Cdk11 <sup> P58 </ Sup> Structure And Function Of Steroid Hormone Receptors In Male Hormone Receptor, Vitamin D Receptor Regulation

CDK11p58, a member of the large family of p34cdc2-related kinases, is associated with cell cycle progression, tumorigenesis, and apoptotic signaling. Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the carcinogenesis of human prostate cancers (PCas). In the present investigation, we demonstrate that CDK11p58 repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11p58 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/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1).Vitamin D receptor (VDR) is another member of the nuclear receptor superfamily and regulates transcription of target genes. In this study, we identified CDK11p58 as a novel protein involved in the regulation of VDR as well as AR. Our study demonstrated that CDK11p58 interacted with VDR and repressed VDR-dependent transcriptional activation. Furthermore, overexpression of CDK11p58 decreased the stability of VDR through promoting its ubiquitin-proteasome-mediated degradation. Taken together, these results suggest that CDK11p58 is involved in the negative regulation of VDR.These data suggest that CDK11p58signaling is involved in the negative regulation of AR and VDR function. CDK11p58, a member of p34cdc2-related kinases family, is associated with cell cycle progression, tumorigenesis and pro-apoptotic signaling. It is also required for the maintenance of chromosome cohesion, the maturation of centrosome, the formation of bipolar spindle and the completion of mitosis. Here, we identified that CDK11p58 interacted with itself to form homo-dimers in cells, whereas, D224N, the kinase-dead mutant, failed to form homo-dimers. Importantly, we demonstrated that CDK11p58 was autophosphorylated and the main functions of CDK11p58 such as kinase activity, transactivation of nuclear receptors, and pro-apoptotic signal transduction depended on its autophosphorylation. Furthermore, the in vitro kinase assay suggested that CDK11p58 was autophosphorylated at Thr-370. The mutant T370A that could not be phosphorylated by the wild-type CDK11p58 lost the kinase activity and failed to repress the transactivition of androgen receptor and enhance the cell apoptosis.