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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Glucose-dependent insulinotropic polypeptide ( GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B ( PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression.

The hormone glucose-dependent insulinotropic polypeptide ( GIP) potently stimulates insulin secretion and promotes beta-cell proliferation and cell survival. In the present study we identified Forkhead (Foxo1)-mediated suppression of the bax gene as a critical component of the effects of GIP on cell survival. Treatment of INS-1(832/13) beta-cells with GIP resulted in concentration-dependent activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)/Foxo1 signaling module. In parallel studies, GIP decreased bax promoter activity. Serial deletion analysis of the bax promoter demonstrated that the region -682 to -320, containing FHRE-II (5AAAACAAACA), was responsible for GIP-mediated effects. Foxo1 bound to FHRE-II in gel mobility shift assays, and Foxo1-FHRE-II interactions conferred GIP responsiveness to the bax promoter. INS-1 cells incubated under proapoptotic and glucolipotoxic conditions demonstrated increased nuclear localization of Foxo1 and bax promoter activity and decreased cytoplasmic phospho- PKB/ Foxo1. GIP partially restored expression PKB/ Foxo1 and bax promoter activity. Similar protective effects were found with dispersed islet cells from C57BL/6 mice, but not with those from GIP receptor knock-out ( GIPR(-/-)) mice. GIP treatment reduced glucolipotoxicity- induced cell death in C57 BL/6 and Bax(-/-) islets, but not GIPR(-/-) mouse islets. Chronic treatment of Vancouver diabetic fatty Zucker rats with GIP resulted in down-regulation of Bax and up-regulation of Bcl-2 in pancreatic beta-cells. The results show that PI3K/ PKB/ Foxo1 signaling mediates GIP suppression of bax gene expression and that this module is a key pathway by which GIP regulates beta-cell apoptosis in vivo.[1]

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