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

基本信息

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
项目类别：
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

项目摘要

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）是一个细胞周期控制，可确保准确细胞分裂期间的染色体脱粒。募集许多不同的信号蛋白来产生延迟过渡酶的遗传信号长期以来怀疑是发作和避免异常的染色体错误。促进癌细胞中的基因组不稳定性，但畸变及其性质后果仍然不清楚。升高染色体错误分析。稳定状态，尽管是一个动态的过程，但我们将解决问题。使用系统生物学方法集成的系统生物学方法的SAC信号传导动力学的中心定量数据和数学建模。使用经验的组合和率的问题单个无连接的Kinetchore会生成“ Wait-Anathase”信号？路线是这样。这些问题的主要决定因素会揭示SAC的动态图片信号传导，并允许我们定义出现异常SAC信号的原因和奉献手段癌细胞。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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

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。