Understanding Cell Division

了解细胞分裂

• 批准号: 10188558
• 负责人: GARY J. GORBSKY
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188558
• 关键词: Anaphase; Aneuploidy; Automobile Driving; Biochemical Pathway; Bioinformatics; Cell division; Chromatids; Chromosome Deletion; Chromosome Segregation; Chromosome abnormality; Chromosomes; Complex; Congenital Abnormality; Disease; Elements; Fatigue; Infertility; Kinetochores; Laboratories; Malignant Neoplasms; Metaphase; Metaphase Plate; Mitotic; Molecular; Normal Cell; Oncogenes; Pathway interactions; Process; Protein phosphatase; Regulatory Pathway; Reporting; Source; Testing; Tumor Suppressor Proteins; Vertebrates; Work; anaphase-promoting complex; cell transformation; chromosome missegregation; cohesion; multicatalytic endopeptidase complex; programs; protein complex; ubiquitin-protein ligase

Abstract Cell division requires a complex network of dozens of pathways whose interactions drive key transitions. One of the most critical is the transition from metaphase to anaphase and mitotic exit. The Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase, comprises the central target node of this critical decision point. APC/C activity is sensitive to chromosome congression to the metaphase plate. At metaphase, the APC/C ubiquitylates target mitotic regulators for destruction in the proteasome and induction of chromatid separation and mitotic exit. While regulatory pathways for the APC/C have been identified, complete understanding of how it is tuned to program the metaphase-anaphase transition after chromosome alignment remains unclear. Recent work has implicated the Spindle and Kinetochore Associated (Ska) protein complex as a key element. The studies proposed will clarify the molecular mechanisms by which Ska collaborates with and controls other mitotic regulators, particularly protein phosphatases, governing the temporal and spatial activation of the APC/C to drive the metaphase-anaphase transition. Metaphase, itself, is generally brief, but the Gorbsky laboratory discovered that delays, even short ones, can cause partial or complete chromatid separation, a phenomenon termed “cohesion fatigue.” Cohesion fatigue may be remarkably common as a source of both numerical aneuploidy and large chromosome deletions, duplications and translocations, particularly in cells transformed by activated oncogenes and the loss of tumor suppressors. The Gorbsky laboratory is taking a broad approach to study all potential inputs that contribute to cohesion fatigue. The laboratory is also mapping the short term and long term consequences of cohesion fatigue to determine how it promotes chromosome missegregation and damage. Finally, complete understanding of cell division and its transitions can only occur if all components and regulators of the process are identified. While the mitotic parts list is already large, continued reports of new components indicate that it is not yet complete in vertebrates. Using bioinformatic guidance that has proven highly effective, the Gorbsky lab is testing candidate mitotic regulators and characterizing their functions in cell division in normal and transformed cells.

摘要 细胞分裂需要一个由数十条通路组成的复杂网络，这些通路的相互作用驱动着关键的转变。其中之一 最关键的是中期到后期的过渡和有丝分裂的退出。后期促进 复合体/环体(APC/C)是一种E3泛素连接酶，构成了这一关键决策的中心靶点 指向。APC/C活性对染色体向中期平板聚集敏感。中期，APC/C 泛素化靶向有丝分裂调节剂破坏蛋白酶体和诱导染色单体分离 和有丝分裂退出。虽然已经确定了APC/C的监管途径，但完全理解如何 它被调整为在染色体比对仍不清楚后对中期-后期转换进行编程。近期 研究表明，纺锤体和动粒相关蛋白(Ska)复合体是一个关键元件。这个 提出的研究将阐明Ska与其他有丝分裂细胞合作和控制的分子机制 调节APC/C的时间和空间激活的调节因子，特别是蛋白磷酸酶 中期-后期过渡。中期阶段本身通常是短暂的，但戈尔布斯基实验室发现 这种延迟，即使是很短的延迟，也会导致部分或完全的染色单体分离，这种现象被称为 “凝聚力疲劳。”凝聚力疲劳可能非常普遍，因为它是数字非整倍体和 大量的染色体缺失、重复和易位，特别是在由激活的 癌基因和肿瘤抑制基因的丧失。戈尔布斯基实验室正在采取广泛的方法来研究所有 造成凝聚力疲劳的潜在投入。实验室还在绘制短期和长期的地图 凝聚力疲劳的后果，以确定它如何促进染色体错误分离和损伤。 最后，只有当所有的成分和调节器都存在时，才能完全理解细胞分裂及其转变。 对这一过程进行了识别。虽然有丝分裂部分的清单已经很大，但继续有新成分的报道 这表明它在脊椎动物中还不完整。使用已被证明非常有效的生物信息学指导， 戈尔布斯基实验室正在测试候选的有丝分裂调节剂，并表征它们在正常细胞分裂中的功能 和转化的细胞。