Journal of Biological Chemistry
Volume 277, Issue 33, 16 August 2002, Pages 30010-30018
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MECHANISMS OF SIGNAL TRANSDUCTION
Involvement of c-Jun N-terminal Kinase in Oxidative Stress-mediated Suppression of Insulin Gene Expression*

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Oxidative stress, which is found in pancreatic β-cells in the diabetic state, suppresses insulin gene transcription and secretion, but the signaling pathways involved in the β-cell dysfunction induced by oxidative stress remain unknown. In this study, subjecting rat islets to oxidative stress activates JNK, p38 MAPK, and protein kinase C, preceding the decrease of insulin gene expression. Adenovirus-mediated overexpression of dominant-negative type (DN) JNK, but not the p38 MAPK inhibitor SB203580 nor the protein kinase C inhibitor GF109203X, protected insulin gene expression and secretion from oxidative stress. Moreover, wild type JNK overexpression suppressed both insulin gene expression and secretion. These results were correlated with changes in the binding of the important transcription factor PDX-1 to the insulin promoter; adenoviral overexpression of DN-JNK preserved PDX-1 DNA binding activity in the face of oxidative stress, whereas wild type JNK overexpression decreased PDX-1 DNA binding activity. Furthermore, to examine whether suppression of the JNK pathway can protect β-cells from the toxic effects of hyperglycemia, rat islets were infected with DN-JNK expressing adenovirus or control adenovirus and transplanted under renal capsules of streptozotocin-induced diabetic nude mice. In mice receiving DN-JNK overexpressing islets, insulin gene expression in islet grafts was preserved, and hyperglycemia was ameliorated compared with control mice. In conclusion, activation of JNK is involved in the reduction of insulin gene expression by oxidative stress, and suppression of the JNK pathway protects β-cells from oxidative stress.

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Published, JBC Papers in Press, May 14, 2002, DOI 10.1074/jbc.M202066200

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This work was supported in part by National Institutes of Health Grant DK-35449, by Diabetes and Endocrinology Research Center Grant DK-36836 of the Joslin Diabetes Center which allowed use of the RIA Core, Animal Core, and Media Core, the Diabetes Research and Wellness Foundation, and by an important group of private donors.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Recipient of a fellowship and grant from the Japan Society for the Promotion of Science. To whom correspondence may be addressed. E-mail: [email protected].

**

To whom correspondence may be addressed: Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, MA 02215. Tel.: 617-732-2581; Fax: 617-732-2650, E-mail: [email protected] or [email protected].