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)

Although copper is an essential metal, it is capable of catalyzing the formation of reactive oxygen species that can cause intracellular oxidative damage. We investigated the hypothesis that metal- and oxidative stress-responsive signal transduction pathways mediate the cellular and molecular responses associated with copper exposure. Transient transfection assays using COS-7 cells and mouse metallothionein-I (MT-I) or rat NAD(P)H:oxidoreductase 1-based reporter genes demonstrate that copper activates transcription via metal and antioxidant response elements. Concomitant with copper exposures is a decrease in the level of total glutathione and an increase in oxidized glutathione. Depletion of glutathione, before copper exposure, increases metal- and oxidative stress-inducible transcription and cytotoxicity. Pretreatment with the reactive oxygen scavengers aspirin or vitamin E provides partial protection against copper toxicity and reduces inducible transcription. Experiments using signal transduction inhibitors and a metal transcription factor (MTF)-1 null cell line demonstrate that copper-inducible MT-I transcription is regulated by protein kinase C and mitogen-activated protein kinase signaling pathways and requires MTF-1. The results of these studies indicate that copper activates transcription through both metal- and oxidative stress-responsive signal transduction pathways.
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PMID:Copper-inducible transcription: regulation by metal- and oxidative stress-responsive pathways. 1457 86

Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (+/-)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H(2)O(2)-stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 microM H(2)O(2), indicating that exogenous 500 microM H(2)O(2) was a growth stimulator of rat aortic smooth muscle cells. Exogenous H(2)O(2) significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 microM H(2)O(2)-stimulated rat aortic smooth muscle cells (IC(50): 200 microM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H(2)O(2) in a dose-dependent manner. In 500 microM H(2)O(2)-stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 microM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H(2)O(2)-stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.
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PMID:Antiproliferative mechanisms of raxofelast (IRFI-016) in H2O2-stimulated rat aortic smooth muscle cells. 1474 95

In order to investigate the roles of ERK1/2 mitogen-activated protein kinase in vitamin E succinate (VES)-induced apoptosis in human gastric cancer SGC-7901 cells, apoptosis was observed by DAPI staining and the phosphorylation of ERK1/2 by VES at different doses and different time points was measured by western blot. The results showed that VES obviously induced cells to undergo apoptosis and apoptotic rate after 24 h and 48 h of treatment with VES at 20 micrograms/ml. VES was 14.2% and 89.4%, respectively. The expression of p-ERK was evidently reduced by VES at 5, 10 and 20 micrograms/ml for 24 h. ERK1/2 was immediately activated by VES at 20 micrograms/ml, but the expression was decreased for 2 h, then increased again and reached the top level for 12 h. The data implicated that ERK1/2 pathway might be involved in VES-induced apoptosis, but in the proliferation eventually.
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PMID:[Roles of ERK1/2 MAPK in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells]. 1496 7

Cardiotrophin-1 (CT-1) is a cytokine that is involved in the growth and survival of cardiac cells. In the present study, we demonstrate that treatment of embryoid bodies grown from pluripotent murine embryonic stem (ES) cells with CT-1 significantly stimulated cardiomyogenesis and increased nuclear expression of the proliferation marker Ki-67. The increase in Ki-67 expression was inhibited upon pretreatment with the free radical scavenger vitamin E, indicating a role for reactive oxygen species (ROS) in the signaling cascade. CT-1 treatment of cardiac cells raised intracellular ROS in ES cell-derived cardiomyocytes. ROS were presumably generated by an NADPH-oxidase since ROS generation was down-regulated upon preincubation with the NADPH-oxidase inhibitor diphenylen iodonium chloride (DPI) and LY294002, which inhibits phosphatidylinositol 3 kinase (PI3-kinase). CT-1 activated nuclear factor-kappaB (NF-kappaB) and induced phosphorylation of the Janus kinase signal transducer-2 (Jak-2), the signal transducer and activator of transcription-3 (STAT-3) as well as the extracellular signal-regulated kinase 1,2 (ERK1/2). STAT-3 and ERK1/2 phosphorylation as well as NF-kappaB activation were inhibited by pretreatment with the Jak-2 antagonist AG490, the ERK1/2 inhibitor PD98059, the free radical scavenger vitamin E, the NADPH-oxidase inhibitor DPI, as well as by LY294002. PD98059 failed to inhibit Jak-2 phosphorylation, indicating that the ERK and the Jak/STAT signaling cascade interact on a level downstream of Jak-2. It is concluded that CT-1 stimulates the proliferation of ES cell-derived cardiomyocytes by signaling pathways that involve ROS as signaling molecules in the signal transduction cascade.
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PMID:Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells. 1502 22

Mitochondrial transcription factor A (Tfam, previously mtTFA) is a key regulator of mitochondrial DNA (mtDNA) transcription and replication. We have reported that overexpression of nuclear respiratory factor-1 (NRF-1) and high concentration (50 mM) of glucose increased the promoter activity of the rat Tfam in L6 rat skeletal muscle cells. In this study, we investigated the mechanism of high glucose-induced Tfam transactivation. The addition of 50 mM glucose for 24 h increased Tfam promoter activity up to twofold. The glucose-induced Tfam expression was dose-dependent and cell-type specific. Glucose increased the Tfam promoter-driven transactivity in L6 (skeletal muscle), HIT (pancreatic beta-cell), and CHO (ovary) cells, but not in HepG2 (hepatoma), HeLa, and CV1 (kidney) cells. Among various monosaccharides, only glucose and fructose increased the Tfam promoter activity. Oxidative stress might not be involved in glucose-induced Tfam expression since treatment with antioxidants such as vitamin C, vitamin E, probucol, or alpha-lipoic acid did not suppress the induction. None of the inhibitors of protein kinase C, MAP kinase, and PI3 kinase altered the glucose-induced Tfam promoter activity, suggesting that general phosphorylation is involved in its signaling. However, a dominant negative mutant of NRF-1, in which 200 amino acids of C-terminus were truncated, completely suppressed the glucose-induced Tfam induction. It was concluded that high glucose-induced Tfam transcription in L6 cells might be mediated by NRF-1.
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PMID:Regulation of mitochondrial transcription factor A expression by high glucose. 1512 85

Activity and expression of fatty acid synthase (FAS), a critical enzyme in the de novo biosynthesis of fatty acids in mammals, is exquisitely sensitive to nutritional regulation of lipogenesis in liver or adipose tissue. Surprisingly, a number of studies have demonstrated hyperactivity and overexpression of FAS (oncogenic antigen-519) in a biologically aggressive subset of human breast carcinomas, suggesting that FAS-dependent neoplastic lipogenesis is unresponsive to nutritional regulation. We have assessed the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on the enzymatic activity and protein expression of tumor-associated FAS in SK-Br3 human breast cancer cells, an experimental paradigm of FAS-overexpressing tumor cells in which FAS enzyme constitutes up to 28%, by weight, of the cytosolic proteins. Of the omega-3 PUFAs tested, alpha-linolenic acid (ALA) dramatically reduced FAS activity in a dose-dependent manner (up to 61%). omega-3 PUFA docosahexaenoic acid (DHA) demonstrated less marked but still significant inhibitory effects on FAS activity (up to 37%), whereas eicosapentaenoic acid (EPA) was not effective. Of the omega-6 fatty acids tested, gamma-linolenic acid (GLA) was the most effective dose-dependent inhibitor of FAS activity, with a greater than 75% FAS activity reduction. Remarkably, omega-6 PUFAs linoleic acid (LA) and arachidonic acid (ARA), suppressors of both hepatic and adipocytic FAS-dependent lipogenesis, had no significant inhibitory effects on the activity of tumor-associated FAS in SK-Br3 breast cancer cells. Western blotting studies showed that down-regulation of FAS protein expression tightly correlated with previously observed inhibition of FAS activity, suggesting that ALA-, DHA-, and GLA-induced changes in FAS activity resulted from effects at the protein level. We investigated whether the FAS inhibitory effect of GLA and omega-3 PUFAs correlated with a cytotoxic effect related to a peroxidative mechanism. Measurement of cell viability by MTT assay indicated a significant cellular toxicity after ALA and GLA exposures. Furthermore, we observed a significant correlation between the ability of PUFAs to repress FAS and cause cell toxicity. In the presence of anti-oxidants (vitamin E), ALA and GLA dramatically lost their ability to inhibit FAS activity. Interestingly, a combination of ALA and GLA was FAS inhibitory in an additive manner, and this FAS repression was only partially reversible by vitamin E. In examining the molecular mechanisms underlying resistance of breast cancer-associated FAS to normal dietary fatty acid-induced suppression, a dramatic decrease of FAS accumulation was found after exposure of SK-Br3 cells to mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) inhibitor U0126, phosphatidylinositol-3'-kinase (PI-3'K) blocker LY294002, and/or anti-HER-2/neu antibody trastuzumab. Interestingly, a long-term exposure to pharmacological inhibitors of FAS activity cerulenin [(2S,3R) 2,3-epoxy-4-oxo-7E,10E-dodecadienamide] or C75 also resulted in a significant reduction of FAS accumulation. These data indicate that: a) GLA- and omega-3 PUFA-induced repression of tumor-associated FAS may result, at least in part, from a non-specific cytotoxic effect due to peroxidative mechanisms; b) alternatively, GLA and omega-3 PUFAs have a suppressive effect on FAS expression and activity that can result in the accumulation of toxic fluxes of the FAS substrate malonyl-CoA; c) GLA- and/or omega-3 PUFA-induced repression of tumor-associated FAS may represent a novel mechanism of PUFA-induced cytotoxicity clinically useful against breast carcinomas carrying overexpression of FAS enzyme; d) fundamental differences in the ability of FAS gene to respond to normal fatty acid's regulatory actions in lipogenic tissues may account for the observed extremely high levels of FAS in breast carcinoma; and e) FAS overexpression in SK-Br3 breast cancer cells is driven by increases in HER-2/neu signaling, acting in major part through a constitutive downstream art through a constitutive downstream activation of the MAPK ERK1/2 and PI-3'K/AKT transduction cascades.
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PMID:Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. 1513 77

Vitamin E derivative, RRR-alpha-tocopheryl succinate (vitamin E succinate, VES), is a potent pro-apoptotic agent, inducing apoptosis by restoring both transforming growth factor-beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptosis. Objectives of these studies were to characterize signaling events involved in the pro-apoptotic actions of a naturally occurring form of vitamin E, delta-tocotrienol, and a novel vitamin E analog, alpha-tocopherol ether acetic acid analog [alpha-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, alpha-TEA and delta-tocotrienol induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no or lower levels of apoptosis in normal human mammary epithelial cells and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct alpha-TEA and delta-tocotrienol were identical to those previously reported for VES, that is, alpha-TEA- and delta-tocotrienol-induced apoptosis involved up-regulation of TGF-beta receptor II expression and TGF-beta-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (delta-tocotrienol) and a novel nonhydrolyzable vitamin E analog (alpha-TEA).
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PMID:Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells. 1520 83

Reactive oxygen species (ROS) have been known to play an important role in the pathogenesis of atherosclerosis and several other cardiovascular diseases. It is now apparent that ROS induce endothelial cell damage and vascular smooth muscle cell (VSMC) growth and cardiac remodeling, which are associated with hypertension, atherosclerosis, heart failure, and restenosis. Several lines of evidence have indicated that ROS and mitogen-activated protein (MAP) kinases were involved in vascular remodeling under various pathological conditions. Recently, it was also reported that MAP kinases were sensitive to oxidative stress. MAP kinases play an important role in cell differentiation, growth, apoptosis, and the regulation of a variety of transcription factors and gene expressions. Bioflavonoids and polyphenolic compounds are believed to be beneficial for the prevention and treatment of atherosclerosis and cardiovascular diseases. One of the most widely distributed bioflavonoids, 3,3',4',5,7-penta-hydroxyflavone (quercetin) and its metabolite quercetin 3-O-beta-D-glucuronide (Q3GA) inhibited Angiotensin II-stimulated JNK activation and resultant hypertrophy of VSMC. Several studies have suggested that various antioxidants including probucol, N-acetyl-L-cysteine, diphenylene iodonium, Trolox C (vitamin E analogue), and vitamin C inhibit VSMC growth, which is associated with pathogenesis of cardiovascular diseases. Therefore, inhibition of MAP kinases by antioxidant treatment may prove to be a therapeutic strategy for cardiovascular diseases. In contrast, some clinical studies have reported that antioxidant vitamins did not show beneficial effects in coronary artery disease or in a number of high-risk people. Thus, further studies are needed to clarify why antioxidants showed beneficial effects in vitro, whereas less satisfactory results were obtained in some clinical conditions.
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PMID:Atheroprotective effects of antioxidants through inhibition of mitogen-activated protein kinases. 1530 27

The effects of four natural tocopherols on the proliferation and signaling pathways were examined in the human mastocytoma cell line (HMC-1). The four tocopherols inhibited HMC-1 cell proliferation with different potency (delta > alpha = gamma > beta). Growth inhibition correlated with the reduction of PKB (protein kinase B) phosphorylation by the different tocopherols. The reduction of PKB phosphorylation led to a decrease of its activity, as judged from a parallel reduction of GSKalpha/beta phosphorylation. The translocation of PKB to the membrane, as a response to receptor stimulation by NGFbeta, is also prevented by treatment with tocopherols. In the presence of PKC or PP2A inhibitors, the reduction of PKB phosphorylation by tocopherols was still observed, thus excluding the direct involvement of these enzymes. Other pathways, such as the Ras-stimulated ERK1/2 (extracellular signal responsive kinase) pathway, were not affected by tocopherol treatment. The tocopherols did not significantly change oxidative stress in HMC-1 cells, suggesting that the observed effects are not the result of a general reduction of oxidative stress. Thus, the tocopherols interfere with PKB phosphorylation and reduce proliferation of HMC-1 cells, possibly by modulating either phosphatidylinositol 3-kinase, a kinase phosphorylating PKB (PDK1/2), or a phosphatase that dephosphorylates it. Inhibition of proliferation and PKB signaling in HMC-1 cells by vitamin E suggests a role in preventing diseases with mast cell involvement, such as allergies, atherosclerosis, and tumorigenesis.
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PMID:Inhibition of HMC-1 mast cell proliferation by vitamin E: involvement of the protein kinase B pathway. 1538 41

The aim of the present study was to determine molecular mechanism in hyperglycemia-induced congenital neural tube defects and the its potential pharmacologic rescuing agents. In order to explore these questions, six study groups of Sprague-Dawley rats were employed: Group 1 was normal control rats with normal diet; group 2 represented streptozotocin (STZ) -induced diabetic rats with congenital neural tube defects in offspring; group 3 included STZ-induced diabetic rats with normal offspring; groups 4,5 and 6 included rats exposed to the same STZ-induced diabetic condition, but receiving daily oral supplementation of 80 microg/mL of the sodium salt of arachidonic acid (AA), 400mg of vitamin E and a cocktail of a polyunsaturated fatty acid (safflower oil) plus an antioxidant ( vitamin E) respectively. Yolk sac cells were harvested at gestational day 12 from each rat group. Changes in MAPK signaling pathways were detected by western blot analysis using special antibodies directed against phosphorylated forms of extracellular signal regulated kinase (ERK), Jun N-terminal/stress-activated protein kinase (JNK/SAPK). Furthermore, activity of RAF-1, an upstream kinase in ERK1/2 signaling cascade, was evaluated by immunoprecipitation assay. The results showed that in yolk sac cells in embryopathic offspring from experimentally-induced diabetic rats, activities of ERK1/2 were dramatically decreased (group 2). Consisted with these observation, reduction in RAF-1 kinase activity could be discerned in these diabetic yolk sac cells. In contrast, activities of JNK1/2 were significantly increased in yolk sac cells of group 2. Under rescuing circumstance,activations of ERK1/2 and RAF-1 were increased, and JNK1/2 were decreased. MAP kinase signal pathway plays a very important role in hyperglycemia induced neural tube defects. The supplementation of polyunsaturated fatty acid arachidonic acid, and antioxidant vitamin E rescued conceptuses from diabetic embryopathy by triggering a restoration of normal membrane signaling pathways.
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PMID:[MAP kinase signal pathway in hyperglycemia-induced congenital neural tube defects]. 1564 73


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