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J. Biol. Chem., Vol. 279, Issue 31, 32709-32715, July 30, 2004

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Upstream Determinants of Estrogen Receptor- Regulation of Metastatic Tumor Antigen 3 Pathway^*

Sandip K. Mishra, Amjad H. Talukder, Anupama E. Gururaj, Zhibo Yang, Rajesh R. Singh, My G. Mahoney¶||, Clara Francí**, Ratna K. Vadlamudi, and Rakesh Kumar

From the Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the ^¶Department of Dermatology and Cutaneous Biology Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ^**Unitat de Biologia Cellular Molecular, Institute Municipal d'Investigacio Medica, Universitat Pompeu Fabra, 08003 Barcelona, Spain

Although recent studies have shown a role of estrogen receptor- (ER) in the regulation of epithelial-to-mesenchymal transition via MTA3, the role of upstream determinants of ER regulation of MTA3 and the underlying molecular mechanism remains unknown. Here we show that MTA3 gene regulation by ER is influenced by dynamic changes in levels of nuclear coregulators. MTA3 promoter has a functional ER element half-site with which MTA1 and HDACs interact under basal conditions. Upon estrogen stimulation, these corepressors are derecruited with concomitant recruitment of ER, leading to increased MTA3 transcription and expression. Genetic inactivation of MTA1 pathway promotes the ability of ER to up-regulate MTA3 expression, whereas knockdown of ER enhances MTA1 association with MTA3 gene. Modulation of ER functions, by corepressors (i.e. MTA1 and MTA1s) or coactivators (i.e. AIB1 and PELP1/MNAR), alters ER recruitment to MTA3 chromatin, MTA3 transcription, and expression of downstream epithelial-to-mesenchymal transition components. These studies provide novel insights into the transregulation of the MTA3 gene and reveal novel roles of upstream determinants in modifying the outcome of MTA3 axis and cell differentiation.

Received for publication, March 16, 2004 , and in revised form, May 28, 2004.

^* This study was supported by Grants CA90970, CA098823 (to R. K.), and in part by CA095681 (to R. V.) from the National Institutes of Health. 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.

These authors contributed equally to this work.

^|| Supported by Grant DAMD 17-02-1-0215 from the Department of Defense.

To whom correspondence should be addressed. E-mail: rkumar{at}mdanderson.org.

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