Mechanism of Transcriptional Regulation by Androgen Receptor and its Coactivators in the Context of Chromatin

摘要

Androgens play important roles in the differentiation, development and maintenance of male reproductive functions, as well as in the etiology of prostate cancer. The biological effects of androgens are believed to be mediated through the intracellular androgen receptor (AR), which belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors. Like other NRs, the actions of AR are subject to modulation, either positively or negatively, by an increasing number of co-regulatory proteins, termed coactivators or corepressors. Coactivators are believed to function either as bridging factors between receptors and basal transcription machinery to enhance recruitment of the basal transcription machinery and/or as factors that have capacity to actively remodel repressive chromatin. The purpose of this research is to study the mechanism by which coactivators modulate AR activity in chromatin, the physiological template of transcriptional regulation. In this progress report, we report that we have analyzed how SRC family coactivators, p300, ARA24 and ARA70 modulate AR activity in the context of chromatin using Xenopus oocyte as a model system. We show that expression of SRC-1 and p300 in Xenopus oocytes can significantly enhance both hormone-dependent and independent activation by AR. While ARA24 can stimulate modestly the AR activation, no coactivator activity can be observed for ARA70. We demonstrate that p300 requires both its histone acetyltransferase activity and interaction with SRC family coactivators to stimulate AR activity. By using chromatin immunoprecipitation assay, we demonstrated that R1881-stimulated transcriptional activation by AR is associated with the promoter targeting of multiple cofactors including the SRC-1, p300, SWI/SNF and TRAP/Mediator complex. An increased histone acetylation over the promoter region was also observed.