. This indicates that the protective action of preconditioning by PKC is mediated via activation of p38 MAP kinase. Paradoxically, the presence of SB 203580 and Go 6850 during the lethal stress protected the cells against cell death. The mode of cell death in this study whether necrotic or apoptotic has not been established. Lethal ischemic stress activates p38 MAP kinase. Preconditioning the cells decreases the activation of p38 MAP kinase in response to the second lethal stress. These findings highlight the role of p38 MAP kinase in ischemic preconditioning v ischemia. Furthermore, our findings in an in vitro model using a proliferating cell line indicate that the duration and/or intensity of stimuli activating p38 kinase probably determines whether it would play a beneficial v deleterious role in cell survival in response to stress.
J Mol Cell Cardiol 1998 Aug
PMID:Role of p38 MAP kinase in myocardial stress. 984 Dec 66

Platelet-derived growth factor BB (PDGF BB) activation of the mitogen-activated protein kinases (MAPK), ERK1 and ERK2, has been shown to be necessary for mitogen-stimulated proliferation, but its role in regulating cell migration and its relationship to other chemotactic signaling events, such as CamKII activation, has not been defined. Using a modified Boyden chamber apparatus, we tested the effects of a selective inhibitor of the upstream activator of ERK1/2, MEK1, on PDGF-stimulated rat aortic vascular smooth muscle cells (VSMCs) alone and in combination with KN62, a selective inhibitor of CamKII. The MEK1 inhibitor, PD98059, caused a dose-dependent reduction in ERK2 activity that paralleled a decrease in migration up to 60%. This inhibition of migration was similar to that seen with KN62 and the combined effects of both inhibitors were non-additive. Although KN62 did not affect ERK2 activity in response to PDGF, PD98059 markedly inhibited PDGF-stimulated CamKII activity, suggesting that activation of CamKII by PDGF was dependent on ERK activity and that the effects of ERK inhibition on migration may be mediated through its ability to inhibit CamKII activity. To directly test this, VSMCs were infected with a recombinant adenovirus expressing constitutively activated CamKII. Infection reversed the inhibitory effects of KN62 on migration, but had no effect on the inhibition of migration seen with PD98059. These results suggest that while MAPK may act upstream of CamKII to control its activation in response to PDGF, it also regulates migration independently of CamKII activation.
J Mol Cell Cardiol 1998 Nov
PMID:Regulation of vascular smooth muscle migration by mitogen-activated protein kinase and calcium/calmodulin-dependent protein kinase II signaling pathways. 992 73

This study investigates whether leukemia inhibitory factor (LIF), a potent cardiac hypertrophic cytokine, affects the L-type Ca2+ current (I(Ca,L)) and intracellular Ca2+ concentrations ([Ca2+]i) in cardiomyocytes. I(Ca,L) was recorded using a whole cell patch clamp configuration in guinea pig cardiomyocytes, and the [Ca2+]i transient was detected by use of Fluo-3 in rat cardiomyocytes. Cells were preincubated with LIF (1000 U/ml) for 15 min before whole cell recording. LIF increased I(Ca,L) by 41.8%. LIF synergistically increased I(Ca,L) with isoproterenol. Preincubation with H89 did not inhibit the LIF-induced increase in I(Ca,L), indicating that this phenomenon is PKA-independent. PD98059 completely inhibited the increase in I(Ca,L), and this effect was dose-dependent (IC50=3.6 micromol/l). Other signal transduction inhibitors including AG490, SB203580, chelerythrine, genistein, and KN62 did not affect the LIF-induced increase in I(Ca,L). Perforated patch clamp recording revealed that LIF maximally increased the I(Ca,L) by 25% at 15 min. LIF also increased the peak [Ca2+]i transient level by 63% at 15 min. PD98059 fully inhibited the increase in the [Ca2+]i transient. In conclusion, LIF increased I(Ca,L) and the [Ca2+]i transient in cardiomyocytes, and the Raf-1/MEK/ERK pathway might be involved in the modulation of this activation.
J Mol Cell Cardiol 1999 Jan
PMID:Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, enhances L-type Ca2+ current and [Ca2+]i transient in cardiomyocytes. 1007 31

The signal transduction mechanisms mediating hypertrophic responses in myocardial cells (MCs) remain uncertain. We investigated the role of the extracellular signal-regulated kinase (ERK) cascade in myocardial cell hypertrophy by the strategy of using the adenovirus-mediated overexpression of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), which is the upstream activator of ERK. We generated recombinant adenoviruses expressing constitutively active MEK1 (MEK1 EE) and dominant negative MEK1 (MEK1 DN). Overexpression of MEK1 EE in MCs activated ERK1/2 and subsequently induced atrial natriuretic peptide (ANP) mRNA expression. In addition, MEK1 EE overexpression resulted in an increase in cell size and sarcomeric reorganization. In contrast, overexpression of MEK1 DN in MCs inhibited endothelin-1 (ET-1)-, phenylephrine (PE)-, leukemia inhibitory factor (LIF)-, isoproterenol (ISP)-, and mechanical stretch-induced ERK activation and ANP mRNA expression. MEK1 DN overexpression inhibited ET-1-, PE-, LIF-, and ISP-induced increases in cell size and sarcomeric reorganization. Consistent with the observed effects on cellular morphology, overexpression of MEK1 EE resulted in an increase in amino acid incorporation, while overexpression of MEK1 DN inhibited ET-1-, PE-, LIF-, ISP-, and mechanical stretch-induced increases in amino acid incorporation. These results indicate that the ERK cascade plays an important role in the signaling pathway leading to the development of myocardial cell hypertrophy.
J Mol Cell Cardiol 2000 Jun
PMID:Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy. 1088 49

The overexpression of either oncogenic ras or calmodulin in cardiac myocytes can elicit a hypertrophic response, albeit their recruitment by physiologically relevant stimuli remains unresolved. The present study utilized a pharmacological approach to examine the role of ras and calmodulin in norepinephrine- and endothelin-1-stimulated hypertrophy of neonatal rat cardiac myocytes. The pretreatment of cardiac myocytes with the farnesyltransferase inhibitor BMS-191563 (25 microM) increased the level of unfarnesylated ras in the cytosolic fraction, and caused a concomitant 42 +/- 2% decrease in immunodetectable farnesylated ras in the particulate fraction. In parallel, BMS-191563 pretreatment inhibited norepinephrine-mediated 3H-leucine uptake (80 +/- 10% decrease: n = 6; P<0.01), whereas a significant but less pronounced effect on the endothelin-1 response (46 +/- 6% decrease: n = 6; P<0.05) was observed. The calmodulin inhibitor W7 caused a 50 +/- 10% decrease (n = 8; P<0.05) of norepinephrine stimulated protein synthesis, whereas the endothelin-1 response was unaffected. Consistent with the recruitment of ras, BMS-191563 pretreatment attenuated norepinephrine and endothelin-1-stimulated extracellular signal-regulated kinase (ERK) activity. However, PD098059-mediated inhibition of MEK-dependent stimulation of ERK did not alter the hypertrophic response of either agonist. At the molecular level, the pretreatment with either BMS-191563 or W7 attenuated the norepinephrine-mediated increase of prepro-ANP and -BNP mRNA. Likewise, BMS-191563 caused a significant decrease of endothelin-1-mediated expression of the natriuretic peptide mRNAs, but to a lesser extent, as compared to norepinephrine. Thus, the present study has shown the treatment of neonatal rat cardiac myocytes with a farnesyltransferase inhibitor can attenuate the hypertrophic phenotype in response to physiologically relevant stimuli, thereby supporting a role of the small GTP-binding protein ras. Moreover, these data further suggest alternative ras-independent signaling pathways are also implicated in the hypertrophic response, albeit, there appears to exist a stimulus-specific heterogeneity in their recruitment.
J Mol Cell Cardiol 2000 Jun
PMID:A farnesyltransferase inhibitor attenuates cardiac myocyte hypertrophy and gene expression. 1088 63

Doxorubicin (Dox), an anthracyclin antineoplastic agent, causes dilated cardiomyopathy. CARP has been identified as a nuclear protein whose mRNA levels are exquisitely sensitive to Dox. In this study we investigated the molecular mechanisms underlying the repression of CARP expression by Dox in cultured neonatal rat cardiac myocytes. Dox (1 micromol/l)-mediated decrease in CARP mRNA levels was strongly correlated with BNP but not with ANP mRNA levels. Hydrogen peroxide scavenger catalase (1 mg/ml) but not hydroxyl radical scavengers dimethylthiourea (10 mmol/l) or mannitol (10 mmol/l) blunted the Dox-mediated decrease in CARP and BNP expression. Superoxide dismutase inhibitor diethyldithiocarbamic acid (10 mmol/l), which inhibits the generation of hydrogen peroxide from superoxide metabolism, attenuated the repression. PD98059 (MEK1 inhibitor, 50 micromol/l), SB203580 (p38 MAP kinase inhibitor, 10 micromol/l), calphostin C (protein kinase C (PKC) inhibitor, 1 micromol/l), non-selective protein tyrosine kinase inhibitors genistein (50 micromol/l) or herbimycin A (1 micromol/l) failed to abrogate the downregulation of CARP and BNP expression by Dox. In contrast, H7 (30 micromol/l), a potent inhibitor of serine/threonine kinase, significantly blocked Dox-mediated downregulation of CARP and BNP expression. Transient transfection of a series of 5'-deletion and site-specific mutation constructs revealed that M-CAT element located at -37 of the human CARP promoter mediates Dox-induced repression of CARP promoter activity. These results suggest that a genetic response to Dox is mediated through the generation of hydrogen peroxide, which is selectively linked to the activation of H7-sensitive serine/threonine kinase distinct from PKC and well characterized mitogen-activated protein (MAP) kinases (ERK and p38MAP kinase). Furthermore, our data implicated M-CAT element as a Dox-response element within the CARP promoter in cardiac myocytes.
J Mol Cell Cardiol 2000 Aug
PMID:Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways. 1090 Jan 67

Cardiac hypertrophy is associated with specific alterations in myocardial gene expression; however, the exact mechanisms responsible for altered gene expression are poorly defined. The goal of this study was to investigate whether signaling kinases that are activated during cardiac hypertrophy directly modulate transcription factor activity and regulate gene expression. In an effort to understand this process, we focused our studies on the transcriptional activation of c-fos gene through the serum response element (SRE)/ternary complex factor (TCF) element, during phenylephrine-induced myocyte hypertrophy. In this study, we show that phosphorylated Elk-1, a TCF, binds to c-fos SRE and its binding to SRE is increased upon phenylephrine stimulation. Phenylephrine treatment activates phosphorylation of Elk-1 in the nucleus within five minutes and Elk-1-dependent transcriptional activation is abolished by inhibitors selective for MEK/ERK kinases. These studies implicate that phosphorylation of Elk-1 by ERK kinase pathway is important for early gene activation during phenylephrine-induced myocyte hypertrophy.
J Mol Cell Cardiol 2000 Aug
PMID:Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy. 1090 Jan 71

There is accumulating evidence of complicated interactions among vascular cells, i.e. endothelial cells, smooth muscle cells and monocytes/macrophages, in the regulation of vascular function and remodeling. We have investigated the mechanisms responsible for matrix metalloproteinase (MMP)-1 expression by interactions between monocytes and vascular endothelial cells. THP-1 cells (human monocytic cell line) and human umbilical vein endothelial cells (HUVECs) were cocultured. MMP-1 levels in the culture medium were measured by enzyme-linked immunosorbent assays. Collagenolytic activity in the culture medium was measured by fluorescence labeled-collagen digestion. Immunohistochemistry using an anti-MMP antibody was carried out to determine which types of cell produce MMP-1. The addition of THP-1 cells to HUVECs for 48 h induced increases in MMP-1 levels and collagenolytic activity, which were 5- and 2-fold relative to those of HUVECs alone, respectively. A separate coculture experiment revealed that direct contact of THP-1 cells and HUVECs contributed to enhanced MMP-1 production in the cocolture. Immunohistochemical analysis revealed that both types of cell produce MMP-1 in the coculture. Neutralizing anti-interleukin-1 beta and tumor necrosis factor- alpha antibodies inhibited MMP-1 production by the coculture. The Src kinase and MEK inhibitors significantly inhibited MMP-1 production by the coculture. Coculture of THP-1 cells and HUVECs induced significant increases in Src and mitogen activated protein (MAP) kinase activities. Enhanced MMP-1 expression induced by monocyte-endothelial cell interactions may play an important role in the pathogenesis of atherosclerosis and plaque rupture.
J Mol Cell Cardiol 2000 Aug
PMID:Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial cells. 1090 Jan 72


1 2 3 4 5 6 Next >>