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Originally published In Press as doi:10.1074/jbc.M208924200 on September 10, 2002

J. Biol. Chem., Vol. 277, Issue 47, 45028-45033, November 22, 2002
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Tumor Suppressor Activity of AP2alpha Mediated through a Direct Interaction with p53*

Lisa A. McPhersonDagger , Alexander V. LoktevDagger , and Ronald J. Weigel§

From the Dagger  Department of Surgery, Stanford University, MSLS P228, Stanford, California 94305 and the § Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The AP2 transcription factor family is a set of developmentally regulated, retinoic acid inducible genes composed of four related factors, AP2alpha , AP2beta , AP2gamma , and AP2delta . AP2 factors orchestrate a variety of cell processes including apoptosis, cell growth, and tissue differentiation during embryogenesis. In studies of primary malignancies, AP2alpha has been shown to function as a tumor suppressor in breast cancer, colon cancer, and malignant melanoma. In cell culture models, overexpression of AP2alpha inhibits cell division and stable colony formation, whereas, a dominant-negative AP2alpha mutant increases invasiveness and tumorigenicity. Here we show that AP2alpha targets the p53 tumor suppressor protein. Studies with chromatin immunoprecipitation demonstrate that AP2alpha is brought to p53 binding sites in p53-regulated promoters. The interaction between AP2alpha and p53 augments p53-mediated transcriptional activation, which results in up-regulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. AP2alpha is able to induce G1 and G2 cell cycle arrest only in the presence of wild-type p53. Thus, we conclude that the tumor suppressor activity of AP2alpha is mediated through a direct interaction with p53. These results also provide a mechanism to explain patterns of gene expression in cancers where AP2alpha is known to function as a tumor suppressor.

* This work was supported, in part, by National Institutes of Health Grant R01 CA77350.The costs of publication of this article were defrayed in part by the payment of page charges. The 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: 1025 Walnut St., Suite 605, Philadelphia, PA 19107. Tel.: 215-955-0526; Fax: 215-923-1420; E-mail: ronald.weigel@mail.tju.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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