DIFFERENTIAL REGULATION OF ANDROGEN AND GLUCOCORTICOID RECEPTORS BY RETINOBLASTOMA PROTEIN

The androgen receptor (AR) plays a major role in the development and m aintenance of male primary and secondary sexual characteristics. The g rowth promoting effects of androgens are clearly seen in prostate canc er where treatment by androgen ablation usually leads to tumor regress ion, followed sometime later, by growth of tumor cells that are resist ant to endocrine therapy. We have found that the level of pRB in cells controls AR activity. Overexpression of pRB leads to increased transc riptional activity of the AR. This is similar to the previously report ed potentiation of glucocorticoid receptor activity by pRB. In contras t, loss of pRB activity inhibits AR but not glucocorticoid receptor ac tivity. This inhibition correlates with the unique ability of the AR t o form a protein-protein complex with pRB in vitro. The site of intera ction with pRB lies within the N-terminal domain of the AR and co-loca lizes with the region of the AR that specifies a requirement for pRB. Thus, the AR has a novel requirement for pRB raising the possibility t hat the growth promoting activity of AR is due to its direct interacti on with pRB. Furthermore, loss of pRB activity during progression of p rostate cancer may directly result in a decreased response to androgen s.