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

The role of brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Rodent studies indicate that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. Earlier studies from our laboratory have indicated that long-term treatment with haloperidol (HAL) decreases BDNF, reduced GSH and anti-apoptotic marker, Bcl-xl protein levels and increases the expression of pro-apoptotic proteins in rat frontal cortex. Furthermore, findings from human as well as rodent studies suggest that treatment of schizophrenia must involve the neuroprotective strategies to improve the neuropathology and thereby clinical outcome. In the present study, we investigated the potential of cystamine (CYS), an anti-oxidant and anti-apoptotic compound, to prevent HAL-induced reduction in BDNF, GSH, and Bcl-xl protein levels in mice and the signaling mechanism(s) involved in the beneficial effects of CYS. The results indicated that CYS as well as cysteamine (the FDA-approved precursor of CYS) increased BDNF protein levels in mouse frontal cortex 7 days after treatment. CYS co-treatment prevented chronic HAL treatment-induced reduction in BDNF, GSH, and Bcl-xl protein levels. CYS treatment enhanced TrkB-tyrosine phosphorylation and activated Akt and extracellular signal-regulated kinase (ERK)1/2, downstream molecules of TrkB signaling. In addition, in vitro experiments with mouse cortical neurons showed that CYS prevented the HAL-induced reduction in neuronal cell viability and BDNF protein levels, and increase in apoptosis. BDNF-neutralizing antibody as well as K252a, a selective inhibitor of neurotrophin signaling blocked the CYS-mediated neuroprotection. Moreover, CYS-mediated neuroprotection is also blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. Thus, CYS protects cortical neurons through a mechanism involving TrkB receptor activation, and a signaling pathway involving phosphatidylinositol 3-kinase and MAPK. The findings from the present study may be helpful for the development of novel neuroprotective strategies to improve the treatment outcome of schizophrenia.
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PMID:Cystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex. 1878 74

Extracellular signal-regulated protein kinase (ERK), one of the mitogen-activated protein kinase, has been known to be involved in diverse cellular functions. In this work, we found that basically inhibition of this kinase in cultured cells markedly increased the gamma-glutamate-cysteine ligase (GCL; EC 6.3.2.2) activity, but without any considerable induction of the GCL genes. The increased GCL activity consequently elevated the cellular GSH level and eventually enhanced the cellular antioxidant capacity. Genetic inhibition of B-Raf, the upstream of ERK, also resulted in increased GCL activity and GSH level. Recent evidence also suggests that chronic pro-oxidant exposure results in the loss of ERK phosphorylation in vivo. Therefore, the findings in the present study suggest that inhibition of B-Raf/MEK/ERK pathway might be a promising physiological approach to up-regulate GCL activity and GSH. This study would also help us to understand the comprehensive role of the Raf/MEK/ERK pathway in overall physio/pathological conditions.
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PMID:Regulation of GCL activity and cellular glutathione through inhibition of ERK phosphorylation. 1927 32

In order to overcome chemotherapy resistance, many laboratories are searching for agents that increase the sensitivity of cancer cells to anticancer drugs. Arsenic trioxide (As(2)O(3)) is widely used in treating human acute polymyelocytic leukemia (APL). However, solid tumors and other leukemia cells such as U937 promonocytic leukemia cells are insensitive to As(2)O(3). Esculetin, a coumarin derivative, has previously induced cell cycle arrest and apoptosis of HL-60 cells as well as enhanced taxol-induced apoptosis in HepG2 cells, thereby displaying anticancer potential. In this study, esculetin inhibited proliferation and mitogen activated protein kinases (MAPKs) activation in human leukemia U937 cells. Since inhibitors of MAPKs have modulated the GSH-redox state and enhanced the sensitivity of leukemia cells to As(2)O(3)-provoked apoptosis, we monitored the effect of combining esculetin and As(2)O(3) (2.5 microM) on the GSH level. Our study showed that esculetin, PD98059 (MEK/ERK inhibitor), and SP600125 (JNK inhibitor) similarly enhanced the As(2)O(3)-induced GSH depletion. We found that the As(2)O(3) (2.5 microM) treatment slightly induced apoptosis and the pretreatment of esculetin enhanced the As(2)O(3)-provoked apoptosis significantly. In addition, esculetin enhanced the effect of As(2)O(3) on caspase activation in U937 cells. We compared the combined esculetin and As(2)O(3) treatment to the As(2)O(3) treated alone. The combined esculetin and As(2)O(3) treatment increased Bid cleavage, Bax conformation change and cytochrome C release. The study also indicated that esculetin enhanced the As(2)O(3)-induced lysosomal leakage and apoptosis. Furthermore, pretreatment with N-acetylcysteine (NAC) reduced these enhanced effects. Based on these studies, esculetin enhances the As(2)O(3)-provoked apoptosis by modulating the MEK/ERK and JNK pathways and reducing intracellular GSH levels. GSH depletion led to higher oxidative stress which activated lysosomal-mitochondrial pathway of apoptosis.
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PMID:Enhancement of esculetin on arsenic trioxide-provoked apoptosis in human leukemia U937 cells. 1942 45

In our previous studies, we have shown that benzyl isothiocyanate (BITC) inhibits the growth of human pancreatic cancer cells by inducing apoptosis. In the present study, we demonstrate the activation of all the three (MAPK) family members [extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and P38] in response to BITC treatment. Exposure of Capan-2 cells with varying concentrations of BITC for 24 h resulted in the phosphorylation (activation) of ERK at Thr202/Tyr204, JNK at Thr183/Tyr185 and P38 at Thr180/Tyr182, leading to the induction of apoptosis. Similar MAPK activation was also observed in MiaPaCa-2 cells in response to BITC treatment. However, normal human pancreatic ductal epithelial cells did not show the activation of MAPK's and remained unaffected by BITC treatment. To confirm the role of ERK, JNK and P38 in BITC-induced G(2)/M arrest and apoptosis, Capan-2 cells were pre-treated with MAPK-specific inhibitors or MAPK8-short hairpin RNA (shRNA) prior to BITC treatment. Significant protection from BITC-induced G(2)/M arrest was observed in the cells pre-treated with MAPK kinase (MEK-1) but not JNK or P38 inhibitors. On the other hand, BITC-induced apoptosis was almost completely abrogated in the cells pre-treated with MEK-1, JNK or P38 inhibitors. Similarly, MAPK8-shRNA also offered almost complete protection against BITC-induced G(2)/M arrest and apoptosis. Furthermore, we observed that BITC treatment leads to the generation of reactive oxygen species (ROS) in Capan-2 and MiaPaCa-2 cells, which in part was orchestrated by depletion of reduced glutathione (GSH) level. Blocking ROS generation with N-acetyl-L-cysteine (NAC) significantly prevented GSH depletion and activation of ERK and JNK but not P38. Further, NAC or tiron prevented G(2)/M arrest by blocking G(2)/M regulatory proteins and completely protected the cells from BITC-induced apoptosis. Taken together, our results suggest that BITC-mediated G(2)/M arrest is mediated through ERK activation, whereas apoptosis is via ERK, JNK and P38.
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PMID:Benzyl isothiocyanate-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of MAPK in human pancreatic cancer cells. 1954 4

We were interested in analyzing the regulation by mitogen-activated protein kinases (MAPKs) of cisplatin-provoked toxicity in epithelial renal tubule cell lines, when assayed under culture conditions (cell confluence plus serum deprivation), which mimic the characteristics of a nonproliferating epithelium. Under these restrictive growth conditions, cisplatin induced apoptosis with lower efficacy than in exponentially growing cells, and decreased p38-MAPK phosphorylation in NRK-52E and other (LLC-PK1, MDCK, HK2) cell lines. Moreover, cisplatin-provoked apoptosis was potentiated by cotreatment with p38-MAPK-specific inhibitors (SB203580, SB220025) or transfection with a kinase-negative mutant of MKK6, whereas c-Jun NH2-terminal kinase or extracellular signal-regulated kinase/MAPK and ERK Kinase inhibitors were ineffective. By contrast, when applied to exponentially growing cells, cisplatin stimulated p38-MAPK phosphorylation and apoptosis, was attenuated by kinase inhibitors. Treatment of confluent/serum-deprived cells with cisplatin caused mitochondrial transmembrane potential disruption and activated the mitochondrial apoptotic pathway, as indicated by the decrease in Bcl-X(L) expression, increase in Bax expression and cytochrome c release, and these effects were potentiated by cotreatment with SB203580. Treatment of confluent/serum-deprived cells with cisplatin plus SB203580 decreased the intracellular reduced glutathione (GSH) content, and increased intracellular cisplatin accumulation as well as cisplatin binding to DNA. Cotreatment with the GSH-depleting agent D,L-buthionine-R,S-sulfoximine also potentiated cisplatin-provoked apoptosis. In summary, p38-MAPK inhibition potentiates cisplatin-provoked apoptosis in growth-arrested epithelial renal tubule cells, a result that may be explained at least in part by GSH depletion and drug transport alteration.
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PMID:Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells. 1957 54

Antimycin A (AMA) inhibits succinate oxidase, NADH oxidase, and mitochondrial electron transport chain between cytochrome b and c. We recently demonstrated that AMA inhibited the growth of Calu-6 lung cancer cells through apoptosis. Here, we investigated the effects of AMA and/or MAPK inhibitors on Calu-6 lung cancer cells in relation to cell growth, cell death, reactive oxygen species (ROS), and GSH levels. Treatment with AMA inhibited the growth of Calu-6 cells at 72 h. AMA-induced apoptosis was accompanied by the loss of mitochondrial membrane potential (MMP; Delta Psi m). While ROS were decreased in AMA-treated Calu-6 cells, O2.- among ROS was increased. AMA also induced GSH depletion in Calu-6 cells. Treatment with MEK inhibitor intensified cell death, MMP (Delta Psi m) loss, and GSH depletion in AMA-treated Calu-6 cells. JNK inhibitor also increased cell death, MMP (Delta Psi m) loss, and ROS levels in these cells. Treatment with p38 inhibitor magnified cell growth inhibition by AMA and increased cell death, MMP (Delta Psi m) loss, ROS level, and GSH depletion in AMA-treated cells. Conclusively, all the MAPK inhibitors slightly intensified cell death in AMA-treated Calu-6 cells. The changes of ROS and GSH by AMA and/or MAPK inhibitors were in part involved in cell growth and death in Calu-6 cells.
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PMID:The effects of MAPK inhibitors on antimycin A-treated Calu-6 lung cancer cells in relation to cell growth, reactive oxygen species, and glutathione. 1971 50

Pyrogallol (PG) as a polyphenol compound induces apoptosis in several types of cells. Here, we investigated the effects of MAPK inhibitors on PG-treated calf pulmonary artery endothelial cells (CPAEC) in relation to cell death, ROS and GSH. PG inhibited the growth of CPAEC and also induced cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). PG decreased the ROS level and increased the GSH depleted cell number in CPAEC. JNK inhibitor intensified the growth inhibition by PG whereas p38 inhibitor attenuated the growth inhibition. While MEK and p38 inhibitors decreased CPAEC death by PG, JNK inhibitor increased. None of the MAPK inhibitors significantly increased ROS level in PG-treated CPAEC. JNK inhibitor increased GSH depleted cell number in PG-treated CPAEC whereas p38 inhibitor decreased the number. MAPK inhibitors differently affected cell growth, death, ROS and GSH levels in control CPACE. In conclusion, PG induced apoptosis via the loss of MMP (DeltaPsi(m)) in CPAEC, which is accompanied by GSH depletion. JNK and p38 inhibitors increased and decreased apoptosis in PG-treated CPAEC, respectively, which were correlated with GSH depletion.
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PMID:JNK and p38 inhibitors increase and decrease apoptosis, respectively, in pyrogallol-treated calf pulmonary arterial endothelial cells. 1978 7

Pyrogallol (PG) as a polyphenol compound can generate superoxide anion (O(2)(-)). Here, we investigated the effects of PG and/or MAPK inhibitors on Calu-6 lung cells in relation to cell growth, cell death, reactive oxygen species (ROS) and GSH levels. PG inhibited the growth of Calu-6 cells and induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). While general ROS were decreased in PG-treated Calu-6 cells at 72h, intracellular O(2)(-) level including mitochondrial O(2)(-) was increased. PG also increased GSH depleted cell number in Calu-6 cells. MEK inhibitor slightly prevented cell growth inhibition, cell death and GSH depletion by PG. JNK inhibitor did not affect cell growth, cell death, MMP (DeltaPsi(m)) loss, ROS level and GSH deletion in PG-treated Calu-6 cells but p38 inhibitor mildly enhanced MMP (DeltaPsi(m)) loss, O(2)(-) level and GSH depletion in these cells. Conclusively, MEK inhibitor slightly prevented growth inhibition and death in PG-treated Calu-6 cells. Growth inhibition and death in Calu-6 cells by PG and/or MAPK inhibitors were partially related to O(2)(-) level and GSH content changes.
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PMID:The effects of MAPK inhibitors on pyrogallol-treated Calu-6 lung cancer cells in relation to cell growth, reactive oxygen species and glutathione. 1983 63

Arsenic trioxide (ATO) can regulate many biological functions such as apoptosis and differentiation. We recently demonstrated that ATO-induced apoptosis in Calu-6 lung cancer cells is correlated with glutathione (GSH) content. Here, the effects of ATO and/or mitogen-activated protein kinase (MAPK) inhibitors on Calu-6 cells were investigated in relation to cell growth, cell death, reactive oxygen species (ROS) and GSH levels. Treatment with ATO inhibited the growth of the Calu-6 cells at 72 hours. ATO induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). While general nonspecific ROS decreased in the ATO-treated Calu-6 cells, the intracellular superoxide anion (O(2)(-)) level including mitochondrial O(2)(-) increased. ATO also induced GSH depletion in the Calu-6 cells. The treatment with MAP kinase kinase (MEK), c-Jun N-terminal kinase (JNK) and p38 inhibitors intensified the cell growth inhibition, cell death, MMP (DeltaPsi(m)) loss, and GSH depletion in the ATO-treated Calu-6 cells. In addition, the JNK and p38 inhibitors significantly increased the ROS levels including O(2)(-) in the ATO-treated Calu-6 cells. In conclusion, all the MAPK inhibitors slightly intensify cell death in the ATO-treated Calu-6 cells and the changes of ROS and GSH brought about by ATO and/or MAPK inhibitor treatment partially influence cell growth and death in Calu-6 cells.
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PMID:The effect of MAPK inhibitors on arsenic trioxide-treated Calu-6 lung cells in relation to cell death, ROS and GSH levels. 1984 17

MG132 as a proteasome inhibitor can induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MAPK (MEK, JNK or p38) inhibitors on MG132-induced HeLa cell death in relation to ROS and glutathione (GSH). MG132-induced cell growth inhibition and apoptosis in HeLa cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). MG132 increased ROS level including O(2)(*-) and GSH depleted cell number in HeLa cells. All the MAPK inhibitors slightly enhanced the cell growth inhibition but did not intensify apoptosis in MG132-treated HeLa cells. Each MAPK inhibitor differentially changed the levels of ROS and GSH content in MG132-treated cells. In conclusion, MAPK inhibitors partially influence apoptosis, ROS and GSH levels in MG132-treated HeLa cells.
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PMID:The effects of MAPK inhibitors on a proteasome inhibitor, MG132-induced HeLa cell death in relation to reactive oxygen species and glutathione. 1985 51


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