MULTIPLE G(1) REGULATORY ELEMENTS CONTROL THE ANDROGEN-DEPENDENT PROLIFERATION OF PROSTATIC-CARCINOMA CELLS

Prostatic epithelial cells and most primary prostate tumors are depend ent on androgen for growth, but how androgen regulates cellular prolif eration remains unsolved. Using poorly understood mechanisms, recurren t tumor cells evade the androgen requirement. We utilized androgen-dep endent prostatic tumor cells to demonstrate that androgen exerts its e ffect on the cell cycle by influencing specific aspects of G(1)-S prog ression. Androgen depletion of these cells results in early G(1) arres t, characterized by reduced cyclin dependent kinase activity, and unde rphosphorylated retinoblastoma tumor suppressor protein (RB), The redu ction in kinase activity was partially attributed to reduction of spec ific G(1) cyclins and alternate regulation of cyclin-dependent kinase inhibitors, Using this information, we developed a reliable assay to a ssess the ability of specific G(1) regulatory proteins to circumvent t hese controls and promote androgen-independent growth. As expected, in activation of RE was required for progression through the cell cycle. Surprisingly, overexpression of G(1) cyclins, which drives RE phosphor ylation, was insufficient to promote androgen-independent cell cycle p rogression. Introduction of viral oncoproteins did promote G(1)-S prog ression in the absence of androgen, dependent on their ability to sequ ester RE and related proteins. These results provide the first evidenc e that multiple elements governing the G(1)-S transition dictate andro gen-dependent growth, and the formation of androgen-independent prosta tic tumors may be because of misregulation of these processes.