DNA binding-independent transcriptional activation by the androgen receptor through triggering of coactivators

Androgens have critical roles in the development and maintenance of the mal e reproductive system and are important for progression of prostate cancer. The effects of androgens are mediated by the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear rec eptor superfamily. In the presence of androgens, AR binds to androgen respo nse elements in the vicinity of androgen receptor target genes and activate s transcription. In addition, liganded AR can interfere with the activity o f other transcription factors, such as activator protein-1 and nuclear fact or kappaB, for which DNA binding by AR is not necessary. In this study, we describe a novel ligand-dependent transactivation function for AR that is i ndependent of its DNA binding ability. AR dramatically increased the intrin sic transcriptional activity of the nuclear receptor coactivators glucocort icoid receptor-interacting protein-1 (GRIP1), cAMP response element-binding protein-binding protein, and p300 that are tethered to DNA. This "triggeri ng" phenomenon required both similar and distinctly different regions of AR compared with those needed for ligand-dependent transactivation from andro gen-responsive elements. Furthermore, the domains of GRIP1 required for tri ggering by AR are different from those required when GRIP1 serves as a coac tivator for AR at androgen-responsive promoters. These data suggest that tr iggering may constitute an important part of the mechanism by which AR regu lates transcription.