Identification and characterization of androgen receptor associated coregulators in prostate cancer cells

The androgen receptor (AR) is a member of the nuclear receptor (NR) superfa mily that mediates the effects of androgens on target tissues. Over the las t decade, it has become apparent that NRs require accessory factors for opt imal activation of target gene expression. Numerous NR coregulators have be en identified, with diverse structures and potential mechanisms of coregula tion, creating an increasingly complicated picture of NR action. Due to the expanding complexity of the coregulator field, this review will focus on t he AR ligand-binding domain (LBD) and N-terminal interacting proteins ident ified by our lab. The LBD-interacting proteins ARA70, ARA55 and ARA54 were first characterized and ARA70 was found to have a relatively higher specifi city for the AR in human prostate cancer DU145 cells. Characterization of t he functional relationship between the AR and these coregulators indicated that ARA70 and ARA55 could enhance the androgenic effects of 17 beta -estra diol (E-2) and hydroxyflutamide (HF), an antiandrogen commonly used in the treatment of prostate cancer. ARA160, an AR N-terminal interacting protein also known as TATA element modulatory factor (TMF), was subsequently shown to cooperate with ARA70 in enhancing AR activity. Another AR N-terminal int eracting protein, ARA24, interacted with the poly-Q tract, a region within the N-terminus of the AR linked to Kennedy's disease (X-linked spinal and b ulbar muscular atrophy). More recently, our lab has identified ARA267, a SE T domain containing protein, and supervillin, an F-actin binding protein, a s AR coregulators. Collectively, the data from these studies indicate that these coregulators are necessary for optimal AR transactivation. Interrupti on of the interaction between AR and these proteins may serve as a new ther apeutic target in the treatment of prostate cancer.