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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of 5alpha-dihydrotestosterone (DHT) on insulin-stimulated granulosa cell proliferation was examined using cyclin D2 mRNA as a marker. Granulosa cells from 3-d estradiol-treated immature rats showed a concentration-dependent increase in cyclin D2 mRNA expression in response to insulin. Exposure to DHT reduced the insulin-stimulated cyclin D2 mRNA expression. Inhibition of the two insulin-signaling pathways, ERK and phosphatidylinositol 3 kinase (PI3 kinase), by using specific inhibitors, also reduced this insulin-stimulated response. These results suggest that both ERK and PI3 kinase signaling are involved in insulin stimulated granulosa cell proliferation. DHT exposure resulted in reduced insulin-stimulated ERK phosphorylation. DHT treatment also reduced the insulin mediated insulin receptor substrate-1 and Raf-1 phosphorylation, the upstream molecules of ERK in insulin signaling pathway. Additionally, inhibition of insulin stimulated PI3 kinase activation reduced ERK phosphorylation. The present study therefore shows that the inhibitory effect of DHT on insulin-stimulated granulosa cell proliferation occurs early in the signaling pathway at the level of insulin receptor substrate-1 phosphorylation, leading to reduced ERK phosphorylation and subsequent inhibition of cyclin D2 mRNA expression.
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PMID:Dihydrotestosterone inhibits insulin-stimulated cyclin D2 messenger ribonucleic acid expression in rat ovarian granulosa cells by reducing the phosphorylation of insulin receptor substrate-1. 1621 Mar 59

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.
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PMID:Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. 1624 41

Polycystic ovary syndrome (PCOS) is a common heterogenous endocrine disorder associated with amenorrhoea (or oligomenorrhoea), hyperandrogenism, hirsutism, obesity, insulin resistance, and an approximately 7-fold increased risk of type 2 diabetes mellitus (NIDDM - non-insulin dependent diabetes mellitus). It is a leading cause of female infertility. The prevalence of PCOS among reproductive-age women has been estimated at 4%-12%. Familial aggregation of this syndrome is well established. There are also ethnic and racial variations in the prevalence of the syndrome and its symptoms. Multiple biochemical pathways have been implicated in the pathogenesis of PCOS. Several genes from these pathways have been tested include genes involved in steroid hormone biosynthesis and metabolism (StAR, CYP11, CYP17, CYP19 HSD17B1-3, HSD3B1-2), gonadotropin and gonadal hormones action (ACTR1, ACTR2A-B, FS, INHA, INHBA-B, INHC, SHBG, LHCGR, FSHR, MADH4, AR), obesity and energy regulation (MC4R, OB, OBR, POMC, UCP2-3), insulin secretion and action (IGF1, IGF1R, IGFBPI1-3, INS VNTR, IR, INSL, IRS1-2, PPARG) and many others. Most women with PCOS, both obese and lean, have a degree of insulin resistance. The minisatellite of insulin gene (INS VNTR), especially class III alleles and III/III genotypes might not only determine the predisposition to anovulatory PCOS but also the concomitant risk for development of type 2 diabetes. The function of the insulin receptor (IR) is probably normal in woman with PCOS. However abnormal serine phosphorylation in the receptor may impair signal transduction accounting for a post-binding defect in insulin action. Serine phosphorylation is also involved in the postranslational regulation of 17,20-lyase activity (CYP17). There may be a common aetiology for both insulin resistance and hyperandrogenism. Polymorphic alleles of both IRS-1 and IRS-2 (insulin receptor substrate 1 - 2), alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. There is no evidence to suggest that follistatin gene polymorphisms play a role in the pathogenesis of insulin resistance in PCOS women. PCOS appears to be associated with the absence of the four-repeat-units allele in a polymorphic region of pentanucleotide (TTTTA)n repeats within CYP11A gene, which encodes cytochrome P450scc. It has been hypothesized that up-regulation of this enzyme could lead to increased androgen production. There is no evidence of any association of alleles of CYP19 gene (encoding cytochrome P450arom) with PCOS. Association exists between androgen receptor gene (AR) polymorphisms an androgens action in PCOS. Increased hirustism and decreased CAG repeat length within AR gene has been also demonstrated in women with normal testosterone levels. Expression of estrogen receptor (ERs) as well as 5-alpha-reeducates (SRD5A1-2 genes) activity was analysed in granulosa (GC) and theca cells (TC). The results of this study demonstrate that there are significant alterations in the expression of ERalpha and ERbeta in PCOS that may be related to abnormal follicular development. On the other hand elevated SRD5A activity in polycystic ovaries supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of the syndrome. The genetic aetiology of PCOS remains unknown. There are a number of interlinking factors that affects expression of PCOS. Single cause of PCOS is unlikely. Other possible mechanisms in pathogenesis of PCOS are discussed.
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PMID:[Genetic aspects of polycystic ovary syndrome]. 1635 Jul 21

Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases-diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between diabetes mellitus and hypertension.
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PMID:The multi-faceted cross-talk between the insulin and angiotensin II signaling systems. 1638 35

Signaling through the insulin-like growth factor I receptor (IGF-IR) axis is essential for transformation by many dominantly acting oncoproteins. However, the mechanism by which IGF-IR contributes to oncogenesis remains unknown. To examine this, we compared transformation properties of the oncogenic ETV6-NTRK3 (EN) chimeric tyrosine kinase in IGF-IR-null R- mouse embryo fibroblasts with R- cells engineered to reexpress IGF-IR (R+ cells). We previously showed that R- cells expressing EN (R- EN cells) are resistant to transformation but that transformation is restored in R+ cells. We now show that while R- EN cells have intact Ras-extracellular signal-regulated kinase signaling and cell cycle progression, they are defective in phosphatidylinositol-3-kinase (PI3K)-Akt activation and undergo detachment-induced apoptosis (anoikis) under anchorage-independent conditions. In contrast, R+ cells expressing EN (R+ EN cells) suppress anoikis and are fully transformed. The requirement for IGF-IR in R- EN cells is overcome by ectopic expression of either activated Akt or a membrane-targeted form of EN. Moreover, compared to R- EN cells, R+ EN cells show a dramatic increase in membrane localization of insulin receptor substrate 1 (IRS-1) in association with EN. Since EN is known to bind IRS-1 as an adaptor protein, our findings suggest that IGF-IR may function to localize EN/IRS-1 complexes to cell membranes, in turn facilitating PI3K-Akt activation and suppression of anoikis.
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PMID:The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase. 1647 96

Recent evidence indicates that growth hormone (GH) is involved in liver regeneration. To test whether insulin-like growth factor I (IGF-I) mediates this effect, we studied liver regeneration induced by partial hepatectomy in liver-specific IGF type 1 receptor knockout (LIGFREKO) mice. The absence of IGF-1R caused a significant decrease in hepatocyte proliferation in males (-52%), but not in females, as assessed by Ki67 immunohistochemistry. Cyclin D1 and cyclin A protein levels in the livers of LIGFREKO males were only half those in controls, indicating that cyclin induction during liver regeneration is dependent on IGF-1R signaling. Analyzing the signaling cascade initiated by IGF-1R, we observed a lack of IRS-1 induction in LIGFREKO livers. In contrast, the induction of IRS-2 synthesis was similar in LIGFREKO and control groups, suggesting the existence of differential regulation of IRS synthesis during liver regeneration. Regenerating livers from LIGFREKO animals also showed significantly less activated ERKs than controls. Our findings demonstrate that IGF-1R makes a significant contribution to liver regeneration. Using the LIGFREKO model, we provide new evidence that IGF-1R/IRS-1/ERK signaling may be the intracellular pathway controlling the cell cycle via cyclin D1 and cyclin A in the regenerating liver.
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PMID:Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout. 1648 30

Blockade of growth hormone (GH), decreased insulin-like growth factor-1 (IGF1) action and increased insulin sensitivity are associated with life extension and an apparent slowing of the aging process. We examined expression of genes involved in insulin action, IR, IRS1, IRS2, IGF1, IGF1R, GLUT4, PPARs and RXRs in the hearts of normal and GHR-/- (KO) mice fed ad libitum or subjected to 30% caloric restriction (CR). CR increased the cardiac expression of IR, IRS1, IGF1, IGF1R and GLUT4 in normal mice and IRS1, GLUT4, PPARalpha and PPARbeta/delta in GHR-KO animals. Expression of IR, IRS1, IRS2, IGF1, GLUT4, PPARgamma and PPARalpha did not differ between GHR-KO and normal mice. These unexpected results suggest that CR may lead to major modifications of insulin action in the heart, but high insulin sensitivity of GHR-KO mice is not associated with alterations in the levels of most of the examined molecules related to intracellular insulin signaling.
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PMID:Caloric restriction and growth hormone receptor knockout: effects on expression of genes involved in insulin action in the heart. 1652 78

Grb14 is a molecular adaptor that binds to the activated insulin receptor (IR) and negatively regulates insulin signaling. We have studied the dynamics of interaction of the IR with Grb14, in real time, in living HEK cells, using bioluminescence resonance energy transfer (BRET). Insulin rapidly and dose-dependently stimulated this interaction. Removing insulin from the incubation medium only resulted in a modest decrease in BRET signal, indicating that the interaction between the IR and Grb14 can remain long after insulin stimulus has disappeared. BRET saturation experiments indicated that insulin markedly increases the affinity between IR and Grb14, resulting in recruitment of the adaptor to the activated IR. In addition, using both BRET and co-immunoprecipitation experiments, we demonstrated that insulin induced the dimerization of Grb14, most likely as a result of simultaneous binding of two Grb14 molecules on the activated IR. We also investigated the relationships between IR, Grb14 and the protein tyrosine phosphatase PTP1B. We observed that insulin-induced BRET between the IR and PTP1B was markedly reduced by Grb14, suggesting that Grb14 regulated this interaction in living cells. Using site-specific antibodies against phosphorylated tyrosines of the insulin receptor, we showed that Grb14 protected the three tyrosines of the kinase loop from dephosphorylation by PTP1B, while favouring dephosphorylation of tyrosine 972. This resulted in decreased IRS-1 binding to the IR and decreased activation of the ERK pathway. Our work suggests that Grb14 may regulate signalling through the insulin receptor by controlling its tyrosine-dephosphorylation in a site-specific manner.
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PMID:Interaction between the insulin receptor and Grb14: a dynamic study in living cells using BRET. 1693 61

Vanadium(IV) oxo-bis(maltolato) (BMOV), an organovanadium compound, is a potent insulinomimetic agent and improves glucose homeostasis in various models of diabetes. We have shown previously that BMOV stimulates the phosphorylation of PKB which may contribute as one of the mechanisms for the insulinomimetic effect of this compound. However, the upstream mechanism of BMOV-induced PKB phosphorylation remains elusive. Therefore, in this study, we examine the upstream events leading to BMOV-induced PKB phosphorylation in HepG2 cells. Since BMOV is an inhibitor of protein tyrosine phosphatases and through enhanced tyrosine phosphorylation may activate various protein tyrosine kinases (PTK), we have investigated the potential role of different receptor or nonreceptor PTK in mediating BMOV-induced PKB phosphorylation. Among several pharmacological inhibitors that were tested, only AG1024, a selective inhibitor of IGF-1R-PTK, almost completely blocked BMOV-stimulated phosphorylation of PKB. In contrast, AG1295 and AG1478, specific inhibitors of PDGFR and EGFR, respectively, were unable to block the BMOV response. Moreover, efficient reduction of the level of IGF-1R protein expression by antisense oligonucleotides (ASO) attenuated BMOV-induced PKB phosphorylation. BMOV-induced PKB phosphorylation was associated with an increased level of tyrosine phosphorylation of the IRbeta subunit, IGF-1Rbeta subunit, IRS-1, and p85alpha subunit of PI3-kinase. However, this response was independent of IR-PTK activity because in cells overexpressing a PTK-inactive form of IR, insulin response was attenuated while the effect of BMOV remained intact. A role of PKC in BMOV-induced response was also tested. Pharmacological inhibition with chelerythrine, a nonselective PKC inhibitor, or rottlerin, a PKCdelta inhibitor, as well as chronic treatment with PMA attenuated BMOV-induced PKB phosphorylation. In contrast, GO6976 and RO31-8220 PKCalpha/beta selective inhibitors failed to alter the BMOV effect. Taken together, these data suggest that IGF-1R and PKCdelta are required to stimulate PKB phosphorylation in response to BMOV in HepG2 cells and provide new insights into the molecular mechanism by which this compound exerts its insulinomimetic effects.
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PMID:Involvement of insulin-like growth factor type 1 receptor and protein kinase Cdelta in bis(maltolato)oxovanadium(IV)-induced phosphorylation of protein kinase B in HepG2 cells. 1698 20

Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1beta level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. We demonstrated that IL-1beta slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1beta slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.
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PMID:Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. 1703 56


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