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J. Biol. Chem., Vol. 280, Issue 38, 32835-32842, September 23, 2005

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Expression of an Uncleavable N-terminal RasGAP Fragment in Insulin-secreting Cells Increases Their Resistance toward Apoptotic Stimuli without Affecting Their Glucose-induced Insulin Secretion^*

Jiang-Yan Yang, Joël Walicki, Amar Abderrahmani, Marion Cornu, Gérard Waeber¶, Bernard Thorens, and Christian Widmann1

From the Department of Cellular Biology and Department of Physiology, Faculty of Biology and Medicine, Lausanne University, Bugnon 9, Lausanne 1005, Switzerland and the ^¶Department of Internal Medicine, Lausanne University Hospital, Lausanne 1011, Switzerland

Apoptosis of pancreatic cells is implicated in the onset of type 1 and type 2 diabetes. Consequently, strategies aimed at increasing the resistance of cells toward apoptosis could be beneficial in the treatment of diabetes. RasGAP, a regulator of Ras and Rho GTPases, is an atypical caspase substrate, since it inhibits, rather than favors, apoptosis when it is partially cleaved by caspase-3 at position 455. The antiapoptotic signal generated by the partial processing of RasGAP is mediated by the N-terminal fragment (fragment N) in a Ras-phosphatidylinositol 3-kinase-Akt-dependent, but NF-B-independent, manner. Further cleavage of fragment N at position 157 abrogates its antiapoptotic properties. Here we demonstrate that an uncleavable form of fragment N activates Akt, represses NF-B activity, and protects the conditionally immortalized pancreatic insulinoma TC-tet cell line against various insults, including exposure to genotoxins, trophic support withdrawal, and incubation with inflammatory cytokines. Fragment N also induced Akt activity and protection against cytokine-induced apoptosis in primary pancreatic islet cells. Fragment N did not alter insulin cell content and insulin secretion in response to glucose. These data indicate that fragment N protects cells without affecting their function. The pathways regulated by fragment N are therefore promising targets for antidiabetogenic therapy.

Received for publication, April 14, 2005 , and in revised form, July 5, 2005.

^* This work was supported by Swiss National Science Foundation Grant 3100-066797/1 and the Botnar Foundation (Lausanne, Switzerland). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cellular Biology and Morphology, Biology and Medicine Faculty, University of Lausanne, Bugnon 9, 1005 Lausanne, Switzerland. Tel.: 41-21-692-5123; Fax: 41-21-692-5255; E-mail: Christian.Widmann{at}unil.ch.

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