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J. Biol. Chem., Vol. 280, Issue 45, 37853-37867, November 11, 2005

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Interaction of -Catenin and TIF2/GRIP1 in Transcriptional Activation by the Androgen Receptor^*

Liang-Nian Song and Edward P. Gelmann1

From the Departments of Oncology and Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007-2197

The multifunctional oncoprotein -catenin interacts with the activation function-2 domain of androgen receptor (AR) to stimulate androgen receptor transcriptional activity, increase sensitivity, and broaden specificity of ligand interactions. -Catenin interacts with androgen receptor in close proximity to the binding groove for P160 coactivators such as transcriptional intermediary factor-2 (TIF2)/glucocorticoid receptor interacting protein-1 (GRIP1). -Catenin can also bind directly to TIF2/GRIP1. Both N- and C-terminal regions of -catenin are needed for optimal interaction with TIF2/GRIP1. We show that distinct residues of -catenin are responsible for both binding and functional interactions with androgen receptor and with TCF4, thus allowing the introduction of missense mutations that selectively affect these interactions. -Catenin and TIF2/GRIP1 are each able to mediate binding between the other and androgen receptor in functional interactions that enhance ligand-dependent transcription. The data strongly imply that AR, -catenin, and TIF2/GRIP1 bind in a three-way interaction that mediates transcription. Lastly, we observed that a -catenin C-terminal peptide containing 229 amino acids can bind TIF2/GRIP1 and AR but has a profound dominant inhibitory effect on ligand-dependent transcription. We propose that -catenin may play an integral role in formation of the androgen-receptor transcriptional complex.

Received for publication, April 8, 2005 , and in revised form, July 13, 2005.

^* This work was supported by U.S. Public Health Service Grant CA96854 (to E. P. G.). 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.

¹ To whom correspondence should be addressed: Depts. of Oncology and Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd., NW, Washington, DC 20007-2197. Tel.: 202-444-2207; Fax: 202-444-1229; E-mail: Gelmanne{at}georgetown.edu.

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