Regulation of cytokinesis

胞质分裂的调节

• 批准号: 10794021
• 负责人: Kathleen L Gould
• 金额: $ 22.98万
• 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/10794021
• 关键词: Actins; Architecture; CSNK1A1 gene; Cell Cycle; Cell Death; Cell division; Cell membrane; Cells; Chromosome Segregation; Complement; Cytokinesis; Defect; Development; Ensure; Enzymes; Event; Family; Fission Yeast; Funding; Genetic Screening; Genomic Instability; Goals; Grant; Homeostasis; Human; Knowledge; Learning; Location; Maintenance; Microscopy; Mitosis; Mitotic Checkpoint; Mitotic spindle; Molecular Structure; Myosin ATPase; Parents; Phosphotransferases; Process; Proteins; Proteomics; Regulation; Research; Role; Stress; Testing; Time; Tissues; Work; Yeasts; chromosome replication; daughter cell; design; event cycle; human disease; interdisciplinary approach; model organism; physical separation; prevent; scaffold

Summary of the parent funded grant. 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 and how the CK1 enzymes that regulate this branch of the mitotic checkpoint are activated by spindle stress. 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 14-3-3 proteins 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.

父母资助的赠款的摘要。细胞因子，一个细胞的物理分离为两个 子细胞是细胞分裂的最后阶段，尽管最不理解的是 发育和组织稳态的中心。正确地定时细胞因子，以便发生 仅在染色体复制和隔离之后才能防止灾难性 基因组不稳定性，因此，细胞因子与其他细胞一致严格调节 周期事件。使用强大的模型生物，裂变酵母裂菌酵母Pombe， 我的实验室进行了开创性研究，以识别细胞因子必不可少的蛋白质和 了解构成细胞分裂机械的无数蛋白质如何协调 确保细胞分裂的精美空间和时间控制。我们建议继续我们的 在这两种方面使用多学科方法在该领域追求基本问题的工作 方向。在一个方向上，我们将解决其他事件的细胞因子的夹带 通过研究有丝分裂主轴时导致细胞因子抑制的缺陷来通过有丝分裂。 被破坏以及如何调节有丝分裂检查点的CK1酶是 被纺锤应力激活。在有丝分裂的背景下了解CK1调节 检查站还将建立该酶家族的一般调节机制，该机制 是保守的多功能激酶，在许多人类疾病中起作用。一秒钟 方向，我们将提高我们对收缩的组装和建筑的理解 使用复杂的显微镜方法环。我们将继续建立我们对 收缩环的主要脚手架F-BAR蛋白CDC15通过定义其低聚 在质膜上，以及如何在 CDC15脚手架。我们还将检验我们的假设，即14-3-3蛋白会抑制建立 在不适当的位置和时间处的Cdc15脚手架，确保仅在单元格中组装 有丝分裂期间中间。这些重点的机械研究将与蛋白质组学补充 和大规模的遗传筛选，旨在建立一个功能相互作用网络 收缩环组件。这些研究一起将对理解产生重大影响 从酵母到人类的真核物种中如何精心策划细胞因子。