Cdk5 Interferes Cyclin D1-Dependent Activation of Androgen Receptor

• Main Authors: Li-Ling Lin, 林俐伶
• Other Authors: Ho Lin
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/60187685356086345753

碩士 === 國立中興大學 === 生命科學系所 === 96 === The androgen receptor (AR) is important for the development of prostate cancer. Several protein kinases have been shown to regulate AR transactivation by phosphorylating serine or threonine residues in AR. On the other hand, cyclin D1 harbors a distinct anti-mitogenic function and inhibits androgen-dependent proliferation in prostatic adenocarcinoma. In which, cyclin D1 was reported to directly interact with AR and negatively regulate AR transactivation. Cdk5 protein, the main focus in this study, is a member of serine/threonine cyclin-dependent kinase (CDK) family and its regulator is p35 protein. In contrast to other members of the CDK family, Cdk5 is not directly involved in cell cycle modulation. Our previous results indicated that Cdk5 could associate with AR and performed a positive regulation of AR. In addition, based on the homology between cyclin D1 and p35, the protein interaction between p35 and AR was also identified. Interestingly, we found that overexpression of Cdk5 or p35 in prostate cancer cells significantly decreased the association of cyclin D1 and AR. The ability of the AR to activate endogenous target gene expression was inhibited in the presence of cyclin D1. However, the interaction between Cdk5 and AR significantly increased endogenous PSA expression and PSA secretion. Furthermore, Cdk5 inhibition by siRNA decreased the expression of PSA protein. In conclusion, we suggest that Cdk5 might modulate AR transactivation in prostate cancer through competition with cyclin D1. Therefore, Cdk5 becomes a future candidate of therapeutic target for prostate cancer.