Mechanism and Regulation of Gene Expression by Androgen Receptor in Prostate Cancer

摘要

Our general objective is to use completely defined cell-free transcription systems both to identify novel androgen receptor (AR), associated cofactors and to investigate the mechanism of action of AR coactivators. Toward this objective we have investigated AR and cognate cofactor functions in cell- free transcription systems reconstituted with general initiation factors and cofactors, androgen receptors, and androgen-responsive templates. In this system, we observed an AR-dependent transcription, which could be positively or negatively modulated by various AR cofactors. Relevant to the mechanisms involved, we have identified two Mediator subunits as potential targets for AR and a basal transcription factor (TFIIE) as a potential target for the negative AR cofactor AMINO-TERMINAL ENHANCER OF SPLIT (A ES). We have identified AES and p44 as new AR-interacting proteins, which positively or negatively modulate AR transactivation in vitro and in vivo. We also investigated the expression of AR and various cofactors in primary prostate cancers and found near constant expression of AR and heterogeneous expression of AR cofactors. Modulation of cofactor expression affected the proliferation and colony formation of prostate tumor cells. Together, these findings indicate that the change of expression levels of AR cofactors may play important roles in prostate growth and tumorigenesis.