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

Interleukin-1 beta (IL-1 beta) is a multipotent cytokine participating in a variety of cardiovascular diseases. In this study, we examined the effects of IL-1 beta on the expression of vascular endothelial cell growth factor (VEGF) and pursued the molecular mechanisms underlying this effect. Treatment of cultured neonatal rat cardiac myocytes with IL-1 beta increased the levels of VEGF mRNA in a time- and a concentration-dependent manner. These effects were completely abolished by SB203580 and SB202190 (p38 MAPK inhibitors) but not by PD98059 (MEK1 inhibitor), calphostin C (protein kinase C inhibitor), or genistein (tyrosine kinase inhibitor). While IL-1 beta phosphorylated c-Jun N-terminus protein kinase (JNK) rapidly and transiently, the effect of IL-1 beta on p38 mitogen-activated protein kinase (MAPK) was gradual and persistent. Transient transfection assays showed that IL-1 beta increases the transcription from the VEGF promoter. A series of 5;-deletion and site-specific mutation analyses indicated that IL-1 beta as well as overexpression of p38 MAPK and JNK activate VEGF promoter activity through two G+C-rich sequences located at -73 and -62. Electrophoretic mobility shift and supershift assays showed Sp1 and Sp3 proteins specifically bind to the G+C-rich sequences. The half-life of VEGF mRNA was significantly increased in cells treated with IL-1 beta. Together, these results indicate that IL-1 beta induces VEGF gene expression at both transcriptional and post-transcriptional levels, and IL-1 beta evokes p38 MAPK and JNK signalings, which in turn stimulate the transcription of the VEGF gene through Sp1-binding sites. These findings suggest the role of IL-1 beta as a cytokine inducing VEGF in cardiac myocytes, and imply that activation of stress-activated MAP kinases regulate Sp1 sites-dependent transcription.
J Mol Cell Cardiol 2000 Nov
PMID:Induction of VEGF gene transcription by IL-1 beta is mediated through stress-activated MAP kinases and Sp1 sites in cardiac myocytes. 1104 Jan 1

We examined the relative roles of the mitogen-activated protein kinases (MAPK) in mediating the alpha1-adrenergic receptor (alpha1-AR) stimulated hypertrophic phenotype in adult rat ventricular myocytes (ARVM). Norepinephrine (NE; 1 microM) in the presence of the beta -AR antagonist propranolol (Pro; 2 microM) caused activation of Ras (>six-fold), MAPK/ERK kinase 1 and 2 (MEK1/2, >10-fold) and extracellular signal-regulated kinases 1 and 2 (ERK1/2, approximately 30-fold) within 5 min, as determined by kinase activity assays and Western blots using phospho-specific antibodies. Conversely, p38 and c-Jun amino-terminal kinases (JNK) were not activated by NE/Pro. Activated MEK1/2 signals remained detectable at 2 h, and activated ERK1/2 remained detectable at 48 h. The alpha1-AR selective inhibitor prazosin (100 nM) completely inhibited the NE/Pro-stimulated activation of Ras, MEK1/2 and ERK1/2. The MEK inhibitor PD98059 caused a concentration-dependent inhibition of NE/Pro-stimulated protein synthesis (as assessed by [3H]leucine incorporation and cellular protein accumulation) and ERK1/2 activation, with approximately 50% inhibition at a concentration between 10 and 50 microM, which is consistent with the known IC50 values of PD98059 for MEK1 (4 microM) and MEK2 (50 microM). Thus, these data show that alpha1-AR stimulated hypertrophy in ARVM is dependent on the MEK1/2-ERK1/2 signaling pathway.
J Mol Cell Cardiol 2001 Apr
PMID:MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. 1127 30

Opioids have been previously shown to confer acute and delayed cardioprotection against a prolonged ischemic insult. We have extensively characterized the signal transduction pathway mediating acute cardioprotection and have suggested a role for extracellular signal regulated kinase (ERK) in this cardioprotection. Therefore, we attempted to determine a role for ERK and the stress activated MAP kinase, p38, in opioid-induced delayed cardioprotection by using selective inhibitors of these pathways. All rats were subjected to 30 min of ischemia and 2 h of reperfusion (I/R). Control animals, injected with saline 48 h prior to I/R, had an infarct size/area at risk (IS/AAR) of 61.6 +/- 1.6.48-h pretreatment with TAN-67 (30 mg/kg), a delta1-opioid receptor agonist, maximally reduced IS/AAR (31.2 +/- 6.5). The involvement of ERK was examined with PD 098059, a selective pharmacological antagonist which inhibits the upstream kinase, MEK-1, that phosphorylates and activates ERK. PD 098059 (0.3 mg/kg) did not alter IS/AAR when administered alone (60.7 +/- 4.9). However, PD 098059 (0.3 mg/kg) administration 30 min prior to TAN-67 (30 mg/kg) completely abolished cardioprotection (61.0 +/- 7.6). The selective p38 inhibitor, SB 203580 (1.0 mg/kg), had no effect on IS/AAR in the absence of TAN-67 (53.1 +/- 2.3). Additionally, SB 203580 (1.0 mg/kg) when administered prior to TAN-67 (30 mg/kg) partially abolished cardioprotection (51.3 +/- 6.4). These results suggest that both ERK and p38 are integral components of opioid-induced delayed cardioprotection and may act via parallel pathways.
Basic Res Cardiol 2001 Apr
PMID:ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection. 1132 31

beta -adrenergic agonists stimulate neonatal rat cardiac fibroblast growth, albeit the identity of the signaling event(s) remains equivocal. Isoproterenol (ISO) treatment increased intracellular cyclic AMP levels; however, cyclic AMP-elevating agents had no effect on protein synthesis. The tyrosine kinase inhibitor tyrphostin A25, and the inhibition of ras processing by the farnesyltransferase inhibitor BMS-191563 attenuated ISO-stimulated protein synthesis. Concomitant with increased protein synthesis, ISO stimulated extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K) activity. The MEK1/2 inhibitor PD098059 abrogated ISO-stimulated ERK activity, albeit the increase in protein synthesis was unaffected. By contrast, LY294002 inhibited both ISO-stimulated PI3-K activity, and protein synthesis. ISO treatment did not increase the expression of transforming growth factor-beta(1)(TGF-beta(1)) mRNA, whereas a significant decrease in the steady-state mRNA level of TGF- beta(3)was observed. This latter effect was mimicked by cyclic AMP-elevating agents. Angiotensin II (AII) activation of the AT(1)receptor increased protein synthesis, but in contrast to ISO, the growth response was not inhibited by either tyrphostin A25 or BMS-191563, and was associated with the concomitant expression of both TGF-beta(1)and TGF-beta(3)mRNAs. Analogous to ISO, AII treatment increased ERK and PI3-K activity, and PI3-K was required for protein synthesis. These findings are the first to highlight the activation of PI3-K by a Gs(alpha)-coupled receptor, and its essential role in beta -adrenergic as well as AT(1)receptor-mediated protein synthesis in neonatal rat cardiac fibroblasts. However, despite the conserved role of PI3-K, additional disparate signaling pathways are recruited by ISO and AII, which may differentially influence fibroblast phenotype.
J Mol Cell Cardiol 2001 Jun
PMID:beta-Adrenergic stimulation of rat cardiac fibroblasts promotes protein synthesis via the activation of phosphatidylinositol 3-kinase. 1144 12

Hypertrophy is an adaptive response of the heart to myocardial injury or hemodynamic overload that may progress and contribute to cardiac decompensation and eventually to heart failure. The signaling pathways controlling this response in the cardiac myocyte are poorly understood. A data mining effort of a human failed heart cDNA library was undertaken in an effort to identify novel signaling molecules involved in cardiac hypertrophy. This effort identified a novel kinase (MLK7) homologous to the mixed lineage kinase family of proteins. The mixed lineage kinases are mitogen-activated protein kinase kinase kinases (MAPKKKs) which activate stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase pathways. They contain a catalytic domain with homology to both serine/threonine and tyrosine-specific kinases and a dual leucine zipper. MLK7 is identical to leucine zipper and sterile-alpha motif protein kinase (ZAK) through the leucine zipper domain but has a completely divergent COOH-terminus and shares approximately 40% homology with the other MLKs overall. Expression of MLK7 mRNA is most abundant in skeletal muscle and heart, with expression restricted to the cardiac myocyte. The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate. When expressed in cardiac myocytes, MLK7 activated SAPK/JNK1, and ERK and p38 to a lesser extent. Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes. These data suggest that MLK7 is a new member of the mixed lineage kinase family that modulates cardiac SAPK/JNK pathway and may play a role in cardiac hypertrophy and progression to heart failure.
J Mol Cell Cardiol 2001 Sep
PMID:Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase. 1154 52

Urocortin (Ucn), is a peptide related to hypothalamic corticotrophin-releasing factor (CRF) and binds with a high affinity to the CRF-R2 beta receptor which is expressed in the heart. Ucn promotes cardiac myocyte survival against hypoxia reoxygenation (HR) injury and this involves activation of the mitogen activated protein kinase pathway (MEK1/2 p42/44 MAPK). In this study we report that Ucn stimulates the phosphorylation of protein kinase B (PKB/Akt) via phosphatidylinositol (PI) 3-OH kinase (PI-3 kinase). To investigate the signalling pathways that mediate the anti-apoptotic and cell survival effect of Ucn in hypoxia reoxygenation (HR), gene based inhibitors of MEK1/2, PI-3 kinase and Akt were over-expressed in rat neonatal cardiac myocytes and cell survival effects against HR were assessed. The dominant negative mutants of the MEK1/2, PI-3 kinase and Akt inhibited Ucn mediated cardioprotection in HR and active PI-3 kinase was itself cardioprotective. In addition, chemical inhibitors of the PI-3 kinase pathway, wortmannin and LY294002 inhibit Ucn mediated cardioprotection in HR in both neonatal and adult cardiac myocytes. Hence the PI-3 kinase/Akt pathway is required in addition to MEK1/2 to mediate Ucn cardioprotection in HR. To our knowledge this is the first report of the activation of the PI-3 kinase/Akt pathway by a member of the CRF family of peptides.
J Mol Cell Cardiol 2002 Apr
PMID:Activation of protein kinase B/Akt by urocortin is essential for its ability to protect cardiac cells against hypoxia/reoxygenation-induced cell death. 1199 36

Experiments were performed to define the basis for negative regulation of STAT3 activation (i.e., Tyr705 phosphorylation) by angiotensin II in cardiomyocytes. Treatment of cardiomyocytes with angiotensin II resulted in rapid and sustained phosphorylation of STAT3 on Ser727; in contrast, STAT3 Tyr705 phosphorylation was decreased, with dephosphorylation being most pronounced at 30 minutes. Angiotensin II-induced STAT3 Tyr705 dephosphorylation was not prevented by inhibiting protein synthesis, but was blocked by vanadate or the MEK inhibitor PD98059. PD98059 was found to inhibit angiotensin II-induced Erk activation and STAT3 Ser727 phosphorylation. Angiotensin II also attenuated LIF-induced STAT3 Tyr705 phosphorylation, and this effect could be blocked with PD89059. These results are consistent with Erk-mediated STAT3 Ser727 phosphorylation leading to STAT3 Tyr705 dephosphorylation, and accounting for angiotensin II-mediated STAT3 inhibition in cardiomyocytes. We propose that Erk serves as a scaffolding protein in recruiting either a protein tyrosine or MAP kinase phosphatase to STAT3.
Basic Res Cardiol 2003 Feb
PMID:Angiotensin II effects on STAT3 phosphorylation in cardiomyocytes: evidence for Erk-dependent Tyr705 dephosphorylation. 1249 67

Reactive oxygen species (ROS) can act as signaling molecules to stimulate either hypertrophy or apoptosis in cardiac myocytes. We tested the hypothesis that the phenotypic effects of ROS are due to differential, concentration-dependent activation of specific kinase signaling pathways. Adult rat ventricular myocytes were exposed to H(2)O(2) over a broad concentration range (10-1000 microM). Low concentrations of H(2)O(2) (10-30 microM) increased protein synthesis without affecting survival. Higher concentrations of H(2)O(2) (100-200 microM) increased apoptosis (assessed by TUNEL). Still higher concentrations of H(2)O(2) (300-1000 microM) caused both apoptosis and necrosis. A hypertrophic concentration of H(2)O(2) (10 microM) increased the activity of ERK1/2, but not that of JNK, p38 kinase or Akt. An apoptotic concentration of H(2)O(2) (100 microM) activated JNK, p38 kinase and Akt, and further activated ERK1/2. The MEK1/2 inhibitor U0126 prevented the hypertrophic effect of 10 microM H(2)O(2). The apoptotic effect of 100 microM H(2)O(2) was inhibited bya dominant-negative JNK adenovirus, and was potentiated by U0126 or an Akt inhibitor. Thus, the concentration-dependent effects of ROS on myocyte hypertrophy and growth are due, at least in part, to the differential activation of specific kinase signaling pathways that regulate hypertrophy and apoptosis.
J Mol Cell Cardiol 2003 Jun
PMID:H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. 1278 76

Reduced glutathione (GSH) is an essential, multifunctional tripepetide that controls redox-sensitive cellular processes, but its regulation in the heart is poorly understood. The present study used a pharmocological model of GSH depletion to examine cellular mechanisms controlling cardiac GSH. Inhibition of GSH metabolism was elicited in normal rats by daily injections of buthionine sulfoximine (BSO), a blocker of gamma-glutamylcysteine synthetase, plus 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. After 3 d of BSO/BCNU treatment, intracellular [GSH] was measured in isolated-ventricular myocytes by fluorescence microscopy using the probe monochlorobimane. Basal [GSH] in left-ventricular myocytes from BSO/BCNU-treated rats (2.0 +/- 0.05 amol/microm(3), n = 146) was 50% less than control (4.0 +/- 0.13 amol/microm(3), n = 116; P < 0.05). Incubation of myocytes from BSO/BCNU rats with 0.1 microM insulin normalized [GSH] after a delay of 3-4 h (3.6 +/- 0.29 amol/microm(3), n = 66). This effect of insulin was blocked by pre-treating myocytes with cycloheximide. A protein tyrosine phosphatase inhibitor, bis-peroxovanadium-1,10-phenanthroline (bpV(phen), 1 microM), elicited a similar effect as insulin, while neither agent altered [GSH] in myocytes from control rats. Moreover, the effect of insulin and bpV(phen) to up-regulate GSH was blocked by inhibitors of PI 3-kinase (wortmannin, LY294002), MEK (PD98059) and p38 MAP kinases (SB203580). These data suggest that the insulin-signaling cascade regulates [GSH] in ventricular myocytes by a coordinated activation of PI 3-kinase and MAP kinase pathways. These signaling mechanisms may play essential roles in controlling intracellular redox state and normal function of cardiac myocytes.
J Mol Cell Cardiol 2003 Sep
PMID:Regulation of glutathione in cardiac myocytes. 1296 37

Urocortin (UCN), a member of the Corticotropin-Releasing Factor (CRF) family of peptides is a well described cardioprotective agent. UCN is able to bind to two types of G-protein coupled receptors: CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2), whereas, two homologues of UCN, stresscopin (SCP) or also known as urocortin III (UCNIII) and stresscopin related peptide (SRP), or urocortin II (UCNII), bind exclusively and with high affinity to CRFR2, we hypothesised that they will exhibit more pronounced cardioprotective effects than UCN. We show for the first time that SCP is expressed in rat cardiomyocytes and that the levels of SRP and SCP are increased by hypoxic stress. All three peptides have potent cardioprotective effects in cells exposed to hypoxia/reoxygenation. When used at 10(-8) M they increased the amount of live cells by 25% when added prior to hypoxia, and by 20% when UCN and SCP were added at the onset of reoxygenation. In addition, the peptides are equally are more potent antiapoptotic factors than UCN. The antiapoptotic effects of SCP were more pronounced than SRP and UCN at a concentration of 10(-10) M. Furthermore, SCP and SRP protect cardiomyocytes better than UCN at concentrations up to and including 10(-10) M and reduced the amount of TUNEL positive cells almost by half at concentrations of 10(-12) to 10(-10) M. More importantly, we demonstrate that SCP and SRP are able to protect cardiomyocytes even if they are administered after the hypoxic insult and prior to reoxygenation. In this case SCP was more potent than UCN and SRP at 10(-12) M and both SCP and SRP exhibited higher protection at 10(-8) M compared to UCN. Cardioprotection of cardiomyocytes by 10(-8) M of peptides was abolished when treated with 50 microM LY294002 or 100 microM PD98059, but not by 10 microM SB203580 prior to the hypoxic insult. Transfection of dominant negative Akt and MEK1 also blocked protection by the peptides, whereas dominant negative MEKK6 had no effects, demonstrating that SCP and SRP, like UCN, require activation of p42/44 Mitogen activated protein kinase and Akt/Protein Kinase B in order to produce their cardioprotective effects. In addition, we showed that SCP and UCN are potent activators of the p42/44 MAPK pathway, with SRP able to induce phosphorylation of p42/44 MAPK as well, albeit not as pronounced.
J Mol Cell Cardiol 2003 Oct
PMID:Protective effects of the urocortin homologues stresscopin (SCP) and stresscopin-related peptide (SRP) against hypoxia/reoxygenation injury in rat neonatal cardiomyocytes. 1451 39


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