The Role of Progesterone Receptor Phosphorylation in Target Gene Regulation

孕酮受体磷酸化在靶基因调控中的作用

• 批准号: 7609135
• 负责人: Robert Daryl Ward
• 金额: $ 4.96万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609135
• 关键词: Affect; Binding; Binding Sites; Biology; Breast Cancer Cell; Cell Line; Chromatin; Complex; Consensus; Data; Development; Disease; Drug Delivery Systems; Employee Strikes; Environment; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetically Engineered Mouse; Goals; Growth and Development function; Hormones; Human; In Vitro; Investigation; Knockout Mice; Lead; Learning; Malignant Neoplasms; Mammary gland; Mediating; Microarray Analysis; Modification; Mus; Mutant Strains Mice; Normal tissue morphology; Organ; Other Body Part; Ovarian; Ovary; Phosphorylation; Phosphorylation Site; Physiological; Play; Progesterone; Progesterone Receptors; Progestins; Recruitment Activity; Regulation; Reporter; Research; Research Training; Response Elements; Role; Signal Transduction; Site; Standards of Weights and Measures; Steroid Receptors; Steroids; Testing; Tissues; Transcription Coactivator; Translating; Uterine Cancer; Uterus; concept; experience; human disease; in vivo; innovation; malignant breast neoplasm; mouse model; progesterone receptor A; progesterone receptor B; protein protein interaction; receptor; receptor binding; receptor function; research study; response; steroid hormone; ward

DESCRIPTION (provided by applicant): The steroid hormone, progesterone, plays key roles including the growth and development of the mammary glands, uterus, and ovaries. The physiological effects of progesterone occur mainly through its interaction with the specific steroid receptor, progesterone receptor (PR). The target genes for PR have been identified in various tissues, including those implicated in breast cancer. Phosphorylation is an integral regulator of protein/protein interactions, which are required for steroid receptors (SRs), like PR, to recruit coactivators and interact with target genes. Understanding SR function requires the elucidation of how these complex interactions are regulated. The goal of this proposal is to understand how site-specific protein phosphorylation regulates the activity of the PR. The hypothesis is site-specific PR phosphorylation facilitates protein/protein interactions that are essential for the regulation of subsets of PR target genes. In addition, this phosphorylation is an important prerequisite for context and tissue-specific, physiological actions or PR in response to hormone. We have identified the Ser190 phosphorylation sites in human PR and the homologous site in mice, Ser191, and have extensive experience in studying PR actions and the effects of cell signaling on PR. The specific aims are: 1) to determine the mechanism by which Ser190 phosphorylation modulates PR function in human breast cancer cells, 2) to test the concept that selective elimination of a PR phosphorylation site will compromise PR function in vivo in mice, and 3) to perform limited gene expression studies in wild type and PRAIa191 mutant mice. This will be the first test for a role of any steroid receptor phosphorylation in vivo. It is expected that the site-specific phosphorylation of PR at Ser190 is essential for the regulation of a subset of PR target genes in response to hormone. The destruction of the homologous phosphorylation site in mice will verify its importance in vivo. Successful completion of these studies will have a major impact in demonstrating the importance of how PR modifications can affect its function. By increasing our understanding of how PR and other steroid receptors function, we can develop drugs that target certain functions of the specific steroid receptor to treat diseases like breast cancer and uterine cancer without causing harm to other parts of the body.

描述(申请人提供)：类固醇激素，黄体酮，发挥关键作用，包括乳腺，子宫和卵巢的生长和发育。孕酮的生理作用主要是通过与特定的类固醇受体--孕激素受体(PR)相互作用来实现的。PR的靶基因已经在各种组织中被发现，包括那些与乳腺癌有关的组织。磷酸化是蛋白质/蛋白质相互作用的一个整体调节因子，类固醇受体(SRs)，如PR，需要它来招募辅助激活因子并与靶基因相互作用。要了解SR的功能，需要阐明这些复杂的相互作用是如何调节的。这项建议的目的是了解特定部位的蛋白磷酸化如何调节PR的活性。该假说认为，特定部位的PR磷酸化促进了蛋白质/蛋白质的相互作用，而这些相互作用对于调节PR靶基因的亚组是必不可少的。此外，这种磷酸化是环境和组织特异性生理行为或激素反应PR的重要先决条件。我们已经确定了人PR中的Ser190磷酸化位点和小鼠中的同源位点Ser191，并在研究PR的作用和细胞信号对PR的影响方面拥有丰富的经验。其具体目的是：1)确定Ser190磷酸化调控人乳腺癌细胞PR功能的机制；2)测试选择性消除PR磷酸化位点将损害小鼠体内PR功能的概念；3)在野生型和PRAIa191突变小鼠中进行有限的基因表达研究。这将是第一次在体内测试类固醇受体磷酸化的作用。预期PR在Ser190位点的特异性磷酸化对于调节PR靶基因对激素的反应是必不可少的。小鼠体内同源磷酸化位点的破坏将验证其在体内的重要性。这些研究的成功完成将对证明公关修饰如何影响其功能的重要性产生重大影响。通过增加对PR和其他类固醇受体功能的了解，我们可以开发针对特定类固醇受体的特定功能的药物，以治疗乳腺癌和子宫癌等疾病，而不会对身体其他部位造成伤害。