Regulation of cytokinesis

胞质分裂的调节

基本信息

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
项目类别：
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

项目摘要

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.

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。被破坏了，如何调节有丝分裂检查点的CK1酶是由主轴应力激活，以及如何与纺锤体的其他途径集成杆。在有丝分裂检查点的背景下了解CK1调节也将建立该酶家族的调节的一般机制，这些酶家族是保守的，多功能的激酶在许多人类疾病中具有作用。在第二个方向上，我们将促进我们的使用精致的收缩环的组装和结构理解蛋白质生物化学方法。我们将继续建立对主要脚手架的知识收缩环，F-BAR蛋白Cdc15的定义如何在等离子体上的低聚膜以及如何在CDC15支架上组织其他收缩环组件。我们还将检验我们的假设，即多个细胞周期和极性激酶会抑制建立在不适当的位置和时间处的Cdc15支架的数量有丝分裂期间中间。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。