Regulation of cytokinesis

胞质分裂的调节

• 批准号: 10380944
• 负责人: Kathleen L Gould
• 金额: $ 8.78万
• 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/10380944
• 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; Funding; Genetic Screening; Genomic Instability; Goals; Grant; Homeostasis; Human; Knowledge; Learning; Location; Maintenance; Mitosis; Mitotic Checkpoint; Mitotic spindle; Molecular Structure; Myosin ATPase; Parents; Pathway interactions; Phosphotransferases; Process; Protein Biochemistry; 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

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, how the CK1 enzymes that regulate this branch of the mitotic checkpoint are activated by spindle stress, and how CK1 signaling 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 protein biochemistry 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.

家长资助的补助金摘要。细胞分裂，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，但它是 对发育和组织稳态至关重要。正确计时胞质分裂以使其发生 仅在染色体复制和分离对于防止灾难性后果是必要的之后 基因组不稳定，因此，胞质分裂与其他细胞一致受到严格调节 循环事件。使用强大的模型生物体，裂殖酵母粟酒裂殖酵母， 我的实验室进行了开创性的研究，以确定胞质分裂所必需的蛋白质，并 了解组成细胞分裂机制的无数蛋白质如何协调 确保细胞分裂的精确空间和时间控制。我们建议继续我们的 使用多学科方法在两个领域研究该领域的基本问题 方向。在一个方向上，我们将解决胞质分裂如何与其他事件一起夹带的问题。 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 被破坏了，调节有丝分裂检查点这个分支的 CK1 酶是如何被破坏的 由纺锤体应激激活，以及 CK1 信号如何与纺锤体的其他通路整合 两极。了解有丝分裂检查点背景下的 CK1 调节也将建立 该酶家族的一般调节机制是保守的、多功能的 激酶在许多人类疾病中发挥作用。在第二个方向上，我们将推进我们的 使用复杂的技术了解收缩环的组装和结构 蛋白质生物化学方法。我们将继续积累对主要脚手架的知识 收缩环，F-BAR 蛋白 Cdc15，通过定义它如何在血浆上寡聚化 膜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，即多个细胞周期和极性激酶抑制建立 Cdc15支架在不适当的位置和时间，确保它只在细胞中组装 有丝分裂中期。这些重点机制研究将得到蛋白质组学的补充 以及旨在建立功能相互作用网络的大规模遗传筛选 收缩环组件。总之，这些研究将对理解产生重大影响 从酵母到人类的真核物种中胞质分裂是如何协调的。