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.

摘要 胞质分裂，即一个细胞分裂成两个子细胞的物理分离，是细胞分裂的最后阶段， 尽管人们对它知之甚少，但它是发育和组织动态平衡的核心。正确计时 胞质分裂，使其仅在染色体复制和分离后发生，以防止 灾难性的基因组不稳定，因此，细胞质分裂与其他细胞周期相一致地受到严格调控 事件。使用一种强大的模式生物，裂殖酵母裂殖酵母庞贝，我的实验室已经 进行了开创性的研究，以确定细胞质分裂所必需的蛋白质，并了解无数 组成细胞分裂机制的蛋白质被协调以确保精致的空间和时间 控制细胞分裂。我们建议继续我们在这一领域的基本问题的工作，使用 在两个方向上采取多学科方法。在一个方向上，我们将解决胞质分裂是如何伴随着 通过研究当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，调节有丝分裂检查点的这一分支的CK1酶如何被纺锤体激活 应激，以及CK1信号如何在纺锤体极点与其他途径整合。了解CK1 有丝分裂检查点方面的监管也将为此建立一般的监管机制 酶家族，它们是保守的、多功能的激酶，在许多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的组装和结构的理解 使用复杂的显微镜方法。我们将继续积累我们对 收缩环，F-bar蛋白CDC15，通过定义它如何在质膜上齐聚，以及 其他收缩环部件在CDC15支架上是如何组织的。我们还将检验我们的假设 多个细胞周期和极性激酶在不适当的情况下抑制了CDC15支架的建立 地点和时间，确保它在有丝分裂过程中只在细胞中部组装。这些专注的机械论 研究将得到蛋白质组学和大规模基因筛查的补充，旨在建立 收缩环部件的功能相互作用网络。总而言之，这些研究将产生重大影响 以了解细胞质分裂是如何在从酵母到人类的真核物种中协调进行的。