Checkpoint control of cytokinesis

胞质分裂的检查点控制

• 批准号: 9111001
• 负责人: Kathleen L Gould
• 金额: $ 37.62万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111001
• 关键词: Actomyosin; Address; Animal Model; Biochemical; Biochemistry; Biological; Biological Assay; CSNK1A1 gene; Cell Cycle; Cell Death; Cell division; Cells; Chromosome Segregation; Complement; Coupled; Coupling; Cytokinesis; Data; Data Set; Defect; Development; Disease; Elements; Ensure; Enzymes; Event; Evolution; Failure; Fission Yeast; Fostering; Genetic; Genetic Screening; Genome; Genomic Instability; Germ Cells; Goals; Health; Human; In Vitro; Investigation; KRP protein; Knowledge; Lead; Maintenance; Malignant Neoplasms; Mammalian Cell; Microscopy; Mitosis; Mitotic; Mitotic Checkpoint; Modeling; Modification; Molecular; Mutagenesis; Organism; Orthologous Gene; PLK1 gene; Pathway interactions; Phosphotransferases; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Property; Protein Kinase; Proteins; Proteomics; Regulation; Regulatory Pathway; Resources; Role; Signal Pathway; Signal Transduction; Staging; Stress; Structural Genes; Testing; Tetraploidy; Therapeutic Intervention; Time; Tumor Suppressor Proteins; Yeasts; base; biological adaptation to stress; carcinogenesis; casein kinase I; chromosome replication; comparative; constriction; daughter cell; design; enzyme substrate; experience; follow-up; functional hypothalamic amenorrhea; genome integrity; imaging genetics; inhibitor/antagonist; insight; live cell imaging; phosphoproteomics; prevent; research study; response; small hairpin RNA; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Cytokinesis, the physical division of one cell into two daughter cells, is the final stage of the cell reproductive cycle and the least well understood. Correctly timing the process of 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 events of the cell cycle. We have made significant progress in identifying and characterizing proteins essential for cytokinesis using a leading model organism for cytokinesis studies, the fission yeast Schizosaccharomyces pombe. We now propose to gain a better understanding of how these myriad proteins are controlled. A Hippo-related protein kinase cascade termed the septation initiation network (SIN) controls assembly, maintenance, and constriction of the actomyosin contractile ring and is therefore the immediate upstream regulator of cytokinesis in S. pombe. Our knowledge is limited however as to what ultimately ensures the coordination of SIN activity and thus cytokinesis, with other events of mitosis. Among other mechanisms, SIN function is directly inhibited by the ubiquitin ligase Dma1 and this comprises a second branch of mitotic checkpoint signaling. Given our new understanding that Dma1 is a general inhibitor of the polo-like kinase, Plo1 at mitotic initiation, we will study whether this mechanism of controlling mitotic inhibition is shared with the human tumor suppressor CHFR. We will determine how Dma1 activity and localization are controlled throughout the cell cycle by upstream pathways including one comprising CK1. We propose a comprehensive set of biochemical and cell biological experiments to fill these knowledge gaps. These focused mechanistic studies will be complemented with phosphoproteomic and genetic screens designed to better understand the signaling landscape during mitosis. Although some wiring aspects of the signaling networks may be found to vary between organisms, these studies will have a major impact for understanding how cytokinesis can in principle be entrained with other events of mitosis to protect genome integrity.

描述(申请人提供)：细胞质分裂，一个细胞分裂成两个子细胞，是细胞繁殖周期的最后阶段，也是最不为人所知的。正确计时胞质分裂过程，使其仅在染色体复制和分离之后发生，对于防止灾难性的基因组不稳定是必要的，因此，胞质分裂与细胞周期的其他事件相一致地受到严格调控。我们使用胞质分裂研究的领先模式生物--裂殖酵母庞贝，在鉴定和鉴定胞质分裂所必需的蛋白质方面取得了重大进展。我们现在建议更好地了解这些无数的蛋白质是如何被控制的。河马相关的蛋白激酶级联被称为分隔起始网络(SIN)，控制着肌动球蛋白收缩环的组装、维持和收缩，因此是S.pombe胞质分裂的直接上游调节因子。然而，我们对最终确保SIN活性以及胞质分裂与其他有丝分裂事件的协调的了解有限。在其他机制中，SIN功能直接被泛素连接酶Dma1抑制，这是有丝分裂检查点信号的第二个分支。鉴于我们对Dma1是Polo样激酶的一般抑制物的新理解，Plo1在有丝分裂开始时， 我们将研究这种控制有丝分裂抑制的机制是否与人类肿瘤抑制基因CHFR相同。我们将确定Dma1的活性和定位如何通过上游途径控制整个细胞周期，其中包括一条包含CK1的途径。我们提出了一套全面的生化和细胞生物学实验来填补这些知识空白。这些重点的机制研究将得到磷酸蛋白质组和基因筛选的补充，旨在更好地了解有丝分裂期间的信号格局。尽管信号网络的一些连接方面可能被发现在不同的生物体之间有所不同，但这些研究将对理解细胞质分裂如何原则上与其他有丝分裂事件一起保护基因组完整性具有重大影响。