DNA Binding-independent Transcriptional Activation by the Androgen Receptor through Triggering of Coactivators

Abstract

Androgens have critical roles in the development and maintenance of the male 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 receptor superfamily. In the presence of androgens, AR binds to androgen response elements in the vicinity of androgen receptor target genes and activates transcription. In addition, liganded AR can interfere with the activity of other transcription factors, such as activator protein-1 and nuclear factor κB, for which DNA binding by AR is not necessary. In this study, we describe a novel ligand-dependent transactivation function for AR that is independent of its DNA binding ability. AR dramatically increased the intrinsic transcriptional activity of the nuclear receptor coactivators glucocorticoid receptor-interacting protein-1 (GRIP1), cAMP response element-binding protein-binding protein, and p300 that are tethered to DNA. This "triggering" phenomenon required both similar and distinctly different regions of AR compared with those needed for ligand-dependent transactivation from androgen-responsive elements. Furthermore, the domains of GRIP1 required for triggering by AR are different from those required when GRIP1 serves as a coactivator for AR at androgen-responsive promoters. These data suggest that triggering may constitute an important part of the mechanism by which AR regulates transcription.