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
| Autor: | Tanioka, Toshihiro, Tamura, Yoshiaki, Fukaya, Makiko, Shinozaki, Shohei, Mao, Ji, Kim, Minhye, Shimizu, Nobuyuki, Kitamura, Tadahiro, Kaneki, Masao |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Glycogen Synthase Kinase 3 -- antagonists & inhibitors -- genetics -- metabolism
Insulin Receptor Substrate Proteins -- biosynthesis -- genetics Enzyme Activation -- drug effects -- physiology Nitric Oxide Synthase Type II -- genetics -- metabolism Sciences bio-médicales et agricoles Rats Mice Interleukin-1beta -- genetics -- metabolism Gene Expression Regulation -- drug effects -- physiology Cell Line Tumor Proteasome Endopeptidase Complex -- genetics -- metabolism Leupeptins -- pharmacology Animals Humans Interferon-gamma -- genetics -- metabolism Anthracenes -- pharmacology Cysteine Proteinase Inhibitors -- pharmacology Acetylcysteine -- analogs & derivatives -- pharmacology Insulin-Secreting Cells -- cytology -- metabolism JNK Mitogen-Activated Protein Kinases -- antagonists & inhibitors -- genetics -- metabolism Nitric Oxide Donors -- pharmacology Proteasome Inhibitors |
| Zdroj: | The Journal of biological chemistry, 286 (33 |
| Popis: | Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic β-cells. Gene disruption of IRS-2 results in failure of the β-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in β-cells remains largely unknown. Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, has been implicated in β-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in β-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-1β (IL-1β), alone or in combination with interferon-γ (IFN-γ), 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-3β (GSK-3β) and c-Jun N-terminal kinase (JNK/SAPK) in β-cells. Inhibition of GSK-3β by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in β-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated β-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3β-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expression may contribute to the progression and/or exacerbation of β-cell failure in diabetes. Journal Article Research Support, N.I.H. Extramural Research Support, Non-U.S. Gov't info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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