Molecular Determinants of Androgen Receptor Function

雄激素受体功能的分子决定因素

• 批准号: 7315894
• 负责人: ELIZABETH M. WILSON
• 金额: $ 31.41万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315894
• 关键词: Affinity; Androgen Receptor; Androgen-Insensitivity Syndrome; Androgens; Antigens; Binding; Complex; Defect; Docking; EGF gene; Endometrium; Female; Fertility; Gene Proteins; Genes; Genetic Transcription; Growth Factor; Human; Knock-out; Ligand Binding; Ligand Binding Domain; Ligands; Link; Luteinizing Hormone; Mediating; Modification; Molecular; Monkeys; Mus; Mutation; N-terminal; NCOA2 gene; NCOA3 gene; Ovarian; Ovarian Follicle; Ovary; Pattern; Phosphorylation; Premature Ovarian Failure; Proteins; Receptor Signaling; Regulation; Relative (related person); Role; Signal Transduction; Site; Steroid Receptors; Syndrome; base; folliculogenesis; hormone regulation; male; melanoma; natural Blastocyst Implantation; receptor function; reproductive; response; selective androgen receptor modulator

We have identified melanoma antigen gene product MAGE-n as an androgen receptor (AR) coregulator that increases AR activity in the presence of androgen by modulating steroid receptor pi6o coactivator recruitment. Studies outlined in this proposal will determine whether MAGE-n serves as a docking site for AR coregulators in the normal male and female reproductive tract and in polycystic ovarian syndrome (PCOS). Our hypothesis is that MAGE-n modulates AR activity in human ovary and endometrium by facilitating the recruitment of coregulators to the AR transcription complex through direct and indirect mechanisms. Our studies will establish the temporal pattern of MAGE-n expression over the reproductive cycle in the human and monkey ovary and endometrium. We will establish the function of MAGE-n and AR in the endometrium during the window of receptivity to embryo implantation and explore whether temporal changes in MAGE-n influence folliculogenesis and maturation by modulating AR signaling. Our preliminary studies indicate EGF signaling controls MAGE-n coregulator activity. We will determine the effects of EGF on phosphorylation and ubiqutinylation of MAGE-n and how these post-transcriptional modifications alter interactions between AR and coregulators. We will investigate the structural basis for naturally occurring mutations in AR and MAGE-n that alter AR function without changing high affinity androgen binding. A structural relay between the ligand binding pocket and activation function 2 in the ligand binding domain that occurs in response to high affinity androgen binding will be characterized to determine how naturally occurring gene defects can be overcome by selective AR ligands and modulators. Specific aim i will identify the temporal pattern of expression and hormone regulation of MAGE-n relative to AR and other AR coregulators in human and monkey ovary and human endometrium and alterations in expression associated with PCOS. Specific aim 2 will establish the mechanisms whereby MAGE-ii modulates AR transcriptional activity by acting as a coregulator docking site in normal and PCOS ovary and endometrium. Specific aim 3 will determine the mechanisms whereby EGF signaling modulates AR transcriptional activity through phosphorylation and ubiquitinylation of MAGE-ii. Specific aim 4 will establish the functional basis for naturally occurring AR mutations that cause the androgen insensitivity syndrome and determine whether mutations in the MAGE-n gene cause AIS in the male and premature ovarian failure in the female.

我们已经鉴定出黑色素瘤抗原基因产物 MAGE-n 作为雄激素受体 (AR) 共调节剂， 通过调节类固醇受体 pi6o 共激活剂，在雄激素存在的情况下增加 AR 活性 招聘。该提案中概述的研究将确定 MAGE-n 是否可以作为 正常男性和女性生殖道以及多囊卵巢综合征中的 AR 共调节因子 （多囊卵巢综合症）。我们的假设是 MAGE-n 通过以下方式调节人类卵巢和子宫内膜中的 AR 活性： 通过直接和间接促进 AR 转录复合体招募辅助调节因子 机制。我们的研究将建立生殖细胞中 MAGE-n 表达的时间模式 人类和猴子的卵巢和子宫内膜中的周期。我们将建立MAGE-n和AR的功能 在胚胎着床接受窗口期的子宫内膜中，探索颞叶是否 MAGE-n 的变化通过调节 AR 信号传导影响卵泡发生和成熟。我们的 初步研究表明 EGF 信号控制 MAGE-n 辅助调节器活性。我们将确定 EGF 对 MAGE-n 磷酸化和泛素化的影响以及这些转录后机制 修改改变了 AR 和核心调节器之间的相互作用。我们将研究结构基础 AR 和 MAGE-n 中自然发生的突变可改变 AR 功能而不改变高亲和力 雄激素结合。配体结合口袋和激活函数 2 之间的结构中继 响应于高亲和力雄激素结合而发生的配体结合结构域将被表征为 确定如何通过选择性 AR 配体和调节剂克服自然发生的基因缺陷。 具体目标是确定 MAGE-n 相关表达和激素调节的时间模式 对人类和猴子卵巢以及人类子宫内膜中 AR 和其他 AR 共调节因子的影响以及 与 PCOS 相关的表达。具体目标 2 将建立 MAGE-ii 的机制 通过充当正常和 PCOS 卵巢中的核心调节器对接位点来调节 AR 转录活性 子宫内膜。具体目标 3 将确定 EGF 信号传导调节 AR 的机制 通过 MAGE-ii 的磷酸化和泛素化发挥转录活性。具体目标4将 为导致雄激素不敏感的自然发生的 AR 突变奠定功能基础 综合征并确定 MAGE-n 基因突变是否会导致男性和早产儿的 AIS 女性卵巢功能衰竭。