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

Abstract

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.

This work was supported by the National Natural Scientific Foundation of China (30470442 and 30330320) and CNHLPP (2004BA711A19).

We thank DZijie Sun and Roland Schüle for the AR expression and reporter plasmids described in Materials and Methods.