Regulatory crosstalk between androgen and Wnt signaling

描述（由申请人提供）：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作用，包括胚胎分化、前列腺发育和前列腺癌进展。AR通过结合被称为雄激素反应元件（AREs）的特定基因组位点来调节这些不同的作用，雄激素反应元件（AREs）影响雄激素反应基因（ARGs）的转录。ARE上下文因基因而异，从而使单个调控因子能够在单个细胞核内触发多个调控功能。最近，Wnt信号通路的β -连环蛋白被证明与AR相互作用，这表明AR/ β -连环蛋白复合物可能调节雄激素和Wnt转录反应的一个子集。此外，AR/ β -连环蛋白应答基因可能调节前列腺细胞增殖、死亡和可能的癌症效应。为了验证这些想法，我建议通过基因组技术从原代前列腺上皮细胞中分离基因组AREs并鉴定arc。我将通过染色质免疫沉淀描述AR/ β -连环蛋白复合物的基因组募集，以及AR/ β -连环蛋白复合物在基于细胞的报告构建中的调节活性。这些实验将有助于研究arc在复杂的生理和病理生理过程中的作用，如细胞增殖/死亡调节或前列腺癌进展。总的来说，这些研究将探讨两个重要的哺乳动物信号系统，类固醇激素和Wnt之间的调控串扰。

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.