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J. Biol. Chem., Vol. 279, Issue 23, 24477-24484, June 4, 2004

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Reduction of Menin Expression Enhances Cell Proliferation and Is Tumorigenic in Intestinal Epithelial Cells^*

Christelle Ratineau, Christine Bernard, Gilles Poncet, Martine Blanc, Claire Josso, Sandra Fontanière, Alain Calender, Jean Alain Chayvialle, Chang-Xian Zhang, and Colette Roche¶

From the INSERM U45, 69008 Lyon, France, and CNRS FRE 2692, 69008 Lyon, France and the Institut Fédératif de Recherches 62, Faculté Laënnec, 69008 Lyon, France

Menin, the product of the tumor suppressor gene MEN1, is widely expressed in mammalian endocrine and non-endocrine tissues, including intestine. Its known abundant expression in several types of cells with high proliferative capacity led us to investigate the physiological function of the protein menin in intestinal epithelium, one of the most rapidly growing epithelia. Here we showed that the Men1 gene is mainly expressed in the crypt compartment of the proximal small intestine and that its expression was increased during fasting in vivo, both suggesting a role of menin in the control of cell growth. Indeed, specific reduction of menin expression by transfected antisense cDNA in the rat duodenal crypt-like cell line, IEC-17, increased cell proliferation. The latter is correlated to a loss of cell-cycle arrest in G₁ phase by resting cells and an overexpression of cyclin D1 and cyclin-dependent kinase (Cdk)-4. Furthermore, these cells lost the inhibition of proliferation induced by transforming growth factor-1, associated with a decrease of transforming growth factor- type II receptor expression. As a result of deregulated proliferation, antisense menin transfected IEC-17 cells became tumorigenic as shown in vitro as well as in vivo in immunosuppressed animals. These results indicate that menin contributes to proliferation control in intestinal epithelial cells. The present study reveals an unknown physiological function for menin in intestine that may be important in the regulation of epithelial homeostasis.

Received for publication, February 19, 2004 , and in revised form, March 26, 2004.

^* This work was supported by grants from Ligue Nationale contre le Cancer (to C. Ratineau) and Comité de la Drôme de la Ligue contre le Cancer (to C. Roche). 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.

^¶ To whom correspondence should be addressed: INSERM U45, Faculté de Médecine Laënnec, 7 Rue Guillaume Paradin, 69372 Lyon Cedex 8, France. Tel.: 33-4787-78603; Fax: 33-4787-78780; E-mail: croche{at}lyon.inserm.fr.

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