Regulation of cytokinesis

胞质分裂的调节

• 批准号: 10392903
• 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/10392903
• 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 细胞分裂，即一个细胞物理分离成两个子细胞，是细胞分裂的最后阶段， 尽管人们对其了解最少，但它对于发育和组织稳态至关重要。正确计时 胞质分裂仅在染色体复制和分离之后发生，以防止 灾难性的基因组不稳定性，因此，胞质分裂与其他细胞周期一致受到严格调控 事件。我的实验室使用强大的模型生物——裂殖酵母粟酒裂殖酵母 进行了开创性的研究，以确定胞质分裂所必需的蛋白质，并了解无数的蛋白质如何 组成细胞分裂机制的蛋白质相互协调，以确保精确的空间和时间 细胞分裂的控制。我们建议继续努力解决这一领域的基本问题 两个方向的多学科方法。在一个方向上，我们将解决胞质分裂是如何被夹带的 通过研究有丝分裂纺锤体时导致胞质分裂抑制的缺陷来研究有丝分裂的其他事件 被破坏后，调节有丝分裂检查点分支的 CK1 酶如何被纺锤体激活 应激，以及 CK1 信号如何与纺锤体极的其他通路整合。了解 CK1 有丝分裂检查点背景下的调节也将为此建立一般调节机制 酶家族，是保守的多功能激酶，在多种人类疾病中发挥作用。在一个 第二个方向，我们将加深对收缩环组装和架构的理解 使用复杂的显微镜方法。我们将继续积累对主要支架的知识 收缩环，F-BAR 蛋白 Cdc15，通过定义它如何在质膜上寡聚化，以及 其他收缩环组件如何在 Cdc15 支架上组织。我们还将检验我们的假设 多个细胞周期和极性激酶以不适当的方式抑制 Cdc15 支架的建立 地点和时间，确保它仅在有丝分裂期间在细胞中部组装。这些重点机械 研究将辅之以蛋白质组学和大规模遗传筛选，旨在建立 收缩环组件的功能相互作用网络。这些研究共同将产生重大影响 了解从酵母到人类的真核物种中胞质分裂是如何协调的。