| pubmed-article:21700708 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0030274 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C1171362 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0017932 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0132555 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0600437 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0033414 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0381451 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0699900 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0243125 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0205263 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C0547047 | lld:lifeskim |
| pubmed-article:21700708 | lifeskim:mentions | umls-concept:C1314939 | lld:lifeskim |
| pubmed-article:21700708 | pubmed:issue | 33 | lld:pubmed |
| pubmed-article:21700708 | pubmed:dateCreated | 2011-8-15 | lld:pubmed |
| pubmed-article:21700708 | pubmed:abstractText | Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic ?-cells. Gene disruption of IRS-2 results in failure of the ?-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in ?-cells remains largely unknown. Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, has been implicated in ?-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in ?-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-1? (IL-1?), alone or in combination with interferon-? (IFN-?), 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-3? (GSK-3?) and c-Jun N-terminal kinase (JNK/SAPK) in ?-cells. Inhibition of GSK-3? by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in ?-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated ?-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3?-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expression may contribute to the progression and/or exacerbation of ?-cell failure in diabetes. | lld:pubmed |
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| pubmed-article:21700708 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:21700708 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:21700708 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:21700708 | pubmed:month | Aug | lld:pubmed |
| pubmed-article:21700708 | pubmed:issn | 1083-351X | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:TamuraYoshiak... | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:KitamuraTadah... | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:KanekiMasaoM | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:ShimizuNobuyu... | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:TaniokaToshih... | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:KUSMM | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:FukayaMakikoM | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:ShinozakiShoh... | lld:pubmed |
| pubmed-article:21700708 | pubmed:author | pubmed-author:KimMinhyeM | lld:pubmed |
| pubmed-article:21700708 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:21700708 | pubmed:day | 19 | lld:pubmed |
| pubmed-article:21700708 | pubmed:volume | 286 | lld:pubmed |
| pubmed-article:21700708 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:21700708 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:21700708 | pubmed:pagination | 29388-96 | lld:pubmed |
| pubmed-article:21700708 | pubmed:dateRevised | 2011-11-2 | lld:pubmed |
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| pubmed-article:21700708 | pubmed:year | 2011 | lld:pubmed |
| pubmed-article:21700708 | pubmed:articleTitle | 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. | lld:pubmed |
| pubmed-article:21700708 | pubmed:affiliation | Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. | lld:pubmed |
| pubmed-article:21700708 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:21700708 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| pubmed-article:21700708 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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