Checkpoint control of cytokinesis

胞质分裂的检查点控制

• 批准号: 8799120
• 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/8799120
• 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; Human; In Vitro; Investigation; KRP protein; Knowledge; Lead; Life; Maintenance; Malignant Neoplasms; Mammalian Cell; Microscopy; Mitosis; Mitotic; Mitotic Checkpoint; Modeling; Modification; Molecular; Mutagenesis; Organism; Orthologous 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 Protein; Testing; Tetraploidy; Therapeutic Intervention; Time; Tumor Suppressor Proteins; Yeasts; base; biological adaptation to stress; carcinogenesis; casein kinase I; cellular imaging; chromosome replication; comparative; constriction; daughter cell; design; enzyme substrate; experience; follow-up; functional hypothalamic amenorrhea; human PLK1 protein; inhibitor/antagonist; insight; prevent; public health relevance; 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）：细胞质分裂，一个细胞物理分裂成两个子细胞，是细胞生殖周期的最后阶段，也是最不为人所知的。正确地安排细胞质分裂过程，使其只发生在染色体复制和分离之后，这对于防止灾难性的基因组不稳定是必要的，因此，细胞质分裂与细胞周期的其他事件一起受到严格调节。我们利用分裂酵母裂糖酵母（Schizosaccharomyces pombe）作为细胞质分裂研究的主要模式生物，在鉴定和表征细胞质分裂所必需的蛋白质方面取得了重大进展。我们现在提议更好地了解这些无数的蛋白质是如何被控制的。一种称为分隔起始网络（SIN）的海马相关蛋白激酶级联控制着肌动球蛋白收缩环的组装、维持和收缩，因此是pombe细胞分裂的直接上游调节剂。然而，我们的知识是有限的，什么最终确保协调SIN活性，从而细胞质分裂，与其他事件的有丝分裂。在其他机制中，SIN功能直接受到泛素连接酶Dma1的抑制，这包括有丝分裂检查点信号的第二个分支。鉴于我们对Dma1是有丝分裂起始时polo样激酶（Plo1）的一般抑制剂的新认识，