Androgen Receptor and SRY/SOX Interaction in Prostate

描述（由申请人提供）： 雄激素受体（Androgen receptor，AR）在前列腺的生长发育及发病机制中起重要作用。我们最近的研究结果表明，AR活动可以调制SRY，男性性别决定因子。AR/SRY通过它们各自的DNA结合结构域直接相互作用。SRY DNA结合结构域HMG在其家族成员即SOX蛋白中高度保守。事实上，AR DBD可以与多种SOX蛋白相互作用。AR还能够抑制SRY/SOX 9转录激活。此外，SRY还能与其它类固醇激素受体如雌激素受体、糖皮质激素受体等相互作用，但不与相关的核受体甲状腺受体相互作用。这些结果表明SRY/SOX和类固醇激素受体家族蛋白之间存在普遍和特异的蛋白质相互作用。SRY蛋白在前列腺组织中已被检测到，cDNA微阵列分析显示，在正常前列腺和前列腺癌中存在多种SOX蛋白。本研究旨在阐明AR和SRY/SOX家族相互作用的生物学意义，这两个家族都被证明对细胞和组织的生长和分化至关重要。研究旨在解决AR和SRY/SOX蛋白相互作用的机制。 目标1.将通过突变分析确定AR-SRY相互作用结构域的分子细节。目标二。确定AR-SRY相互抑制的潜在机制，并检验抑制是否通过干扰DNA结合、通过募集辅阻遏物、或通过干扰辅激活物与AR结合或AR N-和C-末端相互作用介导。目的3研究SRY/SOX蛋白在正常和异常前列腺组织中的时间和细胞特异性表达，探讨其在调节AR功能中的作用。 这些研究将对正常前列腺发育的生物学机制、前列腺增生和前列腺癌的发病机制提供新的认识。SRY介导的AR干扰也可能为设计更有效、更特异的AR拮抗剂提供工具。 我的目标是成为一名独立的医生科学家和做研究，这将导致更好地了解人类健康和疾病。这笔赠款将使我有受保护的时间，以进一步扩大我对uroglocal病理学的知识，提高赠款写作技巧和一般的新数据，这将导致未来的成功RO 1应用。

DESCRIPTION (provided by applicant): Androgen receptor (AR) plays an important role in the development and growth, as well as pathogenesis of prostate. Our recent results indicate that AR activity can be modulated by SRY, the male sex-determining factor. The AR/SRY directly interact with each other via their respective DNA binding domains. The SRY DNA binding domain, the HMG, is highly conserved among its family members, namely the SOX proteins. In deed, the AR DBD can interact with a variety of SOX proteins. AR was also able to suppress SRY/SOX9 transciptional activation. Moreover, SRY can interact with other steroid hormone receptors, such as estrogen and glucocoticoid receptors, but not with the related nuclear receptor, thyroid receptor. These results suggest that there is a general and specific protein interaction between the SRY/SOX and steroid hormone receptor family proteins. SRY protein has been detected in the prostate tissue, cDNA microarray analysis has reveals the presence of several SOX proteins in the normal prostate and prostate cancers. This proposal is define the biological significance of the interaction of AR and SRY/SOX families, which are both proven to be crucial for cell and tissue growth and differentiation. Studies are designed to address the mechanism of AR and SRY/SOX protein interaction. Aim 1. is to will determine the molecular details of AR-SRY interaction domains by mutational analysis. Aim 2. is to define the potential mechanism of AR-SRY mutual inhibition and test the hypothesis whether the inhibition mediated through interference of DNA binding; through recruitment of corepressor(s); or by interference of coactivator binding to AR or of AR N- and C-terminal interaction. Aim 3 it to assess the temporal and cell specific SRY/SOX protein expression in normal and abnormal prostate, which will shed light to their potential role in modulating AR functions. These studies will provide new understandings to the biological mechanisms of normal prostate development, to the pathogenesis of prostate hyperplasia and cancer. SRY mediated AR interference may also provide a tool for the design of more efficiently and specifically AR antagonist. My carrier goal is to become an independent physician scientist and doing research, which will lead to better understanding of human health and disease. This grant will allow me protected time to further expand my knowledge on uroglocal pathology, sharpen grant writing skills and general new data that will lead to future success in RO1 application.