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Abstract
The androgen receptor is a member of the steroid receptor superfamily. In general, AR is located in various target tissues, with its levels and activity altered with the onset of various cellular events: sexual development, hair follicle growth and malignant transformation. Furthermore, mutations or abnormal expression of AR in prostate cancer may play a key role in the process that changes prostate cancer from androgen-dependent to an androgen-independent stage.
For the past decades, the influence of androgens and androgen receptor is well documented but the molecular mechanism of the influence remains unclear. To understand the mechanism of androgen-AR function, we decided to use a yeast two-hybrid system to isolate AR-associated proteins that may contribute the regulation of AR. Our works were summarized as the following. First, we successfully identified the first ligand-dependent AR associated protein, ARA$\sb{70}$, which may function as a specific coactivator for inducing the transcriptional activity of AR in human prostate cells. Second, the ARA$\sb{70}$ is important for E2-mediated AR transcriptional activity. The E2-mediated activation of androgen-target genes in the presence of AR and ARA$\sb{70}$ in human prostatic cells suggests that a coactivator may be able to change the steroid receptor specificity and may provide us with a new strategy for androgen-ablative therapy of prostate cancer (for example) developing a peptide or other compound that can block the interaction of AR and ARA$\sb{70}$). Third, our data indicate that ARA$\sb{70}$ can confer the partial agonist activity on antiandrogen, HF. This may provide one possible explanation for the failure of androgen ablative therapy and the "flutamide syndrome" for prostate cancer treatment. Furthermore, we have identified a CRE-like cis-acting element on the promoter of human AR.
Our aims are to study the normal regulation and various mal-functions of AR, and to expedite prostate cancer cure. The cloning of a specific AR associated protein, ARA$\sb{70}$, let us have the opportunity to investigate the AR function in various aspects. The possible roles of ARA$\sb{70}$ have been explored, we would continue our work in this long journey.
