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.

家长资助补助金摘要。胞质分裂，一个细胞物理分离成两个 子细胞，是细胞分裂的最后阶段，虽然它是最不清楚的，但它是 对发育和组织平衡至关重要。正确地定时胞质分裂， 只有在染色体复制和分离后，才有必要防止灾难性的 基因组不稳定性，因此，胞质分裂与其它细胞一起受到严格调节 循环事件。使用一种强大的模式生物，裂殖酵母粟酒裂殖酵母， 我的实验室进行了开创性的研究，以确定细胞分裂所必需的蛋白质， 了解构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时空控制。我们建议继续我们的 在这一领域采用多学科方法开展基本问题的工作， 方向在一个方向上，我们将解决胞质分裂是如何夹带其他事件， 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，调节有丝分裂检查点的这个分支的CK 1酶是如何被破坏的？ 以及CK 1信号如何与纺锤体上的其他通路整合 波兰人了解CK 1在有丝分裂检查点的调节也将建立 这种酶家族的一般调节机制是保守的，多功能的， 在许多人类疾病中发挥作用的激酶。在第二个方向，我们将推进我们的 了解收缩环的组装和结构， 蛋白质生物化学方法。我们将继续建立我们的知识的主要脚手架 收缩环，F-BAR蛋白Cdc 15，通过定义它如何在血浆中寡聚化， 膜以及其他收缩环组件如何在Cdc 15支架上组织。我们 也将测试我们的假设，多个细胞周期和极性激酶抑制建立 Cdc 15支架在不适当的位置和时间，确保它只在细胞中组装 在有丝分裂的中间。这些集中的机制研究将补充蛋白质组学 和大规模的基因筛选，旨在建立一个功能性的相互作用网络， 收缩环成分。总之，这些研究将对理解 从酵母到人类的真核生物中胞质分裂是如何协调的。