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Mol. Cell. Biol. doi:10.1128/MCB.01753-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cyclin D3/CDK11^p58 Complex Is Involved in the Repression of Androgen Receptor

Key Laboratory of Medical Molecular Virology Ministry of Education and Health, Gene Research Center, Shanghai Medical College and Institutes of Biomedical Sciences, and Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China

^* To whom correspondence should be addressed. Email: jxgu{at}shmu.edu.cn.

	Abstract

Androgen receptor (AR) is essential for maintenance of the male reproductive systems, and is critical for carcinogenesis of human prostate cancers (PCas). D-type cyclins are closely related to the repression of AR function. It has been well documented that cyclin D1 inhibits AR function through multiple mechanisms, but the mechanism how cyclin D3 exerts its repressive role in the AR signaling pathway remains to be identified. In the present investigation we demonstrate that cyclin D3 and the 58kDa isoform of cyclin-dependent kinase 11 (CDK11^p58) repressed AR transcriptional activity as measured by reporter assays in transformed cells and prostate-specific antigen (PSA) expressions in PCa cells. AR, cyclin D3 and CDK11^p58 formed a ternary complex in cells, and were colocalized in the luminal epithelial layer of prostate. Androgen receptor activity is controlled by phosphorylation at specific sites. We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11^p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional unit 1 (TAU1). Furthermore, androgen-dependent proliferation of PCa cells was inhibited by cyclin D3/CDK11^p58 through AR repression. These data suggest that cyclin D3/CDK11^p58 signaling is involved in the negative regulation of AR function.

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