Regulation of cytokinesis

母公司资助的赠款摘要。胞质分裂，将一个细胞物理分离成两个细胞 子代细胞是细胞分裂的最后阶段，尽管人们对它知之甚少，但它是 对发育和组织动态平衡至关重要。正确地安排胞质分裂的时间，使其发生 只有在染色体复制和分离之后才有必要防止灾难性 基因组不稳定，因此，胞质分裂与其他细胞一致受到严格的调控 周期事件。利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 了解组成细胞分裂机制的无数蛋白质是如何协调的 确保细胞分裂的精致时空控制。我们建议继续我们的 在这一领域使用多学科方法在两个方面寻求基本问题的工作 方向。在一个方向上，我们将解决细胞质分裂是如何与其他事件 通过研究当有丝分裂纺锤体时导致胞质分裂抑制的缺陷进行有丝分裂 被破坏，那么调节有丝分裂检查点这一分支的CK1酶是如何 由纺锤体应激激活，以及CK1信号如何与纺锤体上的其他通路整合 电线杆。在有丝分裂检查点的背景下理解CK1的调控也将建立 该酶家族的一般调节机制是保守的、多功能的 在许多人类疾病中起作用的蛋白激酶。在第二个方向，我们将推进我们的 使用Complex了解收缩环的组装和结构 蛋白质生物化学方法。我们将继续积累我们对主要断头台的知识 收缩环，F-bar蛋白CDC15，通过定义它如何在血浆上齐聚 膜以及其他收缩环组件如何组织在CDC15支架上。我们 也将检验我们的假设，即多个细胞周期和极性激酶抑制建立 在不适当的位置和时间对CDC15支架进行组装，确保其仅在细胞内组装 有丝分裂中期。这些重点机制研究将与蛋白质组学相辅相成。 和大规模基因筛查，旨在建立一个功能性的相互作用网络 收缩环部件。总而言之，这些研究将对理解 细胞质分裂是如何在从酵母到人类的真核生物中被协调的。

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.