| First Author | Tanioka T | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 33 | Pages | 29388-96 |
| PubMed ID | 21700708 | Mgi Jnum | J:175918 |
| Mgi Id | MGI:5287931 | Doi | 10.1074/jbc.M110.192732 |
| Citation | Tanioka T, et al. (2011) Inducible nitric-oxide synthase and nitric oxide donor decrease insulin receptor substrate-2 protein expression by promoting proteasome-dependent degradation in pancreatic beta-cells: involvement of glycogen synthase kinase-3beta. J Biol Chem 286(33):29388-96 |
| abstractText | Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic beta-cells. Gene disruption of IRS-2 results in failure of the beta-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in beta-cells remains largely unknown. Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, has been implicated in beta-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in beta-cells. Here, we show that iNOS and NO donor decreased IRS-2 protein expression in INS-1/832 insulinoma cells and mouse islets, whereas IRS-2 mRNA levels were not altered. Interleukin-1beta (IL-1beta), alone or in combination with interferon-gamma (IFN-gamma), reduced IRS-2 protein expression in an iNOS-dependent manner without altering IRS-2 mRNA levels. Proteasome inhibitors, MG132 and lactacystin, blocked the NO donor-induced reduction in IRS-2 protein expression. Treatment with NO donor led to activation of glycogen synthase kinase-3beta (GSK-3beta) and c-Jun N-terminal kinase (JNK/SAPK) in beta-cells. Inhibition of GSK-3beta by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in beta-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated beta-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3beta-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expresssion may contribute to the progression and/or exacerbation of beta-cell failure in diabetes. |
