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)

Phosphatidylethanolamine N-methyltransferase 2 (PEMT2) is an isoform of PEMT that converts phosphatidylethanolamine to phosphatidylcholine in mammalian liver. Overexpression of PEMT2 led to inhibition of proliferation of hepatoma cells [J. Biol. Chem. 269 (1994) 24531]. The present study aims to unravel the molecular mechanism of the reduced proliferation, especially the signaling transducer proteins involved in this process. Thus, we chose PI3K/Akt pathway that is initiated by growth factors and leads to cell survival and proliferation. Rat hepatoma CBRH-7919 cells transfected with pemt2-cDNA showed that: (1) signaling proteins including c-Met, PDGF receptor, PI3K, Akt and Bcl-2 all had reduced expression as shown by Western blotting studies; (2) flow cytometric and DNA ladder assays showed that 22.9% of the pemt2-transfected cells were undergoing apoptosis; (3) the activity of Akt was decreased as shown by Western blotting using antibody directed against p-Akt (Thr308); (4) wortmannin and PD98059, inhibitors of PI3K and MEK, respectively, both inhibited Akt activity, indicating that PI3K and MAPK pathways were merging at Akt in CBRH-7919 cells. The above results suggest that overexpression of PEMT2 strongly downregulated the PI3K/Akt signaling pathway at multiple sites and induced apoptosis. This, at least partly, explains the molecular mechanism of impaired proliferation induced by pemt2 transfection.
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PMID:Overexpression of PEMT2 downregulates the PI3K/Akt signaling pathway in rat hepatoma cells. 1196 Jul 51

Induction of low-density lipoprotein (LDL) receptor transcription in response to depletion of cellular sterols in animal cells is well established. The intracellular signal or signals involved in regulating this process, however, remain unknown. Using a specific inhibitor of protein kinase C (PKC), calphostin C, we show the requirement of this kinase in the induction process in human hepatoma HepG2 cells. Overexpression of PKC epsilon, but not PKC alpha, -gamma, -delta, or -zeta was found to dramatically induce (approximately 18-fold) LDL receptor promoter activity. Interestingly, PKC epsilon-mediated induction was found to be sterol resistant. To further establish that PKC epsilon is involved in the sterol regulation of LDL receptor gene transcription, endogenous PKC epsilon was specifically inhibited by transfection with antisense PKC epsilon phosphorothionate oligonucleotides. Antisense treatment decreased endogenous PKC epsilon protein levels and completely blocked induction of LDL receptor transcription following sterol depletion. PKC epsilon-induced LDL receptor transcription is independent of the extracellular signal-regulated kinase 1 and 2 (p42/44(MAPK)) cascade, because the MEK-1/2 inhibitor, PD98059 did not inhibit, even though it blocked p42/44(MAPK) activation. Finally, photoaffinity labeling studies showed an isoform-specific interaction between PKC epsilon and sterols, suggesting that sterols may directly modulate its function by hampering binding of activators. This was confirmed by PKC activity assays. Altogether, these results define a novel signaling pathway leading to induction of LDL receptor transcription following sterol depletion, and a model is proposed to account for a new function for PKC epsilon as part of a sterol-sensitive signal transduction pathway in hepatic cells.
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PMID:Critical role of diacylglycerol- and phospholipid-regulated protein kinase C epsilon in induction of low-density lipoprotein receptor transcription in response to depletion of cholesterol. 1199 13

Transforming growth factor (TGF) beta1 is a potent inducer of apoptosis in the liver. During TGF-beta1-induced apoptosis, 3 mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK], and p38 kinase) showed simultaneously sustained activation in FaO rat hepatoma cells. TGF-beta1-induced apoptosis was markedly enhanced when ERK activation was selectively inhibited by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059. In contrast, both interfering with p38 activity by overexpression of the dominant negative (DN) MKK6 mutant and inhibition of the JNK pathway by overexpression of the DN SEK1 mutant resulted in suppression of mitochondrial cytochrome c release, abrogating TGF-beta1-induced apoptosis. In addition, antiapoptotic Bcl-2 blocked mitochondrial cytochrome c release, suppressing TGF-beta1-induced activation of JNK and p38. Inhibition of ERK activity enhanced TGF-beta1-induced p38 and JNK activation. However, inhibition of the JNK pathway suppressed p38 but induced transient ERK activation. Similarly, interfering with the p38 pathway also attenuated JNK activation but generated transient ERK activation in response to TGF-beta1. These results indicate that disrupting one MAP kinase pathway affects the TGF-beta1-induced activation of other MAP kinases, suggesting cross-talk among MAP kinase pathways. In conclusion, we propose that the balance and integration of MAP kinase signaling may regulate commitment to TGF-beta1-induced apoptosis modulating the release of cytochrome c from mitochondria.
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PMID:Role of MAP kinases and their cross-talk in TGF-beta1-induced apoptosis in FaO rat hepatoma cell line. 1202 21

IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.
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PMID:Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. 1208

Growth stimulation and inhibition are both associated with tyrosine phosphorylation. We examined the effects of epidermal growth factor (EGF), a growth stimulant, and compound 5 (Cpd 5), a protein-tyrosine phosphatase (PTPase) inhibitor, which inhibits the growth of the same Hep3B hepatoma cells. We found that both EGF and Cpd 5 induced tyrosine phosphorylation of EGF receptor (EGFR) and ERK. However, the phosphorylation caused by EGF was transient and that caused by Cpd 5 was prolonged. Furthermore, Cpd 5 action caused a strong nuclear phospho-ERK signal and induced phospho-Elk-1, a nuclear target of ERK activation, in contrast to the weak effects of EGF. An ERK kinase assay demonstrated that ERK activated by Cpd 5 could phosphorylate its physiological substrate, Elk-1. The MEK inhibitors PD098056 and U0126 abrogated both the induction by Cpd 5 of phospho-ERK, its nuclear translocation and phospho-Elk-1 and also antagonized its growth inhibitory effects. Furthermore, phospho-ERK phosphatase and phospho-Elk-1 activities were lost from nuclear extracts from Cpd 5 treated, but not EGF treated cells. In conclusion, the data show that Cpd 5 causes growth inhibition as a consequence of prolonged ERK and Elk-1 phosphorylation, likely a result of inhibition of multiple PTPases, including those acting on phospho-EGFR, on phospho-ERK, and on phospho-Elk-1, in contrast to the kinase driven transient activation resulting from EGF.
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PMID:Transient and sustained ERK phosphorylation and nuclear translocation in growth control. 1211 21

Secretion of growth hormone (GH) in adult male rats is characterized by high peak and undetectable trough levels, both of which are required for male-specific pattern of liver gene expression and GH-induced phosphorylation of STAT5. The present study suggests that regulation of GH receptor (GHR) levels in rat hepatoma cells by repeated GH stimulation determines GH responsiveness via the JAK2/STAT5 pathway. A short exposure to GH rapidly reduced GHR levels which resulted in an equal desensitization of the JAK2/STAT5 pathway. Recovery of GH-induced STAT5 phosphorylation correlated with the time-dependent recovery of GHR levels during incubation in the absence of GH. Acute GH also induced phosphorylation of ERK1/2 and Akt, and this induction was also inhibited by prior exposure to GH. However, unlike the JAK2/STAT5 pathway, the effect of GH to activate the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways did not recover following prolonged incubation in the absence of GH. Thus, GH administration desensitizes the JAK2/STAT5 pathway, possibly because of down-regulation of GHR, whereas an additional post-receptor mechanism is required for the prolonged refractoriness of the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways toward a second GH stimulation. Our study suggests that both receptor and post-receptor mechanisms are important in GH-induced homologous desensitization.
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PMID:Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation. 1216 50

c-Jun has a variety of functions including proliferation, differentiation and death. c-Jun is specifically phosphorylated by c-Jun N-terminal kinase (JNK) which is regulated by Ras-MEKK1-MKK4/7 pathway. Previous studies showed that c-Jun protein plays a positive role in cell proliferation of normal hepatocytes and was detected in hepatocellular carcinoma (HCC) tissues. However, the function of c-Jun in HCC cells has not been examined. The aim of this study was to investigate whether the MEKK1-JNK signaling pathway and c-Jun may be involved in the survival and proliferation of HCC. Surprisingly, an active not dominant negative form of MEKK1 (CA-MEKK1) remarkably inhibited the colony formation of HCC cells. Gel retardation assays indicated that CA-MEKK1 induces c-Jun DNA binding, and luciferase assays exhibited that CA-MEKK1 enhances the transactivating activity of c-Jun in HCC cells. These results suggested that the inhibitory effect of CA-MEKK1 on colony formation is likely to be mediated by c-Jun. As expected, when wild-type c-Jun was transfected, the colony formation was significantly reduced. Especially in HuH7 cells, c-Jun transfected cells failed to make any colonies. Our data suggested that c-Jun activation can induce negative effect on survival and proliferation of HCC cells.
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PMID:MEKK1 induces c-Jun complexes that act as negative regulators for cell survival and proliferation of HCC cells. 1216 99

Selective induction of Phase II over Phase I drug-metabolizing enzymes has been proposed as a mechanism for reduction of chemical carcinogenesis. Enzymes likely to play a role in this amelioration include the glutathione S-transferases (GSTs) and among compounds that selectively induce key GSTs are tert-butylhydroquinone (tBHQ) and oltipraz [4-methyl-5-(2-pyrazinyl)-3H-1,2-dithiole-3-thione]. In vivo, and in hepatoma cells (H4IIE), these two agents induce rat GSTA2 mRNA to a similar extent. However, with a luciferase reporter construct containing 1651 bp of the proximal 5' flanking region of the rGSTA2 gene in the same cell line and under similar conditions, luciferase activity was induced to a much greater extent by tBHQ than by oltipraz. A similar large intercompound differential was seen with reporter constructs containing either the rGSTA2 ARE enhancer and HNF1 site (-872 to -582) or XRE enhancer and HNF1 site (-1110 to -812). In H4IIE cells, the rGSTA2 mRNA response to each agent was completely inhibited by 1 microM actinomycin-D cotreatment. With 1 microM cycloheximide cotreatment however, some induction by tBHQ remained, while induction by oltipraz was completely abolished. The induction response to tBHQ but not oltipraz was augmented by pretreatment with PD98059, a MEK1/2 specific inhibitor. Notwithstanding induction characteristics in common, oltipraz, and tBHQ have sufficient dissimilarities to indicate that rGSTA2 upregulation by the two agents is not identical.
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PMID:Cell-based studies reveal differences in glutathione S-transferase induction between oltipraz and tert-butylhydroquinone. 1224 83

Insulin regulates metabolic activity, gene transcription, and cell growth by modulating the activity of several intracellular signaling pathways. Insulin activation of one mitogen-activated protein kinase cascade, the MEK/ERK kinase cascade, is well described. However, the effect of insulin on the parallel p38 pathway is less well understood. The present work examines the effect of inhibiting the p38 signaling pathway by use of specific inhibitors, either alone or in combination with insulin, on the activation of ERK1/2 and on the regulation of gene transcription in rat hepatoma cells. Activation of ERK1/2 was induced by insulin and was dependent on the activation of MEK1, the kinase upstream of ERK in this pathway. Treatment of cells with p38 inhibitors also induced ERK1/2 activation/phosphorylation. The addition of p38 inhibitors followed by insulin addition resulted in a greater than additive activation of ERK1/2. The two genes studied, c-Fos and Pip92, are immediate-early genes that are dependent on the ERK1/2 pathway for insulin-regulated induction because the insulin effect was inhibited by pretreatment with a MEK1 inhibitor. The addition of p38 inhibitors induced transcription of both genes in a dose-dependent manner, and insulin stimulation of both genes was enhanced by prior treatment with p38 inhibitors. The ability of the p38 inhibitors to induce ERK1/2 and gene transcription, both alone and in combination with insulin, was abolished by prior inhibition of MEK1. These data suggest possible cross-talk between the p38 and ERK1/2 signaling pathways and a potential role of p38 in insulin signaling.
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PMID:Insulin signal transduction pathways and insulin-induced gene expression. 1236 32

Compound 5 (Cpd 5) or 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone, is an inhibitor of protein phosphatase Cdc25A and causes persistent activation of extracellular signal-regulated kinase (ERK) and cell growth inhibition. To study the mechanism(s) by which persistent ERK phosphorylation might induce cell growth inhibition, we used Cpd 5 as a tool to examine its effects on the activity of CREB (cAMP response element-binding protein) transcription factor in Hep3B human hepatoma cells. We found that CREB activity, including its DNA binding ability and phosphorylation on residue Ser-133, was strongly inhibited by Cpd 5, followed by suppression of CRE-mediated transcription of cyclin D1 and Bcl-2 genes. Cpd 5-mediated suppression of CREB phosphorylation and transcriptional activity was antagonized by mitogen-activated protein kinase kinase inhibitors PD 98059 and U-0126, implying that this inhibition of CREB activity was regulated at least in part by the ERK pathway. The phosphorylation of ribosomal S6 kinase (pp90(RSK)), a CREB kinase in response to mitogen stimulation, was also found to be inhibited by Cpd 5 action. This inhibition of pp90(RSK) phosphorylation is likely the result of its increased association with CREB-binding protein (CBP), which subsequently caused inhibition of CREB phosphorylation and activity. To support the hypothesis that Cpd 5 effects on Cdc25A inhibition with subsequent ERK activation could cause CREB inhibition, we examined the effects of Cdc25A inhibition without the use of Cpd 5. Hep3B cells were transfected with C430S Cdc25A mutant, and ERK was found to be phosphorylated in a constitutively activated manner, which was accompanied by decreased CREB phosphorylation and increased recruitment of CBP to pp90(RSK). These data provide evidence that CBP.RSK complex formation in response to persistent ERK phosphorylation by Cpd 5 down-regulates CREB activity, leading to inhibition of both cAMP response element-mediated gene expression and cell growth.
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PMID:Persistent ERK phosphorylation negatively regulates cAMP response element-binding protein (CREB) activity via recruitment of CREB-binding protein to pp90RSK. 1254 Aug 38


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