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J. Biol. Chem., Vol. 281, Issue 37, 26932-26942, September 15, 2006

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MicroRNA-9 Controls the Expression of Granuphilin/Slp4 and the Secretory Response of Insulin-producing Cells^*

Valérie Plaisance, Amar Abderrahmani, Véronique Perret-Menoud, Patrick Jacquemin^¶1, Frédéric Lemaigre^¶, and Romano Regazzi²

From the Department of Cell Biology and Morphology, University of Lausanne, Rue de Bugnon 9, 1005 Lausanne, Switzerland, the Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1005 Lausanne, Switzerland, and the ^¶Hormone and Metabolic Research Unit, Université catholique de Louvain, Institute of Cellular Pathology, 1200 Brussels, Belgium

Insulin release from pancreatic -cells plays an essential role in blood glucose homeostasis. Several proteins controlling insulin exocytosis have been identified, but the factors determining the expression of the components of the secretory machinery of -cells remain largely unknown. MicroRNAs are newly discovered small non-coding RNAs acting as repressors of gene expression. We found that overexpression of mir-9 in insulin-secreting cells causes a reduction in exocytosis elicited by glucose or potassium. We show that mir-9 acts by diminishing the expression of the transcription factor Onecut-2 and, in turn, by increasing the level of Granuphilin/Slp4, a Rab GTPase effector associated with -cell secretory granules that exerts a negative control on insulin release. Indeed, electrophoretic mobility shift assays, chromatin immunoprecipitation, and transfection experiments demonstrated that Onecut-2 is able to bind to the granuphilin promoter and to repress its transcriptional activity. Moreover, we show that silencing of Onecut-2 by RNA interference increases Granuphilin expression and mimics the effect of mir-9 on stimulus-induced exocytosis. Our data provide evidence that in insulin-producing cells adequate levels of mir-9 are mandatory for maintaining appropriate Granuphilin levels and optimal secretory capacity.

Received for publication, February 8, 2006 , and in revised form, June 12, 2006.

^* This work was supported in part by the Swiss National Foundation (Grant 3100A0-105425 to A. A. and Grant 3200B0-101746 to R. R.), Alfediam-Takeda (to V. P.), the Belgian State Program on Interuniversity Poles of Attraction, the French Community of Belgium, and the Belgian Fund for Scientific Medical Research. 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 Research Associate of the National Fund for Scientific Research (Belgium).

² To whom correspondence should be addressed: Dept. of Cell Biology and Morphology, Rue du Bugnon 9, 1005 Lausanne, Switzerland. Tel.: 41-21-692-5280; Fax: 41-21-692-5255; E-mail: Romano.Regazzi{at}unil.ch.

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