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（由申请人提供）：一个细胞分为两个子细胞的细胞因子是细胞生殖循环的最后阶段，也是最不理解的阶段。正确地将细胞因子的过程计时，以便仅在染色体复制和隔离之后才能防止灾难性的基因组不稳定性，因此，在与细胞周期的其他事件中，严格调节细胞因子。我们在鉴定和表征蛋白质的蛋白质中取得了重大进展，该蛋白质使用领先的模型生物体进行细胞因子研究，即裂变酵母酵母菌酸果实Charomyces Pombe。现在，我们建议更好地了解这些众多蛋白质的控制。河马相关的蛋白激酶级联反应称为分隔起始网络（SIN）控制肌动蛋白收缩环的组装，维护和收缩，因此是S. Pombe中细胞因子的直接上游调节剂。但是，我们的知识是有限的，即最终确保犯罪活动的协调以及其他有丝分裂事件的协调。在其他机制中，泛素连接酶DMA1直接抑制罪名，这包括有丝分裂检查点信号的第二个分支。鉴于我们的新了解，DMA1是polo样激酶的一般抑制剂，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剂CHFR共享。我们将通过上游途径（包括一项包含CK1）来确定在整个细胞周期中如何控制DMA1活性和定位。我们提出了一组全面的生化和细胞生物学实验，以填补这些知识差距。这些集中的机械研究将与磷蛋白质组学和遗传筛选相辅相成，旨在更好地了解有丝分裂期间的信号传导局势。尽管可能发现信号网络的某些接线方面在生物体之间有所不同，但这些研究将对理解如何与其他有丝分裂事件夹带的细胞因子如何保护基因组完整性，从而产生重大影响。