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)

The present study was undertaken to determine whether an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, simvastatin, modulates the cellular action of arginine vasopressin (AVP) in the cultured rat glomerular mesangial cells. AVP increases cellular free calcium ([Ca2+]i) in a dose-dependent manner. The 1 x 10(-7) M AVP-mobilized [Ca2+]i was significantly reduced in the cells pretreated with 1 x 10(-6) M simvastatin. AVP produced a biphasic change in cellular pH, namely, an early acidification followed by a sustained alkalinization, and the AVP-induced cellular alkalinization disappeared after exposing to simvastatin. 1 x 10(-7) M AVP activated mitogen-activated protein (MAP) kinase from 15.5-30.4 pmol/mg protein, an effect significantly less in the presence of simvastatin. Also, 1 x 10(-7) M AVP significantly increased [3H]thymidine incorporation by 1.6-fold, and its incorporation was totally diminished in cells pretreated with simvastatin. The AVP-induced [Ca2+]i mobilization and MAP kinase activation were totally restored when cells were preexposed to a mixture of mevalonate and simvastatin. [3H]AVP receptor binding was not affected by the simvastatin treatment. 1 x 10(-7) AVP increased inositol trisphosphate production by 1.8-fold, which was significantly reduced by the presence of simvastatin. These results may indicate that nonsterol pathway plays a crucial role in the cellular action of AVP to produce cell growth of glomerular mesangium.
 ...
PMID:Simvastatin inhibits the cellular signaling and proliferative action of arginine vasopressin in cultured rat glomerular mesangial cells. 772 Jun 43

We have recently reported that the activation of mitogen-activated protein kinase (MAPK) through specific protein kinase C (PKC) isoforms is required for basic fibroblast growth factor (bFGF)-induced proliferation of coronary smooth muscle cells (cSMC). In this study, we investigated the effects of the 3hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase inhibitor lovastatin on bFGF-induced signal transduction in cSMC. The present study shows that lovastatin inhibits bFGF-stimulated DNA synthesis in cSMC, and that this inhibition is reversed by mevalonate (50 micromol/l) and by geranylgeranyl-pyrophosphate (1-5 micromol/l). Although lovastatin prevented Ras farnesylation the amount of bFGF-stimulated MAPK phosphorylation decreased only partially after lovastatin treatment. In addition, lovastatin pretreatment resulted in a sustained phosphorylation of MAPK. We observed a dose-dependent lovastatin-dependent increase in PKC activity, which could be prevented by mevalonate. This increase was comparable to the one induced by calyculin A (2 nmol/l), an inhibitor of protein phosphatase PP-1 and PP-2A. Lovastatin inhibited the expression of the PP-1 protein, which is involved in bFGF-induced DNA synthesis in cSMC. Thus, our data suggest that, lovastatin possibly affects the dephosphorylation processes of PKC and MAPK by inhibition of PP-1/PP-2A protein phosphatases which are involved in the bFGF-induced mitogenesis in cSMC.
 ...
PMID:Lovastatin blocks basic fibroblast growth factor-induced mitogen-activated protein kinase signaling in coronary smooth muscle cells via phosphatase inhibition. 1132 84

Ceramide is a lipid second messenger that acts on multiple-target enzymes, some of which are involved in other signal-transduction systems. We have previously demonstrated that endogenous ceramide modifies the metabolism of brain ethanolamine plasmalogens. The mechanism involved was studied. On the basis of measurements of breakdown products, specific inhibitor effects, and previous findings, we suggest that a plasmalogen-selective phospholipase A2 is the ceramide target. Arachidonate-rich pools of the diacylphosphatidylethanolamine subclass were also affected by ceramide, but the most affected were plasmalogens. Concomitantly with production of free arachidonate, increased 1-O-arachidonoyl ceramide formation was observed. Quinacrine (phospholipase A2 inhibitor) and 1-O-octadecyl-2-O-methyl-rac-glycerol-3-phosphocholine (CoA-independent transacylase inhibitor) prevented all of these ceramide-elicited effects. Therefore, phospholipase and transacylase activities are tightly coupled. Okadaic acid (phosphatase 2A inhibitor) and PD 98059 (mitogen-activated protein kinase inhibitor) modified basal levels of ceramide and sphingomyelinase-induced accumulation of ceramide, respectively. Therefore, they provided no evidence to determine whether there is a sensitive enzyme downstream of ceramide. The evidence shows that there are serine-dependent and thiol-dependent enzymes downstream of ceramide generation. Furthermore, experiments with Ac-DEVD-CMK (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is downstream of ceramide in activating the brain plasmalogen-selective phospholipase A2.
 ...
PMID:Signaling events mediating activation of brain ethanolamine plasmalogen hydrolysis by ceramide. 1249 73

We determined whether mitogen-activated protein kinase (MAPK) and 5'-AMP-activated protein kinase (AMPK) signalling cascades are activated in response to intense exercise in skeletal muscle from six highly trained cyclists (peak O(2) uptake (.V(O2,peak)) 5.14 +/- 0.1 l min(-1)) and four control subjects (Vdot;(O(2))(,peak) 3.8 +/- 0.1 l min(-1)) matched for age and body mass. Trained subjects completed eight 5 min bouts of cycling at approximately 85% of .V(O2,peak) with 60 s recovery between work bouts. Control subjects performed four 5 min work bouts commencing at the same relative, but a lower absolute intensity, with a comparable rest interval. Vastus lateralis muscle biopsies were taken at rest and immediately after exercise. Extracellular regulated kinase (ERK1/2), p38 MAPK, histone H3, AMPK and acetyl CoA-carboxylase (ACC) phosphorylation was determined by immunoblot analysis using phosphospecific antibodies. Activity of mitogen and stress-activated kinase 1 (MSK1; a substrate of ERK1/2 and p38 MAPK) and alpha(1) and alpha(2) subunits of AMPK were determined by immune complex assay. ERK1/2 and p38 MAPK phosphorylation and MSK1 activity increased (P < 0.05) after exercise 2.6-, 2.1- and 2.0-fold, respectively, in control subjects and 1.5-, 1.6- and 1.4-fold, respectively, in trained subjects. Phosphorylation of histone H3, a substrate of MSK1, increased (P < 0.05) approximately 1.8-fold in both control and trained subject. AMPKalpha(2) activity increased (P < 0.05) after exercise 4.2- and 2.3-fold in control and trained subjects, respectively, whereas AMPKalpha(1) activity was not altered. Exercise increased ACC phosphorylation (P < 0.05) 1.9- and 2.8-fold in control and trained subjects. In conclusion, intense cycling exercise in subjects with a prolonged history of endurance training increases MAPK signalling to the downstream targets MSK1 and histone H3 and isoform-specific AMPK signalling to ACC. Importantly, exercise-induced signalling responses were greater in untrained men, even at the same relative exercise intensity, suggesting muscle from previously well-trained individuals requires a greater stimulus to activate signal transduction via these pathways.
 ...
PMID:Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise. 1252 21

The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of heritable hypertension-associated cerebrovascular injury. This study sought to compare SHRSP to the stroke-resistant SHR strain to identify genes and protein pathways whose expression and/or function was significantly altered between the strains prior to the onset of stroke. Cerebral cortex gene expression profiles from male SHRSPs and matched SHRs were examined by Affymetrix microarray analysis. mRNAs encoding the brain-derived neurotrophic factor receptor (TrkB) and multiple kinases of the MAPK/AKT signaling pathways, including JNK2, AKT2, and PI3K, were differentially expressed between SHRSP and SHR. Because these data suggest altered function in pathways involving MAP and AKT kinase activity, we performed Western blot using phosphorylation state-specific antibodies to characterize activity of MAP kinase and PI3K/AKT pathways. Changes in the levels of the phosphorylated forms of these kinases paralleled the changes in transcript levels observed between the strains. Two-dimensional gel electrophoresis and peptide fragment mass fingerprinting were used to identify altered protein substrates of these kinases. Protein profiling of kinase substrates further supported the notion of perturbed kinase-mediated signaling in SHRSP and identified adenylyl cyclase associated protein 2, TOAD-64, propionyl CoA carboxylase, APG-1, and valosin-containing protein as kinase targets whose phosphorylation state is altered between these strains. Altered gene and protein expression patterns in SHRSP are consistent with increased vulnerability of this strain to cerebrovascular injury.
 ...
PMID:Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility. 1290 46

The terminal complement complex C5b-9 is known to participate in inflammatory processes including atherosclerosis. Inflammation appears to be a direct consequence of C5b-9-mediated cell stimulation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may exert anti-inflammatory effects on vascular cells independent of lowering plasma cholesterol. Thus, we studied activation of vascular smooth muscle cells (VSMCs) by C5b-9 focusing on whether inhibition of the HMG-CoA reductase can reduce the proinflammatory effects of C5b-9.C5b-9 in sublytic concentrations increased the proliferation of human VSMCs and induced a time-dependent activation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Proliferation and ERK1/2 activation could be inhibited by the specific ERK inhibitor PD98059. HMG-CoA inhibition with cerivastatin-reduced VSMC proliferation and C5b-9-induced ERK1/2 activation. Cerivastatin also reduced the C5b-9-induced synthesis of the proinflammatory interleukin-6 (IL-6). Furthermore, C5b-9 induced activation of the transcription factors activator protein- 1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which could be inhibited by pretreatment of VSMCs with cerivastatin. L-mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effects of cerivastatin. The present study in VSMCs shows that cerivastatin inhibits IL-6 synthesis and cell proliferation induced by the terminal complement complex C5b-9. This may be an important mechanism contributing to the beneficial effects of HMG-CoA reductase inhibitors beyond lowering of plasma cholesterol.
 ...
PMID:HMG-CoA reductase inhibition reduces the proinflammatory activation of human vascular smooth muscle cells by the terminal complement factor C5b-9. 1455 80

Insulin has a major anabolic function leading to storage of lipidic and glucidic substrates. All its effects result from insulin binding to a specific membrane receptor which is expressed at a high level on the 3 insulin target tissues: liver, adipose tissue and muscles. The insulin receptor exhibits a tyrosine-kinase activity which leads, first, to receptor autophosphorylation and then to tyrosine phosphorylation of substrates proteins, IRS proteins in priority. This leads to the formation of macromolecular complexes close to the receptor. The two main transduction pathways are the phosphatidylinositol 3 kinase pathway activating protein kinase B which is involved in priority in metabolic effects, and the MAP kinase pathway involved in nuclear effects, proliferation and differentiation. However, in most cases, a specific effect of insulin requires the participation of the two pathways in a complex interplay which could explain the pleiotropy and the specificity of the insulin signal. The negative control of the insulin signal can result from hormone degradation or receptor dephosphorylation. However, the major negative control results from phosphorylation of serine/threonine residues on the receptor and/or IRS proteins. This phosphorylation is activated in response to different signals involved in insulin resistance, hyperinsulinism, TNFalpha or increased free fatty acids from adipose tissue, which are transformed inside the cell in acyl-CoA. A deleterious role for molecules issued from the adipose tissue is postulated in the resistance to insulin of the liver and muscles present in type 2 diabetes, obesity and metabolic syndrome.
 ...
PMID:[Insulin signaling: mechanisms altered in insulin resistance]. 1459 14

The present study was carried out to assess the possible role of mitogen-activated protein kinase (MAPK) in the meiosis-inducing action of the AMP-activated protein kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR). Cumulus cell-enclosed oocytes (CEO) or denuded oocytes (DO) from immature, eCG-primed mice were cultured 4 hr in Eagle's minimum essential medium containing dbcAMP plus increasing concentrations of AICAR or okadaic acid (OA). OA is a phosphatase inhibitor known to stimulate both meiotic maturation and MAPK activation and served as a positive control. Both OA and AICAR were potent inducers of meiotic resumption in mouse oocytes and brought about the phosphorylation (and thus, activation) of MAPK, but by different kinetics: MAPK phosphorylation preceded GVB in OA-treated oocytes, while that resulting from AICAR treatment appeared only after GVB. The MEK inhibitors, PD98059 and U0126, blocked the meiotic resumption induced by AICAR but not that induced by OA. Although the MEK inhibitors suppressed MAPK phosphorylation in both OA- and AICAR-treated oocytes, meiotic resumption was not causally linked to MAPK phosphorylation in either group. Furthermore, AICAR-induced meiotic resumption in Mos-null oocytes (which are unable to stimulate MAPK) was also abrogated by PD98059 treatment. A non-specific effect of the MEK inhibitors on AICAR accessibility to the oocyte was discounted by showing that they failed to suppress either nucleoside uptake or AICAR-stimulated phosphorylation of acetyl CoA carboxylase (ACC), a substrate of AMPK. The suppression of AICAR-induced maturation by MEK inhibitors must, therefore, be occurring by actions unrelated to MEK stimulation of MAPK; consequently, it would be prudent to consider this possible non-specific action of the inhibitors when they are used to block MAPK activation in mouse oocytes.
 ...
PMID:MEK inhibitors block AICAR-induced maturation in mouse oocytes by a MAPK-independent mechanism. 1557 Jun 12

Modulation of T cell response is a novel property of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors. Previously we reported the benefits of atorvastatin treatment in experimental autoimmune encephalomyelitis, the murine model of the T cell-mediated autoimmune disorder multiple sclerosis, in which a blockade of the T cell cycle by atorvastatin was attributed to an accumulation of the negative regulator p27(Kip1). We show in this report that, in line with the documented role of p27(Kip1) in T cell anergy, treatment with atorvastatin results in a deficient response to a second productive stimulus in human T cells. This effect of atorvastatin was dependent on HMG-CoA reduction and required IL-10 signaling. Importantly, atorvastatin induced an early and sustained phosphorylation of ERK1, but not ERK2, which was crucial for the induction of anergy. On the basis of the therapeutic impact of HMG-CoA reductase inhibitors, the present findings should pave the way for future therapeutic concepts related to tolerance induction in neuroinflammatory disorders such as multiple sclerosis.
 ...
PMID:Atorvastatin induces T cell anergy via phosphorylation of ERK1. 1584 62

The aim of this study was to evaluate changes in the regulation of lipid metabolism and mitogen-activated protein kinases (MAPK) in the liver of C57BL/6 mice as they age. This was done by assessing the status of total cholesterol content and its enzyme, acyl-CoA: cholesterol acyltransferase (ACAT), in liver microsomal preparations and the low-density lipoprotein receptor (LDLr) mRNA expression in the livers of 4-24-month-old C57B/6 mice, without exogenous cholesterol feeding. With aging, there was an increase in cholesterol content and ACAT activity in liver microsomes. Northern blot analysis and real-time quantitative polymerase chain reaction data showed that ACAT-2 mRNA increased with age as well. LDLr expression decreased significantly in an age-dependent manner. In addition, we studied the basal and activated forms of MAPK, e.g. extracellular regulatory kinase (ERK-1/2), c-jun NH2-terminal kinase (JNK-1/2) and p38 MAPK. During aging, there was a considerable decrease in phosphorylated ERK-1/2 level while JNK-1/2 and p38 MAPK levels increased with age. Our studies showed an altered LDLr expression and altered phosphorylated MAPK in the liver of C57BL/6 mice during aging. These alterations might contribute to the development of atherosclerosis, hypercholesterolemia and other cholesterol-related conditions.
 ...
PMID:Age-related alteration in hepatic acyl-CoA: cholesterol acyltransferase and its relation to LDL receptor and MAPK. 1588 29


1 2 3 4 5 6 Next >>