Differential Modulation of Androgen Receptor-mediated Transactivation by Smad3 and Tumor Suppressor Smad4*

Smad proteins have been demonstrated to be key com-ponents in the transforming growth factor signaling cascade. Here we demonstrate that Smad4, together with Smad3, can interact with the androgen receptor (AR) in the DNA-binding and ligand-binding domains, which may result in the modulation of 5-dihydrotes-tosterone-induced AR transactivation. Interestingly, in the prostate PC3 and LNCaP cells, addition of Smad3 can enhance AR transactivation, and co-transfection of Smad3 and Smad4 can then repress AR transactivation in various androgen response element-promoter re-porter assays as well as Northern blot and reverse tran-scription-PCR quantitation assays with prostate-spe-cific antigen mRNA expression. In contrast, in the SW480C7 cells, lacking endogenous functional Smad4