Regulatory Enzymes and Systems in Cell Cycle Control

细胞周期控制中的调节酶和系统

• 批准号: 9918408
• 负责人: DAVID Owen MORGAN
• 金额: $ 94.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-06-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918408
• 关键词: Activator Appliances; Award; Behavior; Binding; Biochemical; Biological Process; Cancer Etiology; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell division; Cells; Cellular biology; Chromosome Segregation; Chromosomes; Computer Models; Cyclic AMP-Dependent Protein Kinases; Cyclin-Dependent Kinases; Cytology; Defect; Development; Disease; Enzymes; Eukaryotic Cell; Event; Genetic; Malignant Neoplasms; Methods; Mitosis; Mitotic; Modification; Phosphoric Monoester Hydrolases; Phosphorylation; Process; Proteins; Regulation; Reproduction; Research; Research Personnel; Saccharomyces cerevisiae; Saccharomycetales; Substrate Interaction; System; Time; Ubiquitination; Work; anaphase-promoting complex; daughter cell; event cycle; genetic regulatory protein; human disease; insight; public health relevance; single molecule; tumor progression; ubiquitin ligase

 DESCRIPTION (provided by applicant): The proposed work explores the regulatory system that controls the eukaryotic cell division cycle, with an emphasis on the mechanisms that trigger cell-cycle events at the correct time and in the correct order, resulting in robust and accurate reproduction of the cell. The cell-cycle control system is composed of master regulatory enzymes that include the cyclin-dependent protein kinases and a ubiquitin ligase called the anaphase-promoting complex or APC. In the proposed studies, these enzymes and their biological functions will be analyzed using biochemical, cytological, and computational approaches in the budding yeast Saccharomyces cerevisiae. Much of the work will focus on mechanisms of APC activation and substrate binding, which depend on transient association of the APC with a rate-limiting activator subunit that binds the substrate. A previously unknown activity that regulates binding of activator to the APC will be identified and characterized, and single-molecule methods will be developed for analysis of APC-activator interactions. Computational modeling will be used to explore how the modulation of APC-substrate interactions leads to the ordered ubiquitination of APC targets during mitosis. Biochemical approaches will be used to dissect the effects of APC phosphorylation on activator function and to explore activator regulation in the spindle assembly checkpoint. The proposed work also includes studies of the regulation of cell-cycle progression by protein phosphorylation, with an emphasis on the control of late mitotic events by a specific phosphatase. The information gained from these studies will provide important new insights into the control of cell-cycle progression, and will thereby enhance our understanding of diseases, such as cancer, in which cell-cycle control or chromosome segregation is defective. These studies will also illuminate general mechanisms of protein ubiquitination and phosphorylation, regulatory modifications of major importance throughout cell biology and human disease.

 描述（由适用提供）：拟议的工作探讨了控制真核细胞分裂周期的调节系统，重点是在正确的时间和正确的顺序触发细胞周期事件的机制，从而导致细胞的稳健且准确地再现。细胞周期控制系统由包括细胞周期蛋白依赖性蛋白激酶和泛素连接酶在内的主调节酶组成，称为过期酶促进酶或APC。在拟议的研究中，这些酶及其生物学功能将使用酿酒酵母的生化，细胞学和计算方法进行分析。大部分工作将集中于APC激活和底物结合的机理，这取决于APC与限制底物的速率限制激活因子亚基的瞬时关联。将确定和表征一种先前未知的活性活性活性的活性，并将开发单分子方法以分析APC-激活剂相互作用。计算建模将用于探索APC底物相互作用的调节如何导致有丝分裂过程中APC靶标有序的泛素化。生化方法将用于剖析APC磷酸化对激活剂函数的影响，并探索主轴组装检查点中的激活因子调节。拟议的工作还包括研究通过蛋白质磷酸化来调节细胞周期进展，重点是通过特定的磷酸酶控制晚期有丝分裂事件。从这些研究中获得的信息将为细胞周期进展的控制提供重要的新见解，从而增强我们对癌症（例如癌症）的理解，在这种疾病中，细胞周期控制或染色体隔离有缺陷。这些研究还将阐明蛋白质泛素化和磷酸化的一般机制，整个细胞生物学和人类疾病的主要重要性的调节修饰。