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)

Glutathione-S-transferases (GSTs) are a family of Phase II detoxification enzymes that catalyse the conjugation of glutathione (GSH) to a wide variety of endogenous and exogenous electrophilic compounds. GSTs are divided into two distinct super-family members: the membrane-bound microsomal and cytosolic family members. Microsomal GSTs are structurally distinct from the cytosolic in that they homo- and heterotrimerize rather than dimerize to form a single active site. Microsomal GSTs play a key role in the endogenous metabolism of leukotrienes and prostaglandins. Human cytosolic GSTs are highly polymorphic and can be divided into six classes: alpha, mu, omega, pi, theta, and zeta. The pi and mu classes of GSTs play a regulatory role in the mitogen-activated protein (MAP) kinase pathway that participates in cellular survival and death signals via protein : protein interactions with c-Jun N-terminal kinase 1 (JNK1) and ASK1 (apoptosis signal-regulating kinase). JNK and ASK1 are activated in response to cellular stress. GSTs have been implicated in the development of resistance toward chemotherapy agents. It is plausible that GSTs serve two distinct roles in the development of drug resistance via direct detoxification as well as acting as an inhibitor of the MAP kinase pathway. The link between GSTs and the MAP kinase pathway provides a rationale as to why in many cases the drugs used to select for resistance are neither subject to conjugation with GSH, nor substrates for GSTs. GSTs have emerged as a promising therapeutic target because specific isozymes are overexpressed in a wide variety of tumors and may play a role in the etiology of other diseases, including neurodegenerative diseases, multiple sclerosis, and asthma. Some of the therapeutic strategies so far employed are described in this review.
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PMID:The role of glutathione-S-transferase in anti-cancer drug resistance. 1457 44

Glutathione plays important roles as an intracellular antioxidant and in the maintenance of cellular thiol-disulfide balance. In addition, glutathione may regulate cell growth signaling induced by oxidative stress. We previously reported that cellular glutathione is up-regulated by bleomycin in bovine pulmonary artery endothelial cells. The present study examined effects of hydrogen peroxide (H(2)O(2)) on cell growth and glutathione levels. Exogenous addition of H(2)O(2) induced biphasic effects on cell growth; 1 micro M was stimulatory and >10 micro M was inhibitory. However, both growth-promoting and inhibitory levels of H(2)O(2) increased cellular glutathione levels. Whereas 1 micro M H(2)O(2) moderately but significantly increased glutathione, 30 micro M caused a more substantial increase. Like bleomycin, both concentrations of H(2)O(2) activated DNA binding of antioxidant response element (ARE), a regulatory element in the promoter of the gamma-glutamylcysteine synthetase heavy chain subunit, a key regulator of glutathione synthesis. However, only high concentrations of H(2)O(2) activated p44/42 mitogen-activated protein (MAP) kinase. Thus, cellular glutathione is up-regulated by H(2)O(2), perhaps via activating ARE-binding factors in a mechanism independent of MAP kinase. H(2)O(2)-mediated increase in glutathione and activation of ARE binding may play important roles in growth and death of pulmonary artery endothelial cells.
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PMID:Regulation of glutathione by oxidative stress in bovine pulmonary artery endothelial cells. 1458 42

Reactive oxygen species (ROS)-mediated compromise of endothelial barrier integrity has been implicated in a number of pulmonary disorders, including adult respiratory distress syndrome, pulmonary edema, and vasculitis. The mechanisms by which ROS increase endothelial permeability are unclear. We hypothesized that ROS-induced changes in cellular redox status (thiols) may contribute to endothelial barrier dysfunction. To test this hypothesis, we used N-acetylcysteine (NAC) and diamide to modulate intracellular levels of cellular glutathione (GSH) and investigated hydrogen peroxide (H(2)O(2))-mediated mitogen-activated protein kinase (MAPK) activation and transendothelial electrical resistance (TER). Exposure of bovine lung microvascular endothelial cells (BLMVECs) to H(2)O(2), in a dose- and time-dependent fashion, increased endothelial permeability. Pretreatment of BLMVECs with NAC (5 mM) for 1 h resulted in partial attenuation of H(2)O(2)-induced TER (a measure of increase in permeability) and GSH. Furthermore, treatment of BLMVECs with diamide, which is known to reduce the intracellular GSH, resulted in significant reduction in TER, which was prevented by NAC. To understand further the role of MAPKs in ROS-induced barrier dysfunction, we examined the role of extracellular signal-regulated kinase (ERK) and p38 MAPK on H(2)O(2)- and diamide-mediated permeability changes. Both H(2)O(2) and diamide, in a dose-dependent manner, activated ERK and p38 MAPK in BLMVECs. However, SB203580, an inhibitor of p38 MAPK, but not PD98059, blocked H(2)O(2)- and diamide-induced TER. Also, NAC prevented H(2)O(2)- and diamide-induced p38 MAPK, but not ERK activation. These results suggest a role for redox regulation of p38 MAPK in ROS-dependent endothelial barrier dysfunction.
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PMID:Redox regulation of reactive oxygen species-induced p38 MAP kinase activation and barrier dysfunction in lung microvascular endothelial cells. 1458 45

Arsenic trioxide (As(2)O(3)) caused apoptosis in U-937 human promonocytic cells. This effect was potentiated by the simultaneous addition of the glutathione (GSH) synthesis inhibitor DL-buthionine-(R,S)-sulfoximine or the protein kinase C activators 12-O-tetradecanoylphorbol-13-acetate (TPA) and bryostatin 1. In addition TPA decreased the intracellular GSH content, caused ERK activation, and potentiated the As(2)O(3)-provoked activation of p38 and JNK. The addition of N-acetyl-L-cysteine, the PKC inhibitor GF109203X, and the MEK/ERK inhibitors PD98059 and U0126 attenuated both apoptosis induction and GSH decrease, whereas the p38 inhibitor SB203580 and the JNK inhibitor SP600125 were ineffective. TPA also potentiated ERK activation and GSH depletion when added simultaneously to cadmium chloride (CdCl(2)) and doxorubicin. However, TPA only enhanced apoptosis in the case of CdCl(2), which is a GSH-sensitive agent, whereas it reduced the toxicity of doxorubicin and other DNA-specific drugs. Finally, preincubation for 14-24 h with TPA did not potentiate but, instead, attenuated the As(2)O(3)- and CdCl(2)-provoked apoptosis. The same result was obtained by preincubation with bryostatin 1 and other differentiation inducers. It is concluded that TPA increases the apoptotic action of As(2)O(3), an effect mediated by ERK activation and GSH depletion. However, the increase in apoptosis is only effective in non-differentiated cells.
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PMID:12-O-tetradecanoylphorbol-13-acetate may both potentiate and decrease the generation of apoptosis by the antileukemic agent arsenic trioxide in human promonocytic cells. Regulation by extracellular signal-regulated protein kinases and glutathione. 1461 70

Sulforaphane (SFN) and its N-acetyl-L-cysteine (NAC) conjugate are effective inhibitors of tumorigenesis in animal models. These compounds induce the expression of the antioxidant response element (ARE)-related genes and cause apoptosis. We studied the role of reduced glutathione (GSH) in the activations of ARE-mediated gene expression, apoptosis, and the activation of c-Jun NH(2)-terminal kinase (JNK) in HepG2-C8 cells. The cellular level of GSH decreased transiently when cells were exposed to SFN and then increased from 4 h, reaching 2.2-fold over control at 24 h. In contrast, SFN-NAC did not change the GSH level substantially during the time of incubation. ARE expression was increased in a dose-dependent manner up to 35 micro M SFN and 75 micro M SFN-NAC, respectively. The induction of ARE by SFN was 8.6-fold higher than that by SFN-NAC. Pretreatment with L-buthionine sulfoximine increased SFN-induced ARE expression significantly. The decrease in ARE expression at higher concentrations of SFN and SFN-NAC was correlated with accelerated apoptotic cell death, with a dose-dependent activation of caspase 3 activity by SFN. On addition of extracellular GSH within 6 h of treatment with SFN, the effect on ARE expression was blocked almost completely. SFN was able to activate JNK1/2, and that activation was blocked by treatment with exogenous GSH. Taken together, these results suggest that the biological effects of SFN and SFN-NAC on the induction of ARE-related gene expression and apoptosis could be different from each other; however, the different effects on ARE-related gene expression and apoptosis elicited by SFN can be blocked by the addition of GSH.
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PMID:Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. 1461 54

Lung epithelial cells produce increased reactive oxygen species (ROS) after hypoxia exposure, and they are more susceptible after hypoxia to injury by agents that generate superoxide [O2-; e.g., 2,3-dimethoxy-1,4-naphthoquinone (DMNQ)]. Cellular GSH and MnSOD both decrease in hypoxic lung epithelial cells, altering the redox state. Because ROS participate in signaling pathways involved in cell death or survival, we tested the hypothesis that mitogen-activated protein kinases (MAPK) were involved in a protective response against cellular injury during reoxygenation. Human lung epithelial A549 cells were incubated in hypoxia (<1% O2 for 24 h) and then reoxygenated by return to air. p38mapk and MKK3 phosphorylation both decreased after hypoxia. During reoxygenation, cells were incubated with DMNQ (0-50 microM), a redox cycling quinone that produces O2-. Hypoxia preexposure significantly increased epithelial cell lysis resulting from DMNQ. Addition of the p38mapk inhibitors SB-202190 or SB-203580 markedly increased cytotoxicity, as did the mitogen/extracellular signal-regulated kinase (MEK) 1/2 inhibitor PD-98059 (all 10 microM), suggesting a protective effect of downstream molecules activated by the kinases. Transfection of A549 cells with a dominant active MKK3 plasmid (MKK3[Glu]) partially inhibited cytolysis resulting from DMNQ, whereas the inactive MKK3 plasmid (MKK3[Ala]) had less evident protective effects. Stress-related signaling pathways in epithelial cells are modulated by hypoxia and confer protection from reoxygenation, since hypoxia and chemical inhibition of p38mapk and MEK1/2 similarly increase cytolysis resulting from O2-.
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PMID:p38mapk and MEK1/2 inhibition contribute to cellular oxidant injury after hypoxia. 1467 18

Oxidative stress has been shown to underlie a diverse range of neuropathological conditions. Glutamate-induced oxidative toxicity is a well described model of oxidative stress-induced neurodegeneration that relies upon the ability of extracellular glutamate to inhibit a glutamate/cystine antiporter, which results in a depletion of intracellular cysteine and the blockade of continued glutathione synthesis. Glutathione depletion leads to a gradual toxic accumulation of reactive oxygen species. We have previously determined that glutamate-induced oxidative toxicity is accompanied by a robust increase in activation of the mitogen-activated protein kinase (MAPK) member extracellular-signal regulated kinase (ERK) and that this activation is essential for neuronal cell death. This study demonstrates that delayed ERK activation is dependent upon the activity of phosphoinositol-3 kinase (PI3K) and that transient but not sustained PI3K inhibition leads to significant protection of neurons from oxidative stress-induced neurodegeneration. Furthermore, we show that transient PI3K inhibition prevents the delayed activation of MEK-1, a direct activator of ERK, during oxidative stress. Thus, this study is the first to demonstrate a novel level of cross-talk between the PI3K and ERK pathways in cultured immature cortical neuronal cultures that contributes to the unfolding of a cell death program. The PI3K pathway, therefore, may serve opposing roles during the progression of oxidative stress in neurons, acting at distinct kinetic phases to either promote or limit a slowly developing program of cell death.
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PMID:Transient phosphatidylinositol 3-kinase inhibition protects immature primary cortical neurons from oxidative toxicity via suppression of extracellular signal-regulated kinase activation. 1471 49

In this study, we used porcine aortic endothelial cells (PAECs) as an in vitro system to investigate the role of intracellular GSH status in arsenite-induced vascular endothelial damage. Exposure of PAECs to l-buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), markedly enhanced the arsenite-induced cytotoxicity. The data implied that intracellular GSH might play an important role in protection of PAECs from arsenite-induced cytotoxicity. Low concentrations of arsenite exposure increased intracellular GSH concentrations, whereas high concentrations of arsenite exposure decreased intracellular GSH concentrations. We further modulated intracellular GSH concentration by using GSH modulators. N-Acetyl cysteine (NAC) and l-cystine (oxidized l-cysteine), by up-regulating intracellular GSH concentrations, were shown to protect PAECs from arsenite-induced cytotoxicity. On the other hand, BSO and monosodium glutamate (MSG), which down-regulated the intracellular GSH concentrations, further potentiated arsenite-induced cytotoxicity. Moreover, exposure of PAECs to NAC alleviated the arsenite-induced JNK/AP-1 activation and apoptosis, whereas exposure of PAECs to BSO enhanced the arsenite-induced JNK/AP-1 activation and apoptosis. These results indicated that an increase in GSH content represented one of the detoxification mechanisms responding to arsenite exposure and probably played critical roles in the regulation of stress-response signaling molecules as well as in protection of PAECs from arsenite attack.
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PMID:The protective role of intracellular GSH status in the arsenite-induced vascular endothelial dysfunction. 1496 8

We have used structure-based design techniques to introduce the drug O(2)-[2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino) phenyl] 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), which is efficiently metabolized to potentially cytolytic nitric oxide by the pi isoform of glutathione S-transferase, an enzyme expressed at high levels in many tumors. We have used mouse embryo fibroblasts (MEFs) null for GSTpi (GSTpi(-/-)) to show that the absence of GSTpi results in a decreased sensitivity to PABA/NO. Cytotoxicity of PABA/NO was also examined in a mouse skin fibroblast (NIH3T3) cell line that was stably transfected with GSTpi and/or various combinations of gamma-glutamyl cysteine synthetase and the ATP-binding cassette transporter MRP1. Overexpression of MRP1 conferred the most significant degree of resistance, and in vitro transport studies confirmed that a GSTpi-activated metabolite of PABA/NO was effluxed by MRP1 in a GSH-dependent manner. Additional studies showed that in the absence of MRP1, PABA/NO activated the extracellular-regulated and stress-activated protein kinases ERK, c-Jun NH(2)-terminal kinase (JNK), and p38. Selective inhibition studies showed that the activation of JNK and p38 were critical to the cytotoxic effects of PABA/NO. Finally, PABA/NO produced antitumor effects in a human ovarian cancer model grown in SCID mice.
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PMID:Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. 1510 35

Selenium is a dietary essential trace nutrient with important biological roles. Selenocompounds were reported to induce apoptosis in many types of tumor cells. In this study, we investigated the signaling pathway involved in the selenite-induced apoptosis using Chang liver cells as a non-malignant cell model. The Chang liver cell apoptosis induced by selenite (10 microM) was confirmed by DNA fragmentation and typical apoptotic nuclear changes. Treatment of selenite increased intracellular reactive oxygen species (ROS) level and c-Jun N-terminal kinase1 (JNK1) phosphorylation. The selenite-induced cell death was attenuated by SP600125, a specific inhibitor of JNK, and by dominant negative JNK1 (DN-JNK1). Antioxidants such as glutathione (GSH), N-acetyl cysteine (NAC), curcumin, epigallocatechin gallate (EGCG) and epicatechin (EC) inhibited selenite-induced intracellular ROS elevation and JNK1 phosphorylation. Our results suggest that selenite-induced apoptosis in Chang liver cells was preceded by the ROS generation and JNK1 activation.
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PMID:Involvement of ROS and JNK1 in selenite-induced apoptosis in Chang liver cells. 1515 Apr 44


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