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J. Biol. Chem., Vol. 279, Issue 21, 21766-21773, May 21, 2004

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Tip110, the Human Immunodeficiency Virus Type 1 (HIV-1) Tat-interacting Protein of 110 kDa as a Negative Regulator of Androgen Receptor (AR) Transcriptional Activation^*

Ying Liu, Byung Oh Kim, Chinghai Kao¶, Chaeyong Jung¶, James T. Dalton||, and Johnny J. He**

From the Department of Microbiology and Immunology, the Walther Oncology Center, the ^¶Department of Urology, and the ^**Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, the ^||Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, Ohio 43210, and the Walther Cancer Institute, Indianapolis, Indiana 46206

Upon binding to androgen, androgen receptor (AR) can activate expression of target genes through its direct binding to the androgen-responsive elements (AREs), which are located within the target gene promoters and/or enhancers. A number of cellular proteins have been identified as co-regulators to regulate this transactivation process. One common structural feature among these co-regulators is the presence of the LXXLL motif (X, any amino acid), the so-called nuclear receptor (NR) box, through which binding of these regulatory proteins to AR occurs. We have recently shown that Tip110 functions to potentiate the transactivation activity of human immunodeficiency virus type I (HIV-1) Tat protein. In this study, we report that Tip110 is a potent AR-binding protein that can suppress AR activity. Tip110 bound to AR in an NR box-dependent manner and inhibited AREs-mediated reporter gene expression. The inhibitory effects were abolished by removal of the NR box. Moreover, knock-down of the constitutive Tip110 expression significantly augmented AR transcriptional activation. In agreement with these findings, Tip110 overexpression blocked the prostate-specific antigen (PSA) gene, a well characterized target gene of AR from expression in LNCaP cells. Further analysis revealed that Tip110 prevented the complex formation between AR and AREs. Taken together, these results indicate that Tip110 is a negative regulator of AR transcriptional activation, and may be directly involved in AR-related developmental, physiological, and pathological processes.

Received for publication, December 31, 2003 , and in revised form, February 27, 2004.

^* This work was supported by Grants R01NS39804 (to J. J. H.), R01MH65158 (to J. J. H.), and R01CA74042 (to C. K.) 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.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Indiana University School of Medicine, R2 302, 950 W. Walnut St., Indianapolis, IN 46202. Tel.: 317-274-7525; Fax: 317-274-7592; E-mail: jjhe{at}iupui.edu.

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				H. V. Heemers and D. J. Tindall Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex Endocr. Rev., December 1, 2007; 28(7): 778 - 808. [Abstract] [Full Text] [PDF]