RETINOBLASTOMA, A TUMOR-SUPPRESSOR, IS A COACTIVATOR FOR THE ANDROGENRECEPTOR IN HUMAN PROSTATE-CANCER DU145 CELLS

The retinoblastoma protein may function as a tumor suppressor by contr olling the progression of the normal cell cycle. Inactivation of Rb ha s been regarded as an important event in prostate carcinogenesis. Howe ver, the detailed mechanism of how Rb is linked to androgen-androgen r eceptor (A-AR), the major factor in promotion of prostate tumor growth , remains unclear. Using GST-Rb pull down assay and mammalian two-hybr id system, we report here that Rb can bind specifically to AR in an an drogen-independent manner. Transient transfection assay demonstrates t hat cotransfection of AR and Rb can further induce AR transcriptional activity 4-fold in the presence of 1 nM dihydrotestosterone in DU145 c ells. Interestingly, cotransfection of Rb and ARA70, the first identif ied AR coactivator, with AR can additively induce AR transcriptional a ctivity 13-fold (from 5-fold to 64-fold). In conclusion, our discovery that Rb can function as a coactivator to induce AR transcriptional ac tivity in prostate cells may represent the first data to link a negati ve growth regulatory protein function in a positive manner, by inducin g the transcriptional activity of AR. (C) 1998 Academic Press.