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J. Biol. Chem., Vol. 281, Issue 15, 9837-9840, April 14, 2006

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Estrogen Receptor- Binds p53 Tumor Suppressor Protein Directly and Represses Its Function^*

Wensheng Liu¹, Santhi D. Konduri¹, Sanjay Bansal¹, Bijaya K. Nayak¹², Sigrid A. Rajasekaran, Sankunny M. Karuppayil³, Ayyappan K. Rajasekaran, and Gokul M. Das⁴

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263 and the Department of Pathology, University of California, Los Angeles, California 90095

Estrogen receptor- (ER) promotes proliferation of breast cancer cells, whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ER binds directly to p53 and represses its function. The activation function-2 (AF-2) domain of ER and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ER by small interfering RNA elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ER and p53. Ionizing radiation together with ER knock down results in additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating p53 and suggest that suppressing p53 function is an important component in the proproliferative role of ER.

Received for publication, January 4, 2006 , and in revised form, February 8, 2006.

^* This work was supported by National Institutes of Health Grant CA-79911, the Charlotte Geyer Foundation, and Wendy Will Case Cancer Fund, Inc. (to G. M. D.), and by the NCI/National Institutes of Health Comprehensive Cancer Center Grant to the Roswell Park Cancer Institute. 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 data and Figs. S1–S5.

¹ These authors contributed equally to this work.

² Current address: Dept. of Radiation Oncology, The University of Texas Health Science Center, San Antonio, TX 78229.

³ Current address: School of Life Sciences, SRTM University, Nanded, Maharashtra 431603, India.

⁴ To whom correspondence should be addressed: Dept. of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Elm & Carlton St., Buffalo, NY 14263. Tel.: 716-845-8542; Fax: 716-845-8857; E-mail: gokul.das{at}roswellpark.org.

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