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Understanding Cell Division

了解细胞分裂

基本信息

批准号：
10439611
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

项目摘要

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。之一最关键的是从中期到后期的过渡和有丝分裂的退出。后期促进 E3泛素连接酶复合体/细胞核小体（APC/C）是这一关键决定的中心靶点点APC/C活性对染色体向中期板的聚集敏感。在中期，APC/C 泛素化酶靶向有丝分裂调节因子，破坏蛋白酶体并诱导染色单体分离和有丝分裂退出。虽然已经确定了APC/C的调控途径，但完全了解如何调控APC/C的表达，它被调整为在染色体比对仍然不清楚之后编程中期-后期转换。最近工作表明纺锤体和动粒相关（Ska）蛋白复合物是一个关键元件。的这项研究将阐明斯卡与其他有丝分裂细胞合作并控制它们的分子机制。调节因子，特别是蛋白磷酸酶，控制APC/C的时间和空间激活，以驱动中期到后期的过渡。中期本身通常是短暂的，但戈尔布斯基实验室发现，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”内聚疲劳作为数量非整倍性和染色体畸变的来源可能是非常常见的。大的染色体缺失、复制和易位，特别是在由活化的癌基因和肿瘤抑制因子的丢失。Gorbsky实验室正在采取广泛的方法来研究所有可能导致凝聚力疲劳的因素。该实验室还绘制了短期和长期内聚疲劳的后果，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因子都被完全理解时，的过程被识别。虽然有丝分裂的部件清单已经很大，但仍有新部件的报告表明它在脊椎动物中还不完全。使用已被证明非常有效的生物信息学指导， Gorbsky实验室正在测试候选的有丝分裂调节因子，并描述它们在正常细胞分裂中的功能。和转化的细胞。