1,721,202 research outputs found
Il ruolo dello stress del reticolo endoplasmico nell'insulino-resistenza indotta dall'iperglicemia cronica nel tessuto muscolare scheletrico.
No full textThe interaction between the Insulin-Like Growth Factor 1 Receptor and PDK1 as potential therapeutic target in neoplastic cells
No full textControl of breast cancer cell growth by adipocyte-released factors.
No full textObesity is one of the most challenging and growing health problems, worldwide. Epidemiologic studies now provide compelling evidence that obesity is a risk factor for both cancer incidence and mortality. In particular, obesity increases rates of breast cancer in postmenopausal women and is associated with poorer survival and increased recurrence of disease, regardless the menopausal status. It is now becoming clear that adipocytes, which represent very abundant cell types surrounding cancer cells, particularly in the mammary gland, could influence several aspects of tumorigenesis, from promoting local invasion to angiogenesis and metastasis. However, the molecular mechanisms involved in the adipocyte control of the malignant phenotype remain poorly understood. I have studied the mechanisms by which adipocytes may integrate metabolic and nutritional inputs and produce signals affecting breast cancer cell phenotypes. I have obtained evidence that conditioned media from 3T3-L1 cells induce growth of MCF7 cells, in a time-dependent manner. In particular, conditioned media from fully differentiated adipocytes are 2-fold more effective than conditioned media from pre-adipocytes in inducing MCF7 growth. Cell cycle analysis by flow cytometry revealed that these changes are due to reduced apoptosis instead of increased proliferation. Pre-incubation with low glucose medium or insulin reduces the effect of adipocyte conditioned media on MCF7 growth. Cytokines/growth factors screening of conditioned media from pre-adipoctyte and adipocyte, cultured in presence or in absence of low glucose medium or insulin, revealed that KC, RANTES and IGF1 could be good candidates in mediating pro-tumorigenic effect of adipocyte conditioned media. Moreover, IGF1R inhibitor AG1024 is able to revert adipocyte conditioned media effect. In conclusion, adipocyte-derived factors promote breast cancer cell growth inhibiting the apoptosis. This effect is more evident in adipocytes than in pre-adipocytes and is altered by insulin or nutritional factors such as glucose. The effects are likely mediated by IGF-1
Atypical protein kinase C dysfunction and the metabolic syndrome.
No full textAtypical protein kinase C isoforms are crucial mediators of glucose uptake in insulin-sensitive tissues. In humans, decreased muscular atypical protein kinase C activity has been found in insulin-resistant states. In a recent report by Farese et al., a novel mouse model is described, featuring selective ablation of an atypical protein kinase C, protein kinase Clambda, in muscle. Phenotyping of these mice demonstrated systemic insulin resistance, reduced glucose tolerance, abdominal obesity and dyslipidemia, thus mimicking human metabolic syndrome. Intriguingly, therefore, atypical protein kinase Clambda deficiency might be sufficient to induce metabolic syndrome in mice
The role of protein kinase C isoforms in insulin action.
No full textInsulin action on target tissues is mediated by specific tyrosine kinase receptors. Upon ligand binding insulin receptors autophosphorylate and phosphorylate intracellular substrates on tyrosine residues. These early events of insulin action are followed by the activation of a number of enzymes, including protein kinase C (PKC). At least 14 PKC isoforms have been identified and cloned to date. PKCs appear to play dual roles in insulin signaling. For instance, they are involved in transduction of specific insulin signals but also contribute to the generation of insulin resistance. In this article, we will analyze the experimental evidence addressing the mechanism by which insulin might activate individual PKC isoforms as well as the role of single PKCs in insulin-induced bioeffects
Mezzi terapeutici e diagnostici per i papillomi.
No full textLa presente invenzione descrive metodi e mezzi diagnostici, nonchè medicamenti nella diagnosi, prognosi e cura del papilloma. tali metodi si basano sulla determinazione dei livelli di PED/PEA-15 e i medicamenti si basano su oligonucleotidi antisenso. Si descrive anche in un animale transgenico non umano che esprime elevati livelli di PED/PEA-15 ed è utile come modello per lo studio del papilloma e valutazione delle cure
Antiphosphotyrosine immunoprecipitation of an insulin-stimulated receptor phosphatase activity from FRTL5 cells
No full textAntiphosphotyrosine immunoprecipitation of an insulin-stimulated receptor phosphatase activity from FRTL5 cells.
No full textPhosphotyrosine-containing proteins (PYPs) from FRTL5 epithelial cells were immunoprecipitated with Sepharose-linked phosphotyrosine antibody and phosphorylated in vitro with insulin and insulin-like growth factor-I (IGF-I) receptor kinases. Insulin preactivation of the kinases resulted in increased phosphorylation of a single 175,000 mol wt PYP (p175) beside insulin and IGF-I receptors. Phosphorylation of both p175 and receptors exhibited almost identical time courses and insulin dose responses, suggesting that p175 may serve as a substrate for the insulin and IGF-I receptor kinases. Preincubation of autophosphorylated receptors with PYPs derived from insulin-stimulated cells decreased 32P-labeled receptor precipitation by antiphosphotyrosine-Sepharose by 50-70% compared to that obtained upon preincubation with PYPs from unstimulated cells. This effect was not the result of PYP-receptor competition, was observed on both in vivo and in vitro phosphorylated receptors, and was almost completely blocked by 100 microM sodium vanadate, suggesting PYP copurification of a phosphotyrosine phosphatase. No phosphatase was recovered in lysates from insulin-unstimulated cells. Maximum activity was detected after 2 min of insulin stimulation, decreasing by more than 50% after 30 min. Antiphosphotyrosine recovery of p175 from cell lysates exhibited almost identical insulin dependency. Complete recovery of both p175 and phosphatase activity was obtained after receptor immunodepletion of the extracts. Thus, a receptor phosphatase activity from insulin-stimulated FRTL5 cells is retained on an antiphosphotyrosine affinity matrix and correlates with phosphorylation of the p175 substrate for the insulin and IGF-I receptor kinases
Thyrotropin regulates autophosphorylation and kinase activity in both the insulin and the insulin-like growth factor-I receptors in FRTL5 cells.
No full textTSH regulation of insulin and insulin-like growth factor-I (IGF-I) receptor kinases has been studied in FRTL5 cultured thyroid cells. Preincubation of intact cells with TSH increased by 2-fold insulin and IGF-I receptor autophosphorylation and phosphorylation of the p175 endogenous substrate for the receptors. Enhanced phosphorylations reached a maximum within 30 min, were maintained for 30 min more, and vanished after 120 min of TSH incubation. TSH dose-responses exhibited half-maximal and maximal effects at 1 and 10 pM, respectively. In vitro, insulin as well as IGF-I receptors purified from cells treated with 10 pM TSH also exhibited 2-fold enhanced receptor autophosphorylation and kinase activity toward the exogenous substrate poly(Glu,Tyr) (4:1). At variance with TSH, cell incubation with either 8-bromo-cAMP or the protein kinase-C activator 12-O-tetradecanoylphorbol-13-acetate inhibited insulin and IGF-I receptor kinases. In intact cells, TSH stimulation of insulin and IGF-I receptor kinases was accompanied by enhanced turnover of phosphate on autophosphorylated receptors, increased receptor tyrosine phosphorylation, and decreased receptor serine/threonine phosphorylation in response to insulin. Incubation of in vivo labeled insulin and IGF-I receptors with extracts from TSH-treated cells also decreased receptor phosphoserine and phosphothreonine content. Furthermore, preincubation of insulin and IGF-I receptors with extracts from TSH-treated cells enhanced in vitro autophosphorylation. The latter effect was inhibited by the serine/threonine phosphatase inhibitors fluoride and okadaic acid, but not by the tyrosine phosphatase inhibitor vanadate. The data suggest that in FRTL5 cells, TSH induces the activity of a Ser/Thr protein phosphatase, which dephosphorylates insulin and IGF-I receptors and enhances their endogenous kinases
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