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J. Biol. Chem., Vol. 279, Issue 52, 54230-54240, December 24, 2004

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Human ADA3 Binds to Estrogen Receptor (ER) and Functions As a Coactivator for ER-mediated Transactivation^*

Gaoyuan Meng, Yongtong Zhao¶, Alo Nag¶, Musheng Zeng, Goberdhan Dimri¶, Qingshen Gao¶, David E. Wazer, Rakesh Kumar||, Hamid Band**, and Vimla Band¶

From the Department of Radiation Oncology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, Divisions of ^¶Cancer Biology and ^**Molecular Oncology, Department of Medicine, ENH Research Institute, Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60201, and ^||Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

We have recently identified the hADA3 protein, the human homologue of yeast transcriptional coactivator yADA3, as a novel HPV16 E6 target. Using ectopic expression approaches, we further demonstrated that hADA3 directly binds to the 9-cis retinoic acid receptors and , and functions as a coactivator for retinoid receptor-mediated transcriptional activation. Here, we examined the role of endogenous hADA3 as a coactivator for estrogen receptor (ER), an important member of the nuclear hormone receptor superfamily. We show that ADA3 directly interacts with ER and ER. Using the chromatin immunoprecipitation assay, we also show that hADA3 is a component of the activator complexes bound to the native ER response element within the promoter of the estrogen-responsive gene pS2. Furthermore, using an ER response element-luciferase reporter, we show that overexpression of ADA3 enhances the ER- and ER-mediated sequence-specific transactivation. Reverse transcription-PCR analysis showed an ADA3-mediated increase in estrogen-induced expression of the endogenous pS2 gene. More importantly, using RNA interference against hADA3, we demonstrate that inhibition of endogenous hADA3 inhibited ER-mediated transactivation and the estrogen-induced increase in the expression of pS2, cathepsin D, and progesterone receptor, three widely known ER-responsive genes. The HPV E6 protein, by targeting hADA3 for degradation, inhibited the ER-mediated transactivation and the protein expression of ER target genes. Thus, our results demonstrate that ADA3 directly binds to human estrogen receptor and enhances the transcription of ER-responsive genes, suggesting a broader role of mammalian hADA3 as a coactivator of nuclear hormone receptors and the potential role of these pathways in HPV oncogenesis.

Received for publication, April 22, 2004 , and in revised form, October 19, 2004.

^* This work was supported by National Institute of Health Grants CA94143, CA96844, and CA81076 (to V. B.) and CA87986, CA76118, CA99900, and CA99163 (to H. B.) This work was initiated while Dr. Band's laboratory was at the New England Medical Center, Tufts University School of Medicine, Boston, MA. 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.

Recipient of fellowship from the Massachusetts Department of Public Health.

Jean Ruggles-Romoser Chair of Cancer Research.

Duckworth Family Chair in Breast Cancer Research. To whom correspondence should be addressed: Division of Cancer Biology, ENH Research Institute, 1001 University Place, Evanston, IL 60201. Tel.: 224-364-7501; Fax: 224-364-7402; E-mail: v-band{at}northwestern.edu.

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