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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,¹ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, People's Republic of China²

Received 16 September 2006/ Returned for modification 20 October 2006/ Accepted 26 July 2007

Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the 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 of 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 58-kDa isoform of cyclin-dependent kinase 11 (CDK11^p58) repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11^p58 formed a ternary complex in cells and were colocalized in the luminal epithelial layer of the prostate. AR 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 activation 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.

Published ahead of print on 13 August 2007.

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