Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoietic cytokines, including interleukin (IL)-3 and erythropoietin (Epo), regulate hematopoiesis by stimulating their receptors coupled with the Jak2 tyrosine kinase to induce receptor tyrosine phosphorylation and activate mainly the STAT5, PI3K/Akt, and Ras/MEK/ERK signaling pathways. Here we demonstrate that IL-3 or Epo induces a rapid and transient (peaking at 30 min) as well as late progressive increase in reactive oxygen species (ROS) in a hematopoietic progenitor model cell line, 32Dcl3, and its subclone expressing the Epo receptor (EpoR), 32D/EpoR-Wt. The cytokine-induced ROS generation was not affected in 32Dcl3 cells depleted of mitochondrial DNA. The antioxidant N-acetyl-L-cysteine (NAC) inhibited IL-3-induced tyrosine phosphorylation of Jak2, IL-3 receptor betac subunit (IL-3Rbetac), and STAT5 as well as activation-specific phosphorylation of Akt, MEK, and ERK, while treatment of cells with H2O2 activated these signaling events. NAC also inhibited the EpoR-induced transphosphorylation of IL-3Rbetac. Moreover, NAC treatment reduced the expression levels of c-Myc, Cyclin D2, and Cyclin E, and induced expression of p27, thus inhibiting the G1 to S phase transition of cells cultured with IL-3. Further studies have shown that the degradation of c-Myc was facilitated or inhibited by treatment of cells with NAC or H2O2, respectively. These data indicate that the rapid generation of ROS by cytokine stimulation, which is at least partly independent of mitochondria, may play a role in activation of Jak2 and the STAT5, PI3K/Akt, and Ras/MEK/ERK signaling pathways as well as in transactivation of cytokine receptors. The cytokine-induced ROS generation was also implicated in G1 to S progression, possibly through stabilization of c-Myc and induction of G1 phase Cyclin expression leading to suppression of p27.
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PMID:Reactive oxygen species generated by hematopoietic cytokines play roles in activation of receptor-mediated signaling and in cell cycle progression. 1598 52

17beta-estradiol (17beta-E2) protects against H2O2-mediated depletion of intracellular ATP and lessens the degree of depolarization of mitochondrial membrane potential (DeltaPsi(m)) in cultured lens epithelial cells consequential to oxidative insult. We now report that 17beta-E2 acts as a positive regulator of the survival signal transduction pathway, MAPK which, in turn, acts to stabilize DeltaPsi(m) in effect, attenuating the extent of depolarization of mitochondrial membrane potential in the face of acute oxidative stress. The SV-40 viral transformed human cell line, HLE-B3 was treated with 17beta-E2 over a time course of 60 min and phosphorylation of ERK1/2 was analyzed by Western blot. ERK1/2 was phosphorylated within 5-15 min in the presence of 17beta-E2. Cell cultures were exposed to the MEK1/2 inhibitor, UO126, subsequent to H2O2+/-17beta-E2 treatment and the DeltaPsi(m) examined using JC-1, a potentiometric dye which serves as an indicator for the state of mitochondrial membrane potential. UO126 treatment attenuated ERK1/2 phosphorylation irrespective of whether estradiol was administered. Mitochondrial membrane depolarization resulting from H2O2 stress was substantially greater in the presence of UO126. The greater the extent of depolarization, the less effective 17beta-E2 treatment was in checking mitochondrial membrane depolarization, indicating that the relative degree of ERK phosphorylation influences mitochondrial stability with oxidative insult. The data support a positive correlation between 17beta-E2 stimulation of ERK1/2 phosphorylation and mitochondrial stabilization that would otherwise cause a complete collapse of DeltaPsi(m).
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PMID:17beta-estradiol stimulates MAPK signaling pathway in human lens epithelial cell cultures preventing collapse of mitochondrial membrane potential during acute oxidative stress. 1605 Sep 86

We examined the effect of EGF on the proliferation of mouse embryonic stem (ES) cells and their related signal pathways. EGF increased [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation in a time- and dose-dependent manner. EGF stimulated the phosphorylation of EGF receptor (EGFR). Inhibition of EGFR tyrosine kinase with AG-1478 or herbimycin A, inhibition of PLC with neomycin or U-73122, inhibition of PKC with bisindolylmaleimide I or staurosporine, and inhibition of L-type Ca2+ channels with nifedipine or methoxyverapamil prevented EGF-induced [3H]thymidine incorporation. PKC-alpha, -betaI, -gamma, -delta, and -zeta were translocated to the membrane and intracellular Ca2+ concentration ([Ca2+]i) was increased in response to EGF. Moreover, inhibition of EGFR tyrosine kinase, PLC, and PKC completely prevented EGF-induced increases in [Ca2+]i. EGF also increased inositol phosphate levels, which were blocked by EGFR tyrosine kinase inhibitors. Furthermore, EGF rapidly increased formation of H2O2, and pretreatment with antioxidant (N-acetyl-L-cysteine) inhibited EGF-induced increase of [Ca2+]i. In addition, we observed that p44/42 MAPK phosphorylation by EGF and inhibition of EGFR tyrosine kinase, PLC, PKC, or Ca2+ channels blocked EGF-induced phosphorylation of p44/42 MAPKs. Inhibition of p44/42 MAPKs with PD-98059 (MEK inhibitor) attenuated EGF-induced increase of [3H]thymidine incorporation. Finally, inhibition of EGFR tyrosine kinase, PKC, Ca2+ channels, or p44/42 MAPKs attenuated EGF-stimulated cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, and CDK4, respectively. In conclusion, EGF partially stimulates proliferation of mouse ES cells via PLC/PKC, Ca2+ influx, and p44/42 MAPK signal pathways through EGFR tyrosine kinase phosphorylation.
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PMID:EGF stimulates proliferation of mouse embryonic stem cells: involvement of Ca2+ influx and p44/42 MAPKs. 1610 8

Oxidative stress is known to induce cell death in a wide variety of cell types, apparently by modulating intracellular signaling pathways. However, the underlying mechanism by which oxidants induce cell death remains unclear. The present study was undertaken to determine the role of the mitogen-activated protein kinase subfamilies in hydrogen peroxide (H2O2)-induced cell death of osteoblastic cells. H2O2 resulted in a time- and dose-dependent cell death, which was, in part, attributed to apoptosis. H2O2-induced cell death was prevented by iron chelator, hydroxyl radical scavengers. But H2O2-induced cell death was not affected by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase activation. H2O2 treatment caused a transient activation of extracellular signal-regulated kinase (ERK), followed by sustained activation. Cell death induced by H2O2 was prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2. But H2O2 induced a transient activation of p38 and c-Jun N-terminal kinase (JNK) without sustained activation and inhibitors of these kinses were not effective in preventing the cell death. H2O2 increased Bax expression and produced hyperpolarization of mitochondrial membrane potential and its effect was prevented by PD98059. The ERK activation and cell death induced by H2O2 were not dependent on the phosphorylation of epidermal growth factor receptor. Taken together, these findings suggest that the ERK signaling pathway plays an active role in mediating H2O2-induced apoptosis of osteoblasts and functions upstream of mitochondria-dependent pathway to initiate the apoptotic signal.
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PMID:Role of mitogen-activated protein kinases in hydrogen peroxide-induced cell death in osteoblastic cells. 1612 95

The MAPK (mitogen-activated protein kinase) pathway is a major intracellular signalling pathway involved in EGF (epithelial growth factor) receptor-mediated cell growth and differentiation. A novel function of MAPK activity in the mechanism of EGF-mediated protection of TJs (tight junctions) from H2O2 was examined in Caco-2 cell monolayers. EGF-mediated prevention of H2O2-induced increase in paracellular permeability was associated with the prevention of H2O2-induced Tyr-phosphorylation, Thr-dephosphorylation and cellular redistribution of occludin and ZO-1 (zonula occludin-1). EGF also prevented H2O2-induced disruption of the actin cytoskeleton and the dissociation of occludin and ZO-1 from the actin-rich detergent-insoluble fractions. MEK (MAPK/ERK kinase, where ERK stands for extracellular signal related kinase) inhibitors, PD98059 and U0126, completely blocked these protective effects of EGF on TJs. EGF rapidly increased the levels of phosphorylated MEK (p-MEK) in detergent-soluble fractions and phosphorylated ERK (p-ERK) in detergent-insoluble fractions. p-ERK was colocalized and co-immunoprecipitated with occludin. GST (glutathione S-transferase) pull-down assay showed that the C-terminal tail of occludin binds to p-ERK in Caco-2 cell extracts. Pair-wise binding studies using recombinant proteins demonstrated that ERK1 directly interacts with the C-terminal tail of occludin. Therefore the present study shows that ERK interacts with the C-terminal region of occludin and mediates the prevention of H2O2-induced disruption of TJs by EGF.
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PMID:MAPK interacts with occludin and mediates EGF-induced prevention of tight junction disruption by hydrogen peroxide. 1613 68

Oxidant stress-mediated regulation of extracellular signal-regulated kinases (ERK1/2) is linked to pathologic outcomes in lung epithelium, yet a role for Ca2+ and Ca2+/cAMP-response element binding protein (CREB) in ERK1/2 signaling has not been defined. In this study, we tested the hypotheses that oxidants induce Ca2+-mediated phosphorylation of ERK and CREB, and that CREB is required for oxidant-induced proliferation and apoptosis. H2O2 initiated an influx of extracellular Ca2+ that was required for phosphorylation of both ERK and CREB in C10 lung epithelial cells. H2O2-mediated CREB phosphorylation was sensitive to MEK inhibition, suggesting that crosstalk between Ca2+, ERK, and CREB signaling pathways contributes to the oxidant-induced response. Reduction of CREB activity, using a dominant-negative CREB construct, inhibited c-fos steady-state mRNA levels, but unexpectedly enhanced bcl-2 steady-state mRNA levels after H2O2 exposure. Whereas inhibition of CREB activity had no detectable effect on H2O2 stimulation of cell cycle, loss of CREB activity significantly reduced the number of cells undergoing apoptosis. These data support a novel communication between Ca2+-ERK1/2 and CREB elicited by H2O2, and further provide evidence that CREB is an important regulator of apoptosis in oxidant-mediated responses of lung epithelial cells.
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PMID:Oxidant-mediated cAMP response element binding protein activation: calcium regulation and role in apoptosis of lung epithelial cells. 1615 Oct 51

Multinucleated cells resulted from mitosis defect have been noted in pathophysiological states of the cells such as inflammation, senescence and cancer. Since oxidative stress has been known to correlate with these pathophysiological conditions, we tested the effect of H2O2 on the cell cycle progression and formation of multinucleated cells. H2O2 induced a significant delay in cell cycle progression in Chang liver cells. Interestingly, H2O2 actively induced hyperamplification of centrosomes (n>or=3) and multipolar spindle formation during mitosis and subsequently increased the generation of multinucleated cells. A significant increase of the phospho-ERK level was observed upon H2O2 treatment but PD98059, an MEK1/2 inhibitor, didn't reduce the frequency of cells with hyperamplified centrosomes. On the other hand, treatment of either H2O2 or adriamycin increased intracellular ROS levels and multinucleated cells, which were significantly suppressed by antioxidants, N-acetylcysteine and PDTC. Thus, our results suggest that oxidative stress can trigger centrosome hyperamplification and multinucleated cell formation, which may promote pathophysiological progression.
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PMID:Centrosome amplification and multinuclear phenotypes are Induced by hydrogen peroxide. 1626 73

The antioxidant response element (ARE) is a transcriptional control element that mediates expression of a set of antioxidant proteins. NF-E2-related factor 2 (Nrf2) is a transcription factor that activates ARE-containing genes. In endothelial cells, the ARE-mediated genes are upregulated by atheroprotective laminar flow through a Nrf2-dependent mechanism. We tested the hypothesis that activation of ARE-regulated genes via adenovirus-mediated expression of Nrf2 may suppress redox-sensitive inflammatory gene expression. Expression of Nrf2 in human aortic endothelial cells (HAECs) resulted in a marked increase in ARE-driven transcriptional activity and protected HAECs from H2O2-mediated cytotoxicity. Nrf2 suppressed TNF-alpha-induced monocyte chemoattractant protein (MCP)-1 and VCAM-1 mRNA and protein expression in a dose-dependent manner and inhibited TNF-alpha-induced monocytic U937 cell adhesion to HAECs. Nrf2 also inhibited IL-1beta-induced MCP-1 gene expression in human mesangial cells. Expression of Nrf2 inhibited TNF-alpha-induced activation of p38 MAP kinase. Furthermore, expression of a constitutively active form of MKK6 (an upstream kinase for p38 MAP kinase) partially reversed Nrf2-mediated inhibition of VCAM-1 expression, suggesting that p38 MAP kinase, at least in part, mediates Nrf2's anti-inflammatory action. In contrast, Nrf2 did not inhibit TNF-alpha-induced NF-kappaB activation. These data identify the Nrf2/ARE pathway as an endogenous atheroprotective system for antioxidant protection and suppression of redox-sensitive inflammatory genes, suggesting that targeting the Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of inflammatory diseases such as atherosclerosis.
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PMID:Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. 1633 37

The possible interplay between extracellular signal-regulated protein kinase (ERK) activation and ethanolamine phosphoglycerides (PG) membrane bilayer translocation following oxidative stress (OS) (0.5 mM H2O2/0.05 mM Fe2+), was examined in oligodendroglia, OLN93, cells with altered plasma membrane PG composition. Cells supplemented with 50 microM docosahexaenoic acid (DHA, 22:6n3) to increase the number of potential double bond targets for OS in ethanolamine-PG (EPG) were compared to cells with diminished content of EPG, attained by the addition of 0.5 mM N,N-dimethylethanolamine (dEa). After 30 min OS, EPG translocation accompanied by sustained ERK activation and nuclear translocation culminating in apoptosis was found in DHA-supplemented cells in contrast to no EPG translocation, a brief ERK activation, but no nuclear translocation, and no cell death in DHA/dEa-supplemented cells. DHA/dEa-supplemented cells pretreated with the protein-tyrosine phosphatases inhibitor Na3VO4 followed by OS, although expressing a sustained ERK activation and nuclear translocation, failed to show apoptosis and lacked EPG translocation. In DHA-supplemented cells U0126, a MEK inhibitor, prevented ERK activation and EPG translocation and protected from cell death. These findings most likely indicate that ERK activation is an indispensable component for the signaling cascades leading to EPG translocation but only activation of the latter is leading to OS-induced apoptotic cell death.
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PMID:Translocation of ethanolamine phosphoglyceride is required for initiation of apoptotic death in OLN-93 oligodendroglial cells. 1634 87

Oxidative stress induces activation of extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase families. However, it is unclear in renal epithelial cells whether the ERK activation is involved in cell survival or cell death in H2O2-treated cells. The present study was undertaken to determine the role of the ERK activation in H2O2-induced apoptosis of renal epithelial cells using opossum kidney (OK) cells, an established proximal tubular epithelial cell line. H2O2 resulted in a time- and dose-dependent apoptosis of OK cells. H2O2 treatment caused marked sustained activation of ERK. The ERK activation was prevented by PD98059 and U0126, inhibitors of ERK1/2 upstream kinase MEK1/2. Apoptosis caused by H2O2 was prevented by U0126. Transient transfection with constitutive active MEK1 increased the H2O2-induced apoptosis, whereas transfection with dominant-negative mutants of MEK1 decreased the apoptosis. H2O2 produced hyperpolarization of mitochondrial membrane potential and activation of caspases-3. H2O2-induced ERK activation was inhibited by the Src family selective inhibitor PP2 and the epidermal growth factor receptor inhibitor AG1478. The presence of AG1478, but not PP2, prevented H2O2-induced cell death. Taken together, our findings suggest that the ERK activation mediated by epidermal growth factor receptor plays an active role in inducing H2O2-induced apoptosis of OK cells and functions upstream of mitochondria-dependent pathway to initiate the apoptotic signal.
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PMID:EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells. 1634 93


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