Regulation of cytokinesis

胞质分裂的调节

• 批准号: 9921422
• 负责人: Kathleen L Gould
• 金额: $ 69.7万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921422
• 关键词: Actins; Animal Model; Architecture; CSNK1A1 gene; Cell Cycle; Cell Death; Cell Polarity; Cell division; Cell membrane; Cells; Chromosome Segregation; Complement; Cytokinesis; Defect; Development; Ensure; Enzymes; Event; Family; Fission Yeast; Genetic Screening; Genomic Instability; Goals; Homeostasis; Human; Knowledge; Learning; Location; Maintenance; Microscopy; Mitosis; Mitotic Checkpoint; Mitotic spindle; Molecular Structure; Myosin ATPase; Pathway interactions; Phosphotransferases; Process; Proteins; Proteomics; Regulation; Research; Role; Signal Transduction; Stress; Testing; Time; Tissues; Work; Yeasts; base; chromosome replication; daughter cell; design; event cycle; human disease; interdisciplinary approach; physical separation; prevent; scaffold

Abstract Cytokinesis, the physical separation of one cell into two daughter cells, is the final stage of cell division, and although it is the least well understood, it is central to development and tissue homeostasis. Correctly timing cytokinesis so that it occurs only after chromosome replication and segregation is necessary to prevent catastrophic genomic instability, and accordingly, cytokinesis is strictly regulated in concert with other cell cycle events. Using a powerful model organism, the fission yeast Schizosaccharomyces pombe, my lab has conducted pioneering research to identify proteins essential for cytokinesis and to learn how the myriad proteins that comprise the cell division machinery are coordinated to ensure the exquisite spatial and temporal control of cell division. We propose to continue our work pursuing fundamental questions in this field using a multi-disciplinary approach in two directions. In one direction, we will tackle how cytokinesis is entrained with other events of mitosis by investigating the defect that leads to inhibition of cytokinesis when the mitotic spindle is disrupted, how the CK1 enzymes that regulate this branch of the mitotic checkpoint are activated by spindle stress, and how CK1 signalling is integrated with other pathways at spindle poles. Understanding CK1 regulation in the context of the mitotic checkpoint will also establish general mechanisms of regulation for this enzyme family, which are conserved, multifunctional kinases with roles in numerous human diseases. In a second direction, we will advance our understanding of the assembly and architecture of the contractile ring using sophisticated microscopy approaches. We will continue to build our knowledge of the major scaffold of the contractile ring, the F-BAR protein Cdc15, by defining how it oligomerizes on the plasma membrane, and how other contractile ring components are organized on the Cdc15 scaffold. We will also test our hypothesis that multiple cell cycle and polarity kinases inhibit the establishment of the Cdc15 scaffold at inappropriate locations and times, ensuring it only assembles in the cell middle during mitosis. These focused mechanistic studies will be complemented with proteomic and large-scale genetic screens designed to establish a functional interaction network of contractile ring components. Together, these studies will have a major impact for understanding how cytokinesis is orchestrated in eukaryotic species from yeast to humans.

抽象的 细胞因子是一个细胞分为两个子细胞的物理分离，是细胞分裂的最后阶段， 尽管它是最不理解的，但它对于发育和组织稳态是至关重要的。正确的时间 细胞因子，因此仅在染色体复制和隔离之后才发生以防止 灾难性的基因组不稳定性，因此，细胞因子与其他细胞周期严格调节 事件。使用功能强大的模型生物，裂变酵母裂菌酵母POMBE，我的实验室有 进行了开创性的研究，以识别细胞因子必不可少的蛋白质并了解众多 构成细胞分裂机械的蛋白质是协调的，以确保精美的空间和时间 控制细胞分裂。我们建议继续我们的工作在该领域追求基本问题的工作 多学科方法在两个方向上。在一个方向上，我们将解决细胞因子的夹带 其他有丝分裂事件通过研究有丝分裂主轴时导致抑制细胞因子的缺陷 被破坏了，如何通过主轴激活调节有丝分裂检查点的CK1酶 应力，以及如何将CK1信号与主轴杆的其他途径集成在一起。了解CK1 在有丝分裂检查点的背景下的调节还将为此建立一般调节机制 酶家族是保守的多功能激酶，在许多人类疾病中作用。在 第二个方向，我们将提高对收缩戒指的组装和架构的理解 使用复杂的显微镜方法。我们将继续建立对主要脚手的知识 收缩环，F-Bar蛋白Cdc15，通过定义其在质膜上的低聚和 如何在Cdc15支架上组织其他收缩环组件。我们还将检验我们的假设 多个细胞周期和极性激酶抑制了在不适当的情况下建立Cdc15脚手架的 位置和时间，确保在有丝分裂过程中仅在细胞中间组装。这些专注的机械 研究将与蛋白质组学和大规模的遗传筛选相辅相成。 收缩环组件的功能相互作用网络。这些研究在一起将产生重大影响 为了了解从酵母到人类的真核物种中的细胞因子如何精心策划。