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J. Biol. Chem., Vol. 282, Issue 40, 29394-29400, October 5, 2007

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Retinoic Acid Inhibits -Catenin through Suppression of Cox-2

A ROLE FOR TRUNCATED ADENOMATOUS POLYPOSIS COLI^*

Annie L. Eisinger, Lincoln D. Nadauld, Dawne N. Shelton, Stephen M. Prescott¹, Diana M. Stafforini², and David A. Jones^¶3

From the Departments of Oncological Sciences and ^¶Medicinal Chemistry and the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112

Mutations in adenomatous polyposis coli (APC) underlie the earliest stages of colorectal carcinogenesis. Consequences of APC mutation include stabilization of -catenin, dysregulation of cyclooxygenase-2 (COX-2) expression, and loss of retinoic acid production, events with poorly defined interactions. Here we showed that treatment of zebrafish expressing a truncated form of Apc with either retinoic acid or a selective COX-2 inhibitor decreased -catenin protein levels and downstream signaling events. Interestingly, the destruction of -catenin in apc mutant embryos following Cox-2 inhibition required the presence of truncated Apc. These findings support roles for retinoic acid and Cox-2 in regulating the stability of -catenin following Apc loss. Furthermore, truncated Apc appears to retain the ability to target -catenin for destruction, but only in the absence of Cox-2 activity. This novel function of truncated Apc may provide a molecular basis for the efficacy of COX-2 inhibitors in the treatment of colon cancer.

Received for publication, October 17, 2006 , and in revised form, August 1, 2007.

^* This work was supported by the American Cancer Society, the NCI, National Institutes of Health, and Huntsman Cancer Foundation. 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 Present address: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.

² To whom correspondence may be addressed: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112. Tel.: 801-585-3402; E-mail: diana.stafforini{at}hci.utah.edu. ³ To whom correspondence may be addressed. Tel.: 801-585-6107; E-mail: david.jones{at}hci.utah.edu.

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