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J. Biol. Chem., Vol. 283, Issue 14, 9454-9464, April 4, 2008

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A Novel Role for Villin in Intestinal Epithelial Cell Survival and Homeostasis^*

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Apoptosis is a key regulator for the normal turnover of the intestinal mucosa, and abnormalities associated with this function have been linked to inflammatory bowel disease and colorectal cancer. Despite this, little is known about the mechanism(s) mediating intestinal epithelial cell apoptosis. Villin is an actin regulatory protein that is expressed in every cell of the intestinal epithelium as well as in exocrine glands associated with the gastrointestinal tract. In this study we demonstrate for the first time that villin is an epithelial cell-specific anti-apoptotic protein. Absence of villin predisposes mice to dextran sodium sulfate-induced colitis by promoting apoptosis. To better understand the cellular and molecular mechanisms of the anti-apoptotic function of villin, we overexpressed villin in the Madin-Darby canine kidney Tet-Off epithelial cell line to demonstrate that expression of villin protects cells from apoptosis by maintaining mitochondrial integrity thus inhibiting the activation of caspase-9 and caspase-3. Furthermore, we report that the anti-apoptotic response of villin depends on activation of the pro-survival proteins, phosphatidylinositol 3-kinase and phosphorylated Akt. The results of our studies shed new light on the previously unrecognized function of villin in the regulation of apoptosis in the gastrointestinal epithelium.

Received for publication, September 24, 2007 , and in revised form, December 19, 2007.

^* This work was supported by NIDDK Grants DK-65006 and DK-54755 (to S. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3 and Videos 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Physiology, the University of Tennessee Health Science Center, Nash 402, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-3410; Fax: 901-448-3505; E-mail: skhurana{at}utmem.edu.

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