Androgen Receptor and SRY/SOX Interaction in Prostate

前列腺中雄激素受体和 SRY/SOX 相互作用

• 批准号: 7240544
• 负责人: Xin Yuan
• 金额: $ 12.9万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7240544
• 关键词: Address; Androgen Receptor; Binding; Biological; Boxing; C-terminal; Cells; Complex; DNA; DNA Binding; DNA Binding Domain; Data; Development; Disease; Estrogen Receptors; Estrogens; Family; Family member; Fingers; Future; Genes; Genitourinary system; Glucocorticoid Receptor; Goals; Grant; Growth; Growth and Development function; HMG Domain; Health; Human; Knowledge; Lead; Life; Light; Maintenance; Male Pattern Baldness; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Microarray Analysis; Molecular; Nuclear Receptors; Pathogenesis; Pathology; Physicians; Physiological; Play; Prostate; Prostatic hypertrophy; Protein Family; Proteins; Range; Receptor Cell; Research; Research Design; Role; Scientist; Signal Pathway; Steroids; Testing; Thyroid Gland; Thyroid Hormone Receptor; Time; Tissues; Writing; base; cDNA Arrays; cell type; design; human SOX1 protein; human SOX11 protein; human SOX12 protein; human SOX13 protein; human SOX14 protein; human SOX15 protein; human SOX17 protein; human SOX18 protein; human SOX21 protein; human SOX4 protein; human SOX5 protein; human SOX6 protein; human SOX7 protein; human SOX8 protein; male; member; mouse Sox5 protein; mouse Sox7 protein; prevent; protein expression; receptor; receptor binding; receptor function; sex; sex determination; sex-determining region Y protein; skills; steroid hormone receptor; success; tool

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.

描述（由申请人提供）： 雄激素受体（AR）在前列腺的发育、生长以及发病机制中发挥着重要作用。我们最近的结果表明 AR 活性可以通过男性性别决定因子 SRY 进行调节。 AR/SRY 通过各自的 DNA 结合域直接相互作用。 SRY DNA 结合域 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/SOX9 转录激活。此外，SRY可以与其他类固醇激素受体相互作用，例如雌激素和糖皮质激素受体，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一般和特异性的蛋白质相互作用。前列腺组织中已检测到SRY蛋白，cDNA微阵列分析揭示了正常前列腺和前列腺癌中存在多种SOX蛋白。该提案定义了 AR 和 SRY/SOX 家族相互作用的生物学意义，这两者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. 是通过突变分析确定 AR-SRY 相互作用结构域的分子细节。目的2.明确AR-SRY相互抑制的潜在机制，并检验该抑制是否通过干扰DNA结合介导的假设；通过辅阻遏物的募集；或通过干扰共激活剂与 AR 的结合或干扰 AR N 端和 C 端的相互作用。目标 3 评估正常和异常前列腺中的时间和细胞特异性 SRY/SOX 蛋白表达，这将揭示它们在调节 AR 功能中的潜在作用。 这些研究将为正常前列腺发育的生物学机制、前列腺增生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医师科学家并进行研究，这将有助于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来进一步扩展我在泌尿局部病理学方面的知识，提高赠款写作技巧和一般新数据，这将导致未来在 RO1 申请中取得成功。