Structural and Systematic Biology of PP2A and Cancer Treatment.

PP2A 的结构和系统生物学和癌症治疗。

• 批准号: 7184556
• 负责人: Yongna Xing
• 金额: $ 10.71万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7184556
• 关键词: Affect; Biochemical; Catalytic Domain; Cell Line; Cell physiology; Cells; Complex; Data; Development; Goals; Growth; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Mammalian Cell; Methods; Methylation; Methyltransferase; Neoplasm Metastasis; Okadaic Acid; Oncogenic; Phosphoric Monoester Hydrolases; Phosphorylation; Process; Protein phosphatase; Proteins; Proteomics; Regulation; Regulatory Element; Research; Role; SET gene; Structure; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Tumor Suppressor Proteins; base; cancer cell; cancer therapy; cell growth; design; dimer; genetic regulatory protein; inhibitor/antagonist; protein structure; small molecule; systematic biology

DESCRIPTION (provided by applicant): Protein phosphatase 2A (PP2A) is a major Ser/Thr protein phosphatase in mammalian cells that is involved in multiple processes. Deregulation of PP2A activity often leads to oncogenic transformation, which has led to the notion that PP2A is an important tumor suppressor. Due to its multi-subunit composition and its ability to interact with numerous regulatory proteins, the structure and regulation of PP2A remains poorly understood. The long-term goal of the applicant is to deduce the mechanism of PP2A regulation using a structural approach and to refine our knowledge of its roles in cell function using proteomic methods. This information will facilitate the development of potential PP2A based strategies for cancer therapy. The immediate goals of this research are i) to solve the structure of PP2A methyltransferase (PMT) and methylesterase (PME) in complex with the PP2A A-C core dimer and thereby elucidate the mechanism of reversible methylation of the catalytic subunit, a process that is essential for PP2A regulation, and to provide the long-awaited structural information for A-C complex; ii) to elucidate the mechanism of cellular inhibitory proteins I1PP2A and I2PP2A to inhibit the phosphatase activity of PP2A using structural and biochemical approach, and to investigate the roles of the common poly-acidic motif existed in PME, alpha4 protein, I1PP2A and I2PP2A; and iii) to resolve the protein phosphorylation profiles in cells affected by small molecule inhibitors such as okadaic acid, and by the methylation process, by alpha4 protein, I1PP2A, I2PP2A and some of the regulatory B-subunits. Their effects on cell growth, proliferation will also be tested on carcinoma cell lines. The activity of PP2A is often down regulated in cancer cells. The inhibitory proteins that down regulate PP2A function, such as PME, alpha4 protein, 11PP2A and I2PP2A are excellent targets for therapeutic intervention of cancer. The proteomic data should facilitate the identification of the regulatory element of PP2A that has the greatest promise for use as a target, and the structural data should provide ultimate clarity to PP2A regulation and function, and facilitate the design of therapeutic compounds that have the greatest potential therapeutic use for slowing or halting the growth, proliferation, and metastasis of oncogenic cells.

描述（由申请人提供）：蛋白磷酸酶2A（PP 2A）是哺乳动物细胞中主要的Ser/Thr蛋白磷酸酶，参与多种过程。PP 2A活性的失调通常导致致癌转化，这导致了PP 2A是重要的肿瘤抑制因子的概念。由于其多亚基组成及其与许多调节蛋白相互作用的能力，PP 2A的结构和调节仍然知之甚少。申请人的长期目标是使用结构方法推导PP 2A调节的机制，并使用蛋白质组学方法完善我们对其在细胞功能中的作用的知识。这些信息将有助于开发基于PP 2A的潜在癌症治疗策略。本研究的近期目标是：（1）解析PP 2A甲基转移酶（PMT）和甲基酯酶（PME）与PP 2A A-C核心二聚体复合物的结构，从而阐明PP 2A调控所必需的催化亚基可逆甲基化的机制，并为A-C复合物提供期待已久的结构信息;（2）从结构和生物化学角度阐明细胞抑制蛋白I1 PP 2A和I2 PP 2A抑制PP 2A磷酸酶活性的机制，并探讨PME、α 4蛋白、I1 PP 2A和I2 PP 2A中存在的共同多酸基序的作用;和iii）解析受小分子抑制剂如冈田酸影响的细胞中的蛋白磷酸化谱，以及受α 4蛋白、I1 PP 2A、I2 PP 2A和一些调节性B亚基的甲基化过程影响的细胞中的蛋白磷酸化谱。还将在癌细胞系上测试它们对细胞生长、增殖的影响。PP 2A的活性通常在癌细胞中下调。PME、α 4蛋白、11 PP 2A和I2 PP 2A等下调PP 2A功能的抑制性蛋白是肿瘤治疗的理想靶点。蛋白质组学数据应有助于鉴定最有希望用作靶点的PP 2A调控元件，结构数据应提供PP 2A调控和功能的最终清晰度，并有助于设计具有最大潜在治疗用途的治疗化合物，用于减缓或停止致癌细胞的生长、增殖和转移。