AR possesses an intrinsic hormone-independent transcriptional activity

Abstract

Recent research has highlighted the functional importance of chromatin structure in transcriptional regulation. We have used Xenopus oocytes as a model system to investigate the action of AR in the context of chromatin. By manipulating the levels of AR expression, we have observed both agonist-dependent and -independent activation by AR. Expression of AR at relatively low levels resulted in strong agonist-dependent activation, whereas high levels of AR also led to hormone-independent activation. By using gel mobility shift and deoxyribonuclease I footprinting assays, we demonstrate that AR expressed in Xenopus oocytes binds to a consensus androgen response element in vitro in a ligand-independent manner. Expression of the coactivators steroid receptor coactivator-1, receptor-associated coactivator-3, and p300 stimulated both agonist-dependent and -independent activation by AR. Furthermore, this hormone-independent activity of AR is also observed in mammalian cells. Antagonists such as casodex can inhibit hormone-independent activity of AR, and this inhibition appears to correlate with the enhanced association with corepressor silencing mediator of retinoid and thyroid hormone receptors. Altogether, our studies reveal that AR has a capacity to activate transcription in a ligand-independent manner.