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)

beta-Neuregulin (betaNRG) is a potent Schwann cell survival factor that binds to and activates a heterodimeric ErbB2/ErbB3 receptor complex. We found that NRG receptor signaling rapidly activated phosphoinositide 3-kinase (PI3K) in serum-starved Schwann cells, while PI3K inhibitors markedly exacerbated apoptosis and completely blocked NRG-mediated rescue. NRG also rapidly signaled the phosphorylation of mitogen-activated protein kinase (MAPK) and the serine/threonine kinase Akt. The activation of Akt and MAPK in parallel pathways downstream from PI3K resulted in the phosphorylation of Bad at different serine residues. PI3K inhibitors that blocked NRG-mediated rescue also blocked the phosphorylation of Akt, MAPK, and Bad. However, selective inhibition of MEK-dependent Bad phosphorylation downstream from PI3K had no effect on NRG-mediated survival. Conversely, ectopic expression of wild-type Akt not only enhanced Bad phosphorylation but also enhanced autocrine- and NRG-mediated Schwann cell survival. Taken together, these results demonstrate that NRG receptor signaling through a PI3K/Akt/Bad pathway functions in Schwann cell survival.
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PMID:Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival. 1131 10

Acceleration of the polyol pathway and enhanced oxidative stress are implicated in the pathogenesis of diabetic complications. We and others recently reported that aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, was upregulated by reactive oxygen and nitrogen species in vascular smooth muscle cells. To clarify the molecular mechanisms underlying these findings, we investigated the signal transduction pathways mediating AR expression using the rat vascular smooth muscle cell line A7r5. A selective epidermal growth factor (EGF) receptor kinase inhibitor, tyrphostin AG1478, significantly suppressed the hydrogen peroxide (H2O2)-induced increase in AR mRNA and enzyme activity. Activation of extracellular signal-regulated protein kinase (ERK) by H2O2 was blunted by AG1478. PD98059, a specific inhibitor of ERK kinase (MEK1), reduced H2O2-induced AR expression. EGF alone elicited activation of ERK and induction of AR expression. Increased level of AR transcript was demonstrated in cells treated with oxidized low-density lipoprotein, and this increase was also suppressed by AG1478. Inhibition of p38 MAP kinase by SB203580 also partially suppressed the H2O2-initiated AR induction. The presence of ponalrestat, an AR inhibitor, significantly accelerated H2O2-induced cell death. These results suggested that AR may act as a survival factor in these cells and that the EGF receptor-ERK pathway is the major signaling pathway involved in the upregulation of AR expression under oxidative stress.
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PMID:EGF receptor-ERK pathway is the major signaling pathway that mediates upregulation of aldose reductase expression under oxidative stress. 1144 Aug 32

Manganese superoxide dismutase Mn-SOD plays a major role in protecting mitochondria from oxidative damage. Overexpression of Mn-SOD maintains cell survival under conditions that lead to apoptotic death. In addition to the antioxidative enzyme, platelet-derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation by activating survival signaling pathways in various cells. Here we show that PDGF induced the expression of the Mn-SOD gene in NIH3T3 cells, and its induction was associated with early growth response-1 (Egr-1), a transcription factor. An electrophoretic mobility shift assay demonstrated that Egr-1 bound to the proximal promoter of the Mn-SOD gene in response to PDGF. The proximal promoter region of Mn-SOD was shown to be transcriptionally responsive to both basal and PDGF stimulation by transfection studies. Forced expression of Egr-1 in the cells activated Mn-SOD transcription in a dose-dependent manner. The pathway by which PDGF induced Egr-1 involved the mitogen-activated protein kinase kinase-1 (MEK1) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), because the effect of PDGF on the induction of Egr-1 was blocked by U0126, a specific MEK1 inhibitor. These findings indicate that the induction of Mn-SOD is part of the anti-apoptotic properties mediated by PDGF.
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PMID:Early growth-responsive-1-dependent manganese superoxide dismutase gene transcription mediated by platelet-derived growth factor. 1151 24

The binding of cytokines to the gp130 receptor activates the STAT3, MEK/MAPK, and PI3K/Akt signalling pathways. To assess the relative importance of these pathways in promoting the survival of cytokine-dependent neurons, we conditionally inactivated STAT3 in mice and inhibited MEK, PI3K, and Akt in cultured neurons using pharmacological reagents and by expressing specific inhibitory proteins. Inactivation of STAT3 enhanced the death of the cytokine-dependent sensory neurons of the nodose ganglion in vivo and substantially reduced the response of these neurons to CNTF and LIF in vitro. LY294002, an inhibitor of PI3K, but not PD98059, an inhibitor of MEK, markedly reduced the response of these neurons to CNTF, as did dominant-negative PI3K, dominant-negative Akt, and overexpression of Ruk (a natural PI3K inhibitor). These results demonstrate that STAT3 and PI3K/Akt signalling play major roles in mediating the survival response of neurons to cytokines.
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PMID:Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons. 1159 Nov 28

Mitogen-activated protein kinases (MAPK) and protein kinase B (PKB or Akt) are major signal transduction molecules regulating cell proliferation, differentiation, and apoptosis. We examined how cultured rat aortic vascular smooth muscle cells (VSMC) at different cell densities respond to selected stimuli and how this is reflected in the two distinct (MAPK and Akt) and yet cross-talking signaling pathways. VSMC were cultured to 100% confluence, reaching contact inhibition, and to 60-70% confluence, as sparse, proliferating cells. They were treated with menadione (an intracellular generator of O(-2)) and/or platelet-derived growth factor homodimer BB (PDGF). In sparse cells, menadione or PDGF alone activated ERK, and together the effect was synergistic, whereas in confluent cells menadione's and PDGF's activations of ERK were, at most, additive. Activation of the upstream ERK kinase (MEK-1) paralleled ERK activation except in sparse cells in which the synergistic effects of menadione and PDGF on ERK could not be fully accounted for by MEK-1 activation. Another member of the MAPK family, p38, did not show significant changes. Akt activation by PDGF alone was present under both cell culture conditions; Akt activation is blocked by menadione. Co-incubation with the reducing agent dithiothreitol or calcium chelators (EDTA/EGTA) inhibited partially or completely menadione's effects on MEK/ERK and Akt pathways, as well as menadione's effects on PDGF-induced ERK and Akt activations. These data suggest that in VSMC, the state of cell confluence determines how distinct pathways of MAPK activation cross talk. In addition while PDGF may function as a survival factor by inducing Akt activation, menadione could promote apoptosis by inhibiting PDGF-induced Akt activation independent of cell density. The effects of menadione, but not those of PDGF, are more dependent on the cellular redox status and extracellular calcium.
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PMID:Rat aortic smooth muscle cell density affects activation of MAP kinase and Akt by menadione and PDGF homodimer BB. 1159 93

Using loss-of-function mutants of Ros and inducible epidermal growth factor receptor-Ros chimeras we investigated the role of various signaling pathways in Ros-induced cell transformation. Inhibition of the mitogen-activated protein kinase (MAPK) pathway with the MEK (MAP/extracellular signal-regulated kinase kinase) inhibitor PD98059 had little effect on the Ros-induced monolayer and anchorage-independent growth of chicken embryo fibroblasts and NIH3T3 cells even though more than 70% of the MAPK was inhibited. In contrast, inhibiting the phosphatidylinositol 3-kinase (PI3K) pathway with the drug LY294002, a dominant negative mutant of PI3K, Deltap85, or the phosphatidylinositol phosphatase PTEN (phosphatase and tensin homologue deleted in chromosome ten) resulted in a dramatic reduction of v-Ros- and epidermal growth factor receptor-Ros-promoted anchorage-independent growth of chicken embryo fibroblasts and NIH3T3 cells, respectively. Parallel and downstream components of PI3K signaling such as the Rho family GTPases (Rac, Rho, Cdc42) and the survival factor Akt were all shown to contribute to Ros-induced anchorage-independent growth, although Rac appeared to be less important for Ros-induced colony formation in NIH3T3 cells. Furthermore, the transformation-attenuated v-Ros mutants F419 and DI could be complemented by constitutively active mutants of PI3K and Akt. Finally, we found that overexpressing a constitutively active mutant of STAT3 (STAT3C) conferred a resistance to the inhibition of Ros-induced anchorage-independent growth by LY294002, suggesting a possible overlap of functions between PI3K and STAT3 signaling in mediating Ros-induced anchorage-independent growth.
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PMID:The role of phosphatidylinositol 3-kinase, rho family GTPases, and STAT3 in Ros-induced cell transformation. 1179 10

We hypothesized that glutathione transferases could be induced and may participate to cellular defenses against the oxidative stress occurring during liver regeneration. Here, we evidenced that murine GSTA1 (mGSTA1), A4, Pi, and Mu are up-regulated during mouse liver regeneration, exhibiting a biphasic pattern of induction correlating early G(1) phase and G(1)/S transition of the cell cycle. Using confocal microscopy immunolocalization and subcellular fractionation, mGSTA4 was demonstrated in both mitochondria and cytosol and found preferentially increased in cytosol during liver regeneration. In addition, mGSTA4 was induced in vivo and in cultured hepatocytes by tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and epidermal growth factor (EGF), factors that play crucial roles in hepatocyte survival and proliferation during liver regeneration. However, the mitogenic effect of EGF was not responsible for the induction of mGSTA4. In transient transfections, IL-6 and EGF, but not TNFalpha, transactivated the human GSTA4 (hGSTA4) promoter cloned upstream of the luciferase reporter gene suggesting that IL-6 and EGF up-regulated hGSTA4 at a transcriptional level, whereas TNFalpha could rather act at a post-transcriptional level. The inhibition of phosphoinositide 3-kinase, p38 MAPK, and MEK/ERK signaling pathways, using specific inhibitors, prevented EGF-dependent induction of mGSTA4 and transactivation of hGSTA4 promoter. Altogether, these data favor the conclusion that, in regenerating hepatocytes, several GST isoforms are induced and that cytokines TNFalpha and IL-6 and survival factor EGF positively regulate mGSTA4 via survival signaling pathways.
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PMID:Pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 and survival factor epidermal growth factor positively regulate the murine GSTA4 enzyme in hepatocytes. 1188 96

The evolutionarily conserved Ras/Raf/MEK/ERK pathway is thought to be essential for proliferation of eukaryotic cells. The human multiple myeloma (MM) cell line 8226 encodes an activated K-ras allele and proliferates without requirement for the main MM growth and survival factor IL-6. Surprisingly, the addition of the MEK1/2 inhibitors PD98059 or U0126 to 8226 cultures at doses that block virtually all ERK1/2 activity had minimal effects on the rapid proliferation of this cell line. In contrast, proliferation of the IL-6-dependent MM cell line, ANBL-6 was blocked by PD98059. Levels of activated forms of the other classical MAP kinases (JNK and p38) were very low during MM cell proliferation and, therefore, do not substitute for the mitogenic activities normally regulated by ERK kinases. These data demonstrate that proliferation of 8226 cells does not require ERK1/2 activity, and suggest that IL-6-independent growth of MM may correlate with independence from a requirement for ERK activity. Other signal transduction pathways that appear to regulate cell cycle progression in these cells were examined.
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PMID:Proliferation of IL-6-independent multiple myeloma does not require the activity of extracellular signal-regulated kinases (ERK1/2). 1220 79

Mammalian neurogenesis is determined by an interplay between intrinsic genetic mechanisms and extrinsic cues such as growth factors. Here we have defined a signaling cascade, a MEK-C/EBP pathway, that is essential for cortical progenitor cells to become postmitotic neurons. Inhibition of MEK or of the C/EBP family of transcription factors inhibits neurogenesis while expression of a C/EBPbeta mutant that is a phosphorylation-mimic at a MEK-Rsk site enhances neurogenesis. C/EBP mediates this positive effect by direct transcriptional activation of neuron-specific genes such as Talpha1 alpha-tubulin. Conversely, inhibition of C/EBP-dependent transcription enhances CNTF-mediated generation of astrocytes from the same progenitor cells. Thus, activation of a MEK-C/EBP pathway enhances neurogenesis and inhibits gliogenesis, thereby providing a mechanism whereby growth factors can selectively bias progenitors to become neurons during development.
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PMID:An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis. 1244 Oct 50

Thioredoxin (TRX) has a role in a variety of biological processes, including cytoprotection and the activation of transcription factors. Nerve growth factor (NGF) is a major survival factor of sympathetic neurons and promotes neurite outgrowth in rat pheochromocytoma PC12 cells. In this study, we showed that NGF induces TRX expression at protein and mRNA levels. NGF activated the TRX gene through a regulatory region positioned from -263 to -217 bp, containing the cAMP-responsive element (CRE). Insertion of a mutation in the CRE in this region abolished the response to NGF. NGF induced binding of CRE-binding protein to the CRE of the TRX promoter in an electrophoretic mobility shift assay. NGF also induced nuclear translocation of TRX. 2'-Amino-3'-methoxyflavone, an inhibitor of mitogen-activated protein kinase kinase, which is a known inhibitor of NGF-dependent differentiation in PC12 cells, suppressed the NGF-dependent expression and nuclear translocation of TRX. Overexpression of mutant TRX (32S/35S) or TRX antisense vector blocked the neurite outgrowth of PC12 cells by NGF. Overexpression of mutant TRX (C32S/C35S) suppressed the NGF-dependent activation of the CRE-mediated c-fos reporter gene. These results suggest that TRX plays a critical regulatory role in NGF-mediated signal transduction and outgrowth in PC12 cells.
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PMID:Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells. 1253 10


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