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)

RNF2, a member of polycomb group (PcG) proteins, is involved in chromatin remodeling. However, mechanisms that regulate RNF2 function are unknown. To identify such mechanisms, RNF2 was expressed in HEK-293 cells and analyzed by 2-D electrophoresis. RNF2 was resolved into at least seven protein spots, migrating toward the lower pI from its expected pI of 6.38, suggesting that RNF2 undergoes post-translational modifications. Western blotting indicated that majority of these RNF2 spots contained phosphoserine(s), which were completely dephosphorylated upon treatment with a phosphatase. SB203580, a specific inhibitor of p38 MAPK, inhibited RNF2 phosphorylation at one site. On the other hand, PD98059, an inhibitor of MEK1/2, inhibited majority of the phosphorylation events in RNF2. Mass spectrometry analysis identified that RNF2 expressed in Sf9 insect cells undergoes co-translational excision of (1)Met coupled to N-acetylation of (2)Ser, and phosphorylation of (41)Ser. Interestingly, (41)Ser is a predicted p38/MAPK phosphorylation site, consistent with the loss of phosphorylation induced by SB203580. Further analysis indicated that RNF2 phosphorylation differentially modulates the expression of transcription factors and histone 2B acetylation. These results provide first evidence for phosphorylation of RNF2, and suggest that the mitogen activated protein kinases including p38 MAPK and ERK1/2 regulate growth, stress response, differentiation and other cellular processes, through phosphorylation of RNF2.
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PMID:RNF2 is the target for phosphorylation by the p38 MAPK and ERK signaling pathways. 1940 34

Insulin-like growth factor-1 (IGF-1) interacts with the Type I receptor to activate two main signaling pathways, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)-Akt cascades, which mediate proliferation or survival of oligodendrocyte (OL) progenitors (OLPs). In other cellular systems, mammalian target of rapamycin (mTOR) and the p70 S6 kinase are downstream effectors that phosphorylate translation initiation factors (e.g. eIF-4E), their regulators (e.g. 4E-binding protein 1, 4E-BP1) and ribosomal protein S6 (S6). The aim of this study was to determine whether these pathways are involved in IGF-1-stimulated protein synthesis, important for growth and differentiation of OLs. Rat cultured OLPs were treated with IGF-1 with or without inhibitors of PI3K (LY294002 or Wortmannin), mTOR (rapamycin), MEK (PD98059), and Akt (III or IV), as well as an adenovirus encoding a dominant negative form of Akt. Protein synthesis, as assessed by [(35)S]-methionine incorporation, was stimulated by IGF-1 and required the upstream activation of PI3K, Akt, mTOR and MEK/ERK. Concordant with the experiments using protein kinase inhibitors, western blotting revealed that IGF-1 stimulates phosphorylation of Akt, mTOR, ERK, S6 and 4E-BP1. Activation of S6 and inactivation of 4E-BP1, necessary for protein synthesis to take place, were dependent on the upstream activation of PI3K and mTOR. Finally, IGF-1 consistently stimulated protein synthesis through mTOR in differentiating OLPs but mRNA transcription was not required at day 4, indicating a differential role of IGF-1 throughout OL development.
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PMID:IGF-1-stimulated protein synthesis in oligodendrocyte progenitors requires PI3K/mTOR/Akt and MEK/ERK pathways. 1945 43

Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E(2) (PGE(2)) levels. PGE(2) signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE(2) inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE(2) accumulation. The hepatocyte growth factor (HGF) receptor, Met, is frequently over-expressed in colorectal tumours and promotes cancer growth, metastasis and resistance to therapy, although the mechanisms for this have not been fully elucidated. Here, we report that HGF/Met signalling can promote PGE(2) biogenesis in colorectal cancer cells via COX-2 up-regulation and 15-PGDH down-regulation at the protein and messenger RNA level. Pharmacological inhibition of MEK and PI3K suggested that both extracellular signal-regulated kinase (ERK) and AKT signalling are required for COX-2 protein up-regulation and 15-PGDH down-regulation downstream of Met. Notably, inhibition of Met with the small molecule inhibitor SU11274 reduced COX-2 expression and increased 15-PGDH expression in high Met-expressing cells. We also show that hypoxia potentiated HGF-driven COX-2 expression and enhanced PGE(2) release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE(2) pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE(2) biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer.
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PMID:HGF/Met signalling promotes PGE(2) biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells. 1963 28

Mutations in receptor tyrosine kinase (RTK) growth factor receptors (epidermal growth factor receptor, platelet-derived growth factor receptor, MET and ERBB2), which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral replication-competent avian leukosis virus long terminal repeat, splice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in Ink4a/Arf(lox/lox) mice in vivo. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.
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PMID:Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation. 1985 33

The purpose of this study was to examine the effects of angiotensin on the release of enkephalin peptides and the expression of the proenkephalin (pEK) gene. Incubation of cultured bovine adrenal medullary (AM) cells in serum-free medium resulted in calcium- and time-dependent accumulation of [Met(5)]-enkephalin (MEK) in the medium. Fifteen minutes to three hours of incubation with 2 nM [Sar(1)]-angiotensin II (s(1)-AII) did not affect basal secretion of MEK; however, longer incubations (24 h) resulted in four- to fivefold increases. Northern and dot blot analyses with bovine pEK cDNA demonstrated increases in the relative abundance of pEK mRNA in angiotensin-treated cells, suggesting that the long-term increases in MEK release may reflect increased expression of pEK gene and MEK synthesis. Stimulation of MEK release and induction of pEK mRNA were concentration dependent (ED(50) approximately 1 nM. Changes in pEK mRNA levels were not observed until 12 h of incubation with s(1)-AII and continued to increase during an additional 12 h of incubation. Addition of an angiotensin antagonist, saralasin, at 0-16 h, but not at 18-20 h, to cells incubated continuously for 24 h with s(1)-AII inhibited changes in pEK mRNA and MEK release. These observations demonstrate the absence of apparent desensitization of angiotensin receptor function and indicate that long-term receptor-ligand interactions are required to induce changes in gene expression and MEK release. Induction of pEK mRNA and stimulation of MEK release were additive to the effects of veratridine and forskolin, respectively, indicating that the effects of angiotensin were not due to membrane depolarization or increased cyclic AMP levels. Angiotensin-induced increases in pEK mRNA were partially inhibited by nifedipine and also by dantrolene and TMB-8, drugs that inhibit voltage-dependent calcium channels and mobilization of calcium from intracellular stores, respectively. s(1)-AII-induced changes in pEK mRNA were inhibited with calmidazolium, suggesting involvement of calmodulin. The participation of protein kinase C in the induction of pEK gene and long-term stimulation of MEK release was indicated by inhibition of the s(1)-AII effects by pretreatment of cells with protein kinase C inhibitor sphingosine. Effects of s(1)-AII on induction of pEK mRNA by angiotensin and by nicotine were prevented by the translational inhibitor cycloheximide. In conclusion, angiotensin receptors were found to control expression of the pEK gene and secretion of MEK. Unlike nicotinic receptors, which may control secretion of enkephalin peptides directly by stimulating exocytosis and indirectly by controlling peptide synthesis, the effects of angiotensin appear to be mediated indirectly at the level of pEK gene expression.
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PMID:Regulation of proenkephalin gene expression by angiotensin in bovine adrenal medullary cells: Molecular mechanisms and nature of the second messenger systems. 1991 1

Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.
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PMID:Recurrent BRAF mutations in Langerhans cell histiocytosis. 3071 31

Treatment outcomes in advanced or metastatic non-small-cell lung cancer (NSCLC) remain unsatisfactory, with low long-term survival rates. Palliative chemotherapy offers a median survival not exceeding 1 year. To date, various combinations of cytotoxic drugs have not improved treatment results beyond what has been observed with platinum doublets. By contrast, molecular targeted drugs may block important pathways that drive cancer progression and achieve long-term disease control. Conflicting results have demonstrated marginal benefit with EGFR inhibitors, anti-EGFR monoclonal antibodies and antiangiogenic strategies in unselected populations of patients with advanced NSCLC. However, patients with an EGFR mutation are likely to respond to agents that target this gene. Novel targeted therapies that interfere with insulin-like growth factor 1 receptor, or the EML4-ALK fusion protein have shown promising activity. Aberrations in other key signaling pathways and molecules, such as RAS/RAF/MEK, PI3K/AKT/mTOR, or MET kinase, have been identified as crucial targets, especially in resistant patients. Novel drugs aimed at these abnormalities are already in the clinic. This Review outlines the current state-of-the-art research for targeted therapy in NSCLC.
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PMID:Targeted therapy in non-small-cell lung cancer--is it becoming a reality? 2055 45

Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, WNT/beta-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success.
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PMID:The role of signaling pathways in the development and treatment of hepatocellular carcinoma. 2063 98

The mechanisms involved in the development of alcoholic liver disease (ALD) are not well established. We investigated the involvement of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) upregulation in mediating hepatic fat accumulation induced by chronic alcohol consumption. Chronic alcohol feeding caused fatty liver and increased hepatic DGAT2 gene and protein expression, concomitant with a significant suppression of hepatic MAPK/ERK kinase/extracellular regulated kinase 1/2 (MEK/ERK1/2) activation. In vitro studies demonstrated that specific inhibitors of the MEK/ERK1/2 pathway increased DGAT2 gene expression and triglyceride (TG) contents in HepG2 cells, whereas epidermal growth factor, a strong ERK1/2 activator, had the opposite effect. Moreover, chronic alcohol feeding decreased hepatic S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio, an indicator of disrupted transmethylation reactions. Mechanistic investigations revealed that N-acetyl-S-farnesyl-L-cysteine, a potent inhibitor of isoprenylcysteine carboxyl methyltransferase, suppressed ERK1/2 activation, followed by an enhanced DGAT2 expression and an elevated TG content in HepG2 cells. Lastly, we demonstrated that the beneficial effects of betaine supplementation in ALD were associated with improved SAM/SAH ratio, alleviated ERK1/2 inhibition, and attenuated DGAT2 upregulation. In conclusion, our data suggest that upregulation of DGAT2 plays an important role in the pathogenesis of ALD, and that abnormal methionine metabolism contributes, at least partially, to DGAT2 upregulation via suppression of MEK/ERK1/2 activation.
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PMID:Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease. 2073 40

Hepatocyte cell death is a characteristic indication in the development of non-alcoholic steatohepatitis (NASH); however, the underlying mechanism is still unclear. In this study, we examined the potential mechanism(s) involved in the development of liver injury using a methionine-choline deficient (MCD) diet feeding NASH model. Male C57BL6/J mice were fed MCD and methionine-choline sufficient (MCS) diet for two weeks before being killed. Our results showed that MCD diet feeding resulted in fatty liver and liver injury, evidenced by increased hepatic triglyceride (TG), plasma alanine aminotransferases and hepatic thiobarbituric acid reactive substances levels in MCD-fed mice. Furthermore, we found that MCD diet feeding caused remarkable suppression of hepatic extracellular signal-regulated kinases (ERK) 1/2 activation and increased transforming growth factor (TGF)-beta1 levels in plasma and the liver tissue. In vitro investigations showed that intracellular MEK/ERK1/2 activation status played a critical role in the determination of sensitivity of hepatocytes to TGF-beta1-induced cell death. HepG2 cells, otherwise resistant to TGF-beta1 killing due to high level of ERK1/2 activation, was sensitized by U0126, a specific MEK/ERK1/2 inhibitor, to TGF-beta1 cytotoxicity. H4IIEC3 cells, which have lower level of constitutive ERK1/2 activity, are sensitive to TGF-beta1-induced cell death. Lastly, we demonstrated that administration of epidermal growth factor, a strong ERK1/2 activator, to MCD-fed mice attenuated liver injury without affecting hepatic TG accumulation. Our findings demonstrated that hepatic ERK1/2 inactivation aggravates TGF-beta1-induced hepatotoxicity, which may contribute, at least in part, to the initiation of liver injury in NASH.
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PMID:Extracellular signal-regulated kinases 1/2 suppression aggravates transforming growth factor-beta1 hepatotoxicity: a potential mechanism for liver injury in methionine-choline deficient-diet-fed mice. 2096 16


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