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)

Depletion of glutathione (GSH) from CYP2E1-expressing cells by treatment with l-buthionine sulfoximine (BSO) causes decreased cell viability. The possible role of mitogen-activated protein kinases (MAPK) in this toxicity was evaluated. SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], an inhibitor of p38 MAPK decreased the BSO-dependent toxicity in HepG2 E47 cells, which express CYP2E1 and in hepatocytes from pyrazole-treated rats. Inhibitors of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, and c-Jun amino-terminal kinase were not protective. SB203580 did not prevent the loss of GSH nor lower the increase in reactive oxygen production; hence, protection by SB203580 was downstream of the elevated oxidative stress. Treatment with BSO caused activation of p38 MAPK whereas activation of nuclear factor-kappaB (NF-kappaB) was decreased; these effects were prevented by SB203580. We speculated that the decrease in NF-kappaB activation prevented production of hepatoprotective factors. One such factor could be nitric oxide (NO); indeed a NO donor decreased the BSO plus CYP2E1-dependent toxicity, whereas inhibition of inducible NO synthase (iNOS) potentiated toxicity. BSO treatment down-regulated iNOS and lowered NO levels, reactions blocked by SB203580; however, protection by SB203580 was the same in the absence or presence of an iNOS inhibitor, indicating that recovery of iNOS and NO production was not the mechanism by which SB203580 afforded protection against the BSO plus CYP2E1-dependent toxicity. Presumably other protective factors besides nitric oxide may be produced from activated NF-kappaB when p38 MAPK is inhibited by SB203580. These results suggest that the activation of p38 MAPK by BSO treatment in CYP2E1-expressing liver cells cause a loss in NF-kappaB-dependent production of hepatoprotective factors. This loss, coupled to CYP2E1-generated oxidant stress, synergize to promote cell injury.
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PMID:Glutathione depletion in CYP2E1-expressing liver cells induces toxicity due to the activation of p38 mitogen-activated protein kinase and reduction of nuclear factor-kappaB DNA binding activity. 1532 68

To date, glutathione (GSH) depletion is the earliest biochemical alteration shown in brains of Parkinson's disease patients, but the role of GSH in dopamine cell survival is debated. In this study we show that GSH depletion, produced with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), induces selectively neuronal cell death in neuron/glia, but not in neuronal-enriched midbrain cultures and that cell death occurs with characteristics of necrosis and apoptosis. BSO produces a dose- and time-dependent generation of reactive oxygen species (ROS) in neurons. BSO activates extracellular signal-regulated kinases (ERK-1/2), 4 and 6 h after treatment. MEK-1/2 and lipoxygenase (LOX) inhibitors, as well as ascorbic acid, prevent ERK-1/2 activation and neuronal loss, but the inhibition of nitric oxide sintase (NOS), cyclo-oxygenase (COX), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) does not have protective effects. Co-localization studies show that p-ERK-1/2 expression after BSO treatment increased in astrocytes and microglial cells, but not in neurons. Selective metabolic impairment of glial cells with fluoroacetate decreased ERK activation. However, blockade of microglial activation with minocycline did not. Our results indicate that neuronal death induced by GSH depletion is due to ROS-dependent activation of the ERK-1/2 signalling pathway in glial cells. These data may be of relevance in Parkinson's disease, where GSH depletion and glial dysfunction have been documented.
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PMID:Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures. 1548 97

The catalytic subunit of glutamylcysteine ligase (GCLC) primarily regulates de novo synthesis of glutathione (GSH) in mammalian cells and is central to the antioxidant capacity of the cell. However, GCLC expression in pancreatic islets has not been previously examined. We designed experiments to ascertain whether GCLC is normally expressed in islets and whether it is up-regulated by interleukin-1 beta (IL-1 beta). GCLC expression levels were intermediate compared with other metabolic tissues (kidney, liver, muscle, fat, and lung). IL-1 beta up-regulated GCLC expression (10 ng/ml IL-1 beta, 3.76 +/- 0.86; 100 ng/ml IL-1 beta, 4.22 +/- 0.68-fold control) via the p38 form of mitogen-activated protein kinase and NF kappa B and also increased reactive oxygen species levels (10 ng/ml IL-1 beta, 5.41 +/- 1.8-fold control). This was accompanied by an increase in intraislet GSH/GSSG ratio (control, 7.1 +/- 0.1; 10 ng/ml IL-1 beta, 8.0 +/- 0.5; 100 ng/ml IL-1 beta, 8.2 +/- 0.5-fold control; p < 0.05). To determine whether overexpression of GCLC increases the antioxidant capacity of the islet and prevents the adverse effects of IL-1 beta on glucose-induced insulin secretion, islets were infected with an adenovirus encoding GCLC. IL-1 beta significantly decreased glucose-stimulated insulin secretion (control, 123.8 +/- 17.7; IL-1 beta, 40.2 +/- 3.9 microunits/ml insulin/islet). GCLC overexpression increased intraislet GSH levels and partially prevented the decrease in glucose-stimulated insulin secretion caused by IL-1 beta. These data provide the first report of GCLC expression in the islet and demonstrate that adenoviral overexpression of GCLC increases intracellular GSH levels and protects the beta cell from the adverse effects of IL-1 beta.
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PMID:Adenoviral overexpression of the glutamylcysteine ligase catalytic subunit protects pancreatic islets against oxidative stress. 1548 76

Mitogen-activated protein kinase (MAPK) pathways are modules involved in the transduction of extracellular signals to intracellular targets in all eukaryotes. In plants, it has been evidenced that MAPKs play a role in the signaling of biotic and abiotic stresses, plant hormones, and cell cycle cues. However, the effect of heavy metals on plant MAPKs has not been well examined. The Northern blot analysis of OsMAPK mRNA levels has shown that only OsMAPK2, but not OsMAPK3 and OsMAPK4, expressed in suspension-cultured cells in response to 100-400 microM Cd treatments. The OsMAPK2 transcripts increased within 12 h upon 400 microM Cd treatment. In addition, we found that 42- and 50-kDa MBP kinases were significantly activated by Cd treatment in rice suspension-cultured cells. And 40-, 42-, 50- and 64-kDa MBP kinases were activated in rice roots. Furthermore, GSH inhibits Cd-induced 40-kDa MBP kinase activation. By immunoblot analysis and immunoprecipitation followed by in-gel kinase assay, we confirmed that Cd-activated 42-kDa MBP kinase is a MAP kinase. Our results suggest that a MAP kinase cascade may function in the Cd-signalling pathway in rice.
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PMID:Cadmium activates a mitogen-activated protein kinase gene and MBP kinases in rice. 1550 54

Previously, studies reported that depletion of cellular GSH by sulfur amino acid deprivation (SAAD) potentiated arsenic (As)-induced cytotoxicity through activation of mitogen-activated protein (MAP) kinases. Deprenyl (selegiline), a selective inhibitor of monoamine oxidase B that is responsible for oxidative metabolism of dopamine, has been used as a therapeutic agent for the treatment of Parkinson's disease. This study investigated (1) whether deprenyl inhibited As-induced toxicity or As toxicity that was potentiated by glutathione (GSH) depletion and (2) whether deprenyl affected MAP kinase activation. Deprenyl protected H4IIE cells against the toxicity induced by As + SAAD in a concentration-dependent manner, but not by As alone. Activation of JNK by SAAD or As, but not that of p38 kinase or ERK1/2, was inhibited by treatment of cells with deprenyl. The cells that had been exposed to As or SAAD exhibited decreases in mitochondrial permeability to rhodamine 123, which was restored by deprenyl treatment or transfection with the plasmid encoding a dominant negative mutant of JNK [JNK1( )]. Transfection of H4IIE cells with the JNK1( ) plasmid, however, failed to protect cells against As toxicity. These results showed that deprenyl inhibits As toxicity potentiated by cellular GSH depletion, but not the toxicity induced by As alone. The cytoprotective effect of deprenyl may be mediated with restoration of mitochondrial function via its inhibition of JNK1.
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PMID:Deprenyl, a therapeutic agent for Parkinson's disease, inhibits arsenic toxicity potentiated by GSH depletion via inhibition of JNK activation. 1551 99

Abstract The dualistic activities of the amyloid beta (Abeta) peptide as a pro-oxidant and ubiquitous constituent of amyloid deposits in Alzheimer's disease plaques and as an antioxidant of purported physiological function has been suggested but the mechanisms are far from being understood. In this report we measure several oxidative stress parameters and signaling cascades in brains of fetal rats subjected to global ischemia in order to evaluate the putative bifunctional properties of the Abeta(1-40) peptide. Intraperitoneal injection of 6 microg Abeta(1-40) into 18-days-old rat fetuses (approximately 3 g body weight) resulted after 24 h in the appearance of the peptide in various fetal organs including brain where it enhanced the levels of glutathione (GSH), glutathione reductase, glutathione peroxidase, and stimulated the levels of pro-survival signaling activities such as Akt serine/threonine kinase, extracellular signal-regulated kinase (ERK) and protein kinase C enzymes. Moreover, pretreatment with Abeta(1-40) reversed the consequences of a transient hypovolemic/hypotensive oxidative stress by restoring GSH levels via its recycling enzymes and by lowering the production of lipid peroxides presumably by activating the aforementioned pro-survival signaling cascades. It also caused a reduction in the number of DAPI-enhanced reactive cells and a decrease in p38 kinase phosphorylation and caspase-9 and -3 activity. These data suggest that pre-exposure to Abeta(1-40) stimulates fetal tolerance to ischemia via regulation of GSH metabolism and as such may be considered as neuroprotective.
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PMID:Amyloid Abeta1-40 preconditions non-apoptotic signals in vivo and protects fetal rat brain from intrauterine ischemic stress. 1552 50

4-Hydroxynonenal (HNE) is one of the major end-products of lipid peroxidation and is increased in response to cellular stress and in many chronic and/or inflammatory diseases. HNE can in turn function as a potent signaling molecule to induce the expression of many genes including glutamate cysteine ligase (GCL), the rate-limiting enzyme in de novo glutathione (GSH) biosynthesis. GSH, the most abundant nonprotein thiol in the cell, plays a key role in antioxidant defense. HNE exposure causes an initial depletion of GSH due to formation of conjugates with GSH, followed by a marked increase in GSH resulting from the induction of GCL. GCL is a heterodimeric protein with a catalytic (or heavy, GCLC) subunit and a modulatory (or light, GCLM) subunit. HNE-mediated induction of both GCL subunits and mRNAs has been reported in rat and human cells in vitro; however, the mechanisms or the signaling pathways mediating the induction of Gclc and Gclm mRNAs by HNE differ between rat and human cells. Activation of the ERK pathway is involved in GCL regulation in rat cells while both the ERK and the JNK pathways appear to be involved in human cells. Downstream, MAPK activation leads to increased AP-1 binding, which mediates GCL induction. Some studies suggest a role for the EpRE element as well. As the concentrations of HNE used in all of the studies reviewed are comparable to what may be found in vivo, this makes the findings summarized in this review potentially relevant to GCL regulation in human health and disease.
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PMID:Mechanisms of glutamate cysteine ligase (GCL) induction by 4-hydroxynonenal. 1568 10

Reactive oxygen species (ROS) play a critical role in cardiac hypertrophy. We have recently shown that the serotonin-degrading enzyme monoamine oxidase A (MAO A) is an important source of hydrogen peroxide in rat heart. In the present study, we investigated the potential role of hydrogen peroxide generated by MAO A in cardiomyocyte hypertrophy by serotonin. Serotonin (5 microM, 48 h) induced hypertrophy in cultured adult rat ventricular myocytes, as reflected by increased 3H-leucine incorporation (+43%, P<0.001) and total protein content (+22%, P<0.001). Serotonin also increased intracellular hydrogen peroxide and oxidative stress production, measured respectively by DCF fluorescence intensity and GSH/GSSG ratio, and promoted ERK1/2 phosphorylation (P<0.001). Serotonin effects were only partially inhibited by the 5-HT2B receptor antagonist SB 206553. In contrast, they were extensively (>80%) prevented by the amine uptake inhibitor imipramine, the MAO inhibitor pargyline and the MEK inhibitor PD 98059. Cardiomyocyte hypertrophy and ERK activation were also inhibited by decreasing intracellular ROS by adenoviral overexpression of catalase or cardiomyocytes treatment with the iron chelator deferoxamine. These data suggest that part of cardiac hypertrophic effect of serotonin requires hydrogen peroxide production by MAO A and ERK1/2 activation. This newly recognized, receptor-independent mechanism of serotonin may contribute to myocardial remodeling and failure.
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PMID:A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. 1570 74

Mercury is a widespread metal in the environment and consequently large populations are currently exposed to low levels of mercury. Endotoxin, a component of the Gram-negative bacteria, promotes inflammatory responses. We recently reported that mercury modulates the production of nitric oxide and various inflammatory cytokines induced by endotoxin in a macrophage cell line (Nitric Oxide 2002, 7:67). The present study was designed to determine the impact of mercury on endotoxin-induced inflammatory cytokine expression and corresponding signal transduction in mouse liver. Male BALB/c mice were exposed continuously to 0, 0.3, 1.5, 7.5, or 37.5 ppm of mercury in drinking water for 14 days and at the end of the treatment period lipopolysaccharide (LPS, 0.5 mg/kg) was injected intraperitoneally 2 hr prior to euthanasia. The doses of mercury and LPS did not cause hepatotoxicity as indicated by unaltered circulating alanine aminotransferase and aspartate aminotransferase levels. Mercury decreased liver glutathione (GSH) and with LPS additively decreased GSH. Mercury activated p38 mitogen-activated protein kinase (MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. In contrast, mercury alone had no effect on activation of extracellular signal-regulated kinase (ERK) but inhibited LPS-induced ERK activation. Mercury increased the expression of tumor necrosis factor alpha (TNFalpha) and further potentiated LPS-induced TNFalpha expression. Mercury did not affect LPS-induced interleukin (IL)-1beta expression but decreased LPS-induced IL-6 expression. Results indicated that low levels of mercury augment LPS-induced TNFalpha expression by altering GSH and p38 MAPK. Mercury modulates LPS-induced p38 and ERK activation and downstream TNFalpha and IL-6 expression in mouse liver.
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PMID:Mercury alters endotoxin-induced inflammatory cytokine expression in liver: differential roles of p38 and extracellular signal-regulated mitogen-activated protein kinases. 1580 65

It has been reported that inhibition of extracellular signal-regulated protein kinases (ERKs) attenuates the toxicity cisplatin (cis-platinum (II)-diammine dichloride) in some cell types. This response was here investigated using human myeloid leukemia cells. Cisplatin stimulated ERK1/2 phosphorylation and caused apoptosis in U-937 promonocytic cells, an effect which was attenuated by the MEK/ERK inhibitors PD98059 and U0126. While ERK1/2 activation was a general phenomenon, irrespective of the used cell type or antitumour drug, the MEK/ERK inhibitors only reduced cisplatin toxicity in human myeloid cells (THP-1, HL-60 and NB-4), but not in RAW 264.7 mouse macrophages and NRK-52E rat renal tubular cells; and failed to reduce the toxicity etoposide, camptothecin, melphalan and arsenic trioxide, in U-937 cells. U0126 attenuated cisplatin-DNA binding and intracellular peroxide accumulation, which are important regulators of cisplatin toxicity. Although cisplatin decreased the intracellular glutathione (GSH) content, which was restored by U0126, treatments with GSH-ethyl ester and dl-buthionine-(S,R)-sulfoximine revealed that GSH does not regulate cisplatin toxicity in the present experimental conditions. In spite of it, PD98059 and U0126 reduced the intracellular accumulation of cisplatin. These results suggest that GSH-independent modulation of drug transport is a major mechanism explaining the anti-apoptotic action of MEK/ERK inhibitors in cisplatin-treated myeloid cells.
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PMID:Pharmacological inhibitors of extracellular signal-regulated protein kinases attenuate the apoptotic action of cisplatin in human myeloid leukemia cells via glutathione-independent reduction in intracellular drug accumulation. 1584 40


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