Regulatory crosstalk between androgen and Wnt signaling

描述(申请人提供)：雄激素受体(AR)是一种类固醇激素受体，介导雄激素的生理和病理生理效应，包括胚胎分化、前列腺发育和前列腺癌进展。AR通过与称为雄激素反应元件(ARES)的特定基因组位点结合来调节这种不同的效应，这些位点影响雄激素反应基因(ARGs)的转录。不同基因之间的环境是不同的，因此使单个调控因子能够在单个核内触发多种调节功能。最近，Wnt信号通路中的β-catenin与AR在功能上相互作用，提示AR/β-catenin复合体可能调节雄激素和Wnt转录反应的一个子集。此外，AR/β-连环蛋白反应基因可能调节前列腺细胞增殖、死亡以及可能的癌症的效应。为了测试这些想法，我建议分离基因组Ares，并通过基因组技术从初级前列腺上皮细胞中识别ARC。我将通过染色质免疫沉淀来表征AR/β-连环蛋白复合体的基因组募集，以及AR/β-连环蛋白复合体在基于细胞的报告结构中的调节活性。这些实验将使研究ARCS在复杂的生理和病理生理过程中的作用成为可能，如细胞增殖/死亡调节或前列腺癌进展。总的来说，这些研究将探索两个重要的哺乳动物信号系统--类固醇激素和Wnt之间的调节串扰。

DESCRIPTION (provided by applicant): 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.