Androgen receptor (AR), a steroid hormone receptor, mediates the physiologic and pathophysiologic effects of androgens including embryonic differentiation, prostate development and prostate cancer progression. AR modulates such diverse effects by binding to specific genomic sites termed androgen response elements (AREs), which influence transcription of androgen responsive genes (ARGs). ARE context differs from gene to gene, thus enabling a single regulator to trigger multiple regulatory functions within a single nucleus. Recently, beta-catenin of the Wnt signaling pathway was shown to functionally interact with AR suggesting that AR/beta-catenin complexes may modulate a subset of androgen and Wnt transcriptional responses. Moreover, AR/beta-catenin responsive genes may regulate effectors of prostate cell proliferation, death and, possibly, cancer. To test these ideas, I propose to isolate genomic AREs and identify ARCs from primary prostate epithelial cells by genomic techniques. I shall characterize the genomic recruitment of AR/beta-catenin complexes by chromatin immunoprecipitation and the regulatory activities of AR/beta-catenin complexes in cellbased reporter constructs. These experiments will enable examination of the roles of ARCs in complex physiologic and pathophysiologic processes, such as cellular proliferation/death regulation or prostate cancer progression. In general, these studies will probe the regulatory crosstalk between two essential mammalian signaling systems, steroid hormones and Wnt.
| Bolton, Eric C; So, Alex Y; Chaivorapol, Christina et al. (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005-17 |
| So, Alex Yick-Lun; Chaivorapol, Christina; Bolton, Eric C et al. (2007) Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS Genet 3:e94 |
