The systems biology of mitotic checkpoint signaling and its relevance to cancer cell biology

有丝分裂检查点信号传导的系统生物学及其与癌细胞生物学的相关性

• 批准号: 10623613
• 负责人: Ajit Joglekar
• 金额: $ 53.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623613
• 关键词: Anaphase; Behavioral Mechanisms; Cancerous; Cell Cycle Regulation; Cell division; Cells; Cellular biology; Chromosome Segregation; Ensure; Experimental Models; Frequencies; Genomic Instability; Goals; Kinetochores; Mitotic Checkpoint; Nature; Process; Signal Transduction; Signaling Protein; Systems Biology; Theoretical model; behavior prediction; biological systems; cancer cell; chromosome missegregation; data modeling; mathematical model; recruit

Project Summary: The Spindle Assembly Checkpoint (SAC) is a cell cycle control that ensures accurate chromosome segregation during cell division. It is activated by unattached kinetochores, which recruit many different signaling proteins to produce an inhibitory signal that delays anaphase onset and averts chromosome missegregation. Aberrant SAC signaling has long been suspected to promote genome instability in cancerous cells, but the nature of the aberrations and their consequences remain unclear. We propose that the perturbation of SAC signaling dynamics can elevate chromosome missegregation. However, the SAC has been mainly studied under quasi stead-state conditions despite being a dynamical process. Therefore, we will tackle questions central to SAC signaling dynamics using a systems biological approach that integrates quantitative data and mathematical modeling. Our goal is to answer the following fundamental questions using a combination of experiments and theoretical modeling: What is the rate at which a single unattached kinetochore generates the ‘wait-anaphase’ signal? Does it change over the course of cell division? Is it sufficiently high to delay anaphase onset indefinitely? What are the main determinants of this rate? Answers to these questions will reveal a dynamical picture of SAC signaling and allow us to define the causes and consequences of aberrant SAC signaling in cancer cells.

项目摘要： 主轴组件检查点（SAC）是一种细胞周期控制，可确保准确的 细胞分裂时染色体分离。它由独立的动粒激活， 募集许多不同的信号蛋白来产生延迟后期的抑制信号 发生并避免染色体错误分离。长期以来，人们一直怀疑SAC信号异常 促进癌细胞中基因组的不稳定性，但畸变的性质及其 后果尚不清楚。我们提出SAC信号动力学的扰动可以 增加染色体错分离。然而，SAC主要是在准 尽管是一个动态的过程，因此，我们将解决问题， SAC信号动力学的核心，使用系统生物学方法， 定量数据和数学建模。我们的目标是回答以下基本问题 使用实验和理论建模相结合的问题： 一个单独的动粒产生“等待后期”信号？它会随着 细胞分裂的过程？它是否足够高以无限期地延迟后期发作？有哪些 这一比例的主要决定因素？这些问题的答案将揭示SAC的动态画面 信号传导，并允许我们定义异常SAC信号传导的原因和后果， 癌细胞

项目成果

Delineating the contribution of Spc105-bound PP1 to spindle checkpoint silencing and kinetochore microtubule attachment regulation.

描述 Spc105 结合 PP1 对纺锤体检查点沉默和动粒微管附着调节的贡献。

• DOI: 10.1083/jcb.201810172
• 发表时间: 2019
• 期刊: The Journal of cell biology
• 作者: Roy,Babhrubahan;Verma,Vikash;Sim,Janice;Fontan,Adrienne;Joglekar,AjitP
• 通讯作者: Joglekar,AjitP

The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex.

• DOI: 10.1038/s41467-023-37235-z
• 发表时间: 2023-03-18
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Chen C;Piano V;Alex A;Han SJY;Huis In 't Veld PJ;Roy B;Fergle D;Musacchio A;Joglekar AP
• 通讯作者: Joglekar AP

Microtubule Attachment and Centromeric Tension Shape the Protein Architecture of the Human Kinetochore.

• DOI: 10.1016/j.cub.2020.09.038
• 发表时间: 2020-12-21
• 期刊: Current biology : CB
• 作者: Kukreja AA;Kavuri S;Joglekar AP
• 通讯作者: Joglekar AP

The copy-number and varied strengths of MELT motifs in Spc105 balance the strength and responsiveness of the spindle assembly checkpoint.

Spc105 中 MELT 基序的拷贝数和不同强度平衡了纺锤体组装检查点的强度和响应性。

• DOI: 10.7554/elife.55096
• 发表时间: 2020
• 期刊: eLife
• 影响因子: 7.7
• 作者: Roy,Babhrubahan;Han,SimonJy;Fontan,AdrienneNicole;Joglekar,AjitP
• 通讯作者: Joglekar,AjitP

Kre28-Spc105 interaction is essential for Spc105 loading at the kinetochore.

• DOI: 10.1098/rsob.210274
• 发表时间: 2022-01
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Roy B;Sim J;Han SJY;Joglekar AP
• 通讯作者: Joglekar AP