Normal prostatic epithelium depends on androgens for growth, development, secretory function, and survival (1-4). Most remarkably, androgen ablation induces massive apoptosis of prostatic epithelium (2, 5-8). Loss of androgen dependence occurs invariably during prostate carcinogenesis, accounting for poor long term success of androgen ablation therapy (9). Recent studies (10) show that acquisition of androgen autonomy occurs despite retention or elevated expression of the androgen receptor (AR) 1 in the majority of prostate tumors. AR, a 110-kDa zinc finger transcription factor belonging to the nuclear receptor superfamily, is activated by phosphorylation (11) and dimerization upon ligand binding. This promotes nuclear localization and binding of AR to androgenresponsive elements in the promoters of androgen-regulated genes. AR-mediated transcription is regulated by many ARinteracting proteins such as ARA 70 (AR-associated proteins) (12) and ARA 160 (13), along with cAMP-response element-binding protein (14), AP-1 (9, 15), and Ets (16). The growing list of recently discovered AR transcriptional co-regulators supports the notion that complex networks of signals tightly regulate transcription by androgens. Understanding how these signals promote growth and maintain cell viability will certainly impact on the therapeutic strategies for the prevention and cure of prostate cancer.TGF-, a potent regulator of cell growth, differentiation, apoptosis, and carcinogenesis in the prostate (17)(18)(19)(20), is under androgenic control. TGF- signals through a cooperative interaction with two cell surface serine/threonine kinase receptors, . TGF- first associates with constitutively active dimeric TRII, which then recruits and activates TRI kinase by transphosphorylation at a juxtamembrane glycine-serine repeat (21,26). With the help of Smad anchor for receptor activation (27), phosphorylated TRI is able to activate Smads 2 and 3 by phosphorylating their carboxyl-terminal serine-serine-Xaa-serine motifs (28). Active Smads 2 and 3 can form heteromeric complexes with co-Smad4, and either directly or through interactions with transcription factors and co-regulators bind to Smad-binding elements (SBEs) in TGF--regulated genes (29 -31). Further activation of Smads 2 and 3 is blocked by Smad7, whose expression is induced upon TGF- stimulation (32).Androgens negatively regulate TGF-1 ligand (17, 33) and receptor expression (34,35), along with Smad expression and activation (36) in the prostate. Recent reports show AR associates with Smad3 and that this association may either enhance
