Androgen Receptor and SRY/SOX Interaction in Prostate

描述(由申请人提供)： 雄激素受体(AR)在前列腺的生长发育和发病机制中起着重要作用。我们最近的结果表明，AR的活性可以受到男性性别决定因子SRY的调节。AR/SRY通过各自的DNA结合域直接相互作用。SRY DNA结合区HMG在其家族成员中高度保守，即Sox蛋白。事实上，AR DBD可以与多种SOX蛋白相互作用。AR还能抑制SRY/SOX9的转录激活。此外，SRY可以与其他类固醇激素受体相互作用，如雌激素和糖皮质激素受体，但不能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。已在前列腺组织中检测到SRY蛋白，基因芯片分析发现在正常前列腺癌和前列腺癌组织中存在多种SOX蛋白。这一建议定义了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。研究旨在探讨AR和SRY/SOX蛋白相互作用的机制。 目的1.通过突变分析确定AR-SRY相互作用结构域的分子细节。目的2.明确AR-SRY相互抑制的可能机制，并检验这种抑制是通过DNA结合的干扰、通过辅阻遏子(S)的募集、还是通过辅活化子与AR的结合或AR N-端和C-端的相互作用来介导的。目的研究正常和异常前列腺组织中SRY/Sox蛋白在时间和细胞上的特异性表达，为其在AR功能调控中的作用奠定基础。 这些研究将对正常前列腺发育的生物学机制、前列腺增生症和癌症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内科科学家，从事研究，这将导致对人类健康和疾病的更好理解。这笔赠款将让我有足够的时间进一步扩大我对尿路局部病理学的了解，提高赠款的写作技能和通用的新数据，从而在未来的RO1应用中取得成功。

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.