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http://purl.uniprot.org/citations/25810038http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25810038http://www.w3.org/2000/01/rdf-schema#comment"

Aims/hypothesis

The role of the redox adaptor protein p66(Shc) as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated.

Methods

The effects of the FA palmitate on p66(Shc) expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66(Shc) expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66(Shc) was investigated using pancreatic islets from p66 (Shc-/-) mice and in INS-1E cells with knockdown of p66(Shc) or overexpression of wild-type and phosphorylation-defective p66(Shc). Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method.

Results

Palmitate induced a selective increase in p66(Shc) protein expression and phosphorylation on Ser(36) and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66(Shc) expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 (Shc-/-) mice and following p66 (Shc) knockdown in INS-1E cells; by contrast, overexpression of p66(Shc), but not that of the phosphorylation-defective p66(Shc) mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66(Shc) were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser(36) and associated with generation of ROS. p66(Shc) protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors.

Conclusions/interpretation

p53-dependent augmentation of p66(Shc) expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.org/dc/terms/identifier"doi:10.1007/s00125-015-3563-2"xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Bugliani M."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Marchetti P."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Avogaro A."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Giorgino F."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Laviola L."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Giorgio M."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Biondi G."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Carchia E."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Perrini S."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Natalicchio A."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Fadini G.P."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Cignarelli A."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Leonardini A."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Tortosa F."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Labarbuta R."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/author"Marrano N."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/name"Diabetologia"xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/pages"1260-1271"xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/title"The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells."xsd:string
http://purl.uniprot.org/citations/25810038http://purl.uniprot.org/core/volume"58"xsd:string
http://purl.uniprot.org/citations/25810038http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/25810038
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