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J. Biol. Chem., Vol. 279, Issue 35, 36865-36875, August 27, 2004

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Cdx1 Inhibits Human Colon Cancer Cell Proliferation by Reducing -Catenin/T-cell Factor Transcriptional Activity^*

Rong-Jun Guo, Edward Huang, Toshihiko Ezaki, Neesha Patel, Kristen Sinclair, Jinling Wu, Peter Klein, Eun-Ran Suh, and John P. Lynch¶

From the Divisions of Gastroenterology and Hematology and Oncology, the Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The cessation of proliferation and the induction of differentiation are highly coordinated processes that occur continuously in the intestinal crypts. The homeodomain transcription factors Cdx1 and Cdx2 regulate intestine-specific gene expression and enterocyte differentiation. Their roles in regulating proliferation are recognized but remain poorly understood. Previously, we demonstrated that Cdx1 expression diminished the proliferation of human colon cancer cells in part by reducing cyclin D1 gene expression. In order to elucidate further the molecular mechanisms underlying this phenomenon, we first hypothesized that Cdx1 or Cdx2 expression reduces colon cancer cell proliferation by inhibiting -catenin/T-cell factor (TCF) transcriptional activity. We report that Cdx1 or Cdx2 expression does inhibit -catenin/TCF transcriptional activity in colon cancer cells. This inhibitory effect is dose-dependent and is observed in different colon cancer cell lines, and the degree of inhibition correlates with the ability of Cdx1 to reduce cell proliferation. Cdx1 expression does not alter -catenin protein levels or intracellular distribution nor does it induce an inhibitory TCF isoform. We also find that Cdx1 expression is lost in Min mouse polyps with increased nuclear localization of -catenin, suggesting that Cdx1 does not support -catenin-mediated transformation. Finally, we show that colon cancer cells effectively reduce Cdx2-mediated inhibition of Wnt/-catenin/TCF transcriptional activity when compared with other model systems. This suggests that colon cancer and possibly crypt epithelial cells can modulate the effects of Cdx2 on -catenin signaling and proliferation. We conclude that Cdx1 and Cdx2 inhibit colon cancer cell proliferation by blocking -catenin/TCF transcriptional activity.

Received for publication, May 11, 2004 , and in revised form, June 15, 2004.

^* This work was supported in part by NIDDK Grants DK02695-02, DK047437-09, and DK062819-01 (to J. P. L.) from the National Institutes of Health, a Pilot Project award from the Center for Molecular Studies in Digestive and Liver Disease (to J. P. L.), and Grant P30-DK50306 from the Morphology, Cell Culture, and Molecular Biology Core Facilities of the NIDDK/National Institutes of Health Center for Molecular Studies in Digestive and Liver Disease at the University of Pennsylvania, and in part by American Cancer Society Grant IRG-78-002-25 and a Glaxo Institute for Digestive Health Research award (to J. P. L.). 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 and reprints should be addressed: Division of Gastroenterology/660 CRB, 415 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-0161; Fax: 215-573-1884; E-mail: lynchj{at}mail.med.upenn.edu.

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