Mechanisms that coordinate cell size and mitotic entry

协调细胞大小和有丝分裂进入的机制

基本信息

批准号：
9235625
负责人：
James B Moseley
金额：
$ 32.4万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-06 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9235625
关键词：
Address Alpha Cell Animal Model Binding Binding Proteins Biochemical Biological Assay Cell Cycle Cell Cycle Arrest Cell Cycle Proteins Cell Cycle Regulation Cell Size Cell division Cell physiology Cell-Free System Cells Cellular biology Cues Data Defect Electron Microscopy Engineering Ensure Fission Yeast Funding Genetic Genetic study Genomic Instability Goals Grant Growth Human In Vitro Knowledge Lead Ligands Malignant Neoplasms Measures Membrane Proteins Microfluidics Mitogen-Activated Protein Kinases Mitosis Mitotic Mitotic Activity Molecular Molecular Models Pathway interactions Phosphorylation Phosphotransferases Physiological Population Process Property Protein Kinase Proteins Research Resolution Scientific Advances and Accomplishments Signal Pathway Signal Transduction Signaling Protein Site Stress Structure System Testing Work Yeasts base biological systems cell cortex cell growth cell type environmental change experimental study human disease imaging approach insight light microscopy molecular modeling prevent quantitative imaging response scaffold

项目摘要

A wide variety of cell types delay cell cycle transitions until they reach a critical size threshold, but the mechanisms that measure size and transmit this information to the core cell cycle machinery are largely unknown. Conserved cell cycle regulators form two discrete populations of large, multi-protein structures called “nodes” at the cortex of fission yeast cells. One population of nodes contains the protein kinases Cdr2, Cdr1, and Wee1, which function in a linear, genetically defined pathway to regulate mitotic entry. We discovered a second population of nodes that contain Skb1, which inhibits mitotic entry by binding to Cdr1 and Wee1. Node assembly is required for control of cell size at division, but we do not know the mechanisms of assembly or signal transduction within nodes. We will address key open questions using powerful genetic, biochemical, and quantitative imaging approaches. We will focus on the fundamental process of cell cycle regulation, but our work has broad implications for spatial control of signal transduction because higher-order clusters and node-like structures are emerging as critical sites of signal transduction throughout cell biology. The specific aims of this grant are to: (1) define the molecular mechanism by which Cdr2 organizes nodes and transmits cell size signals, (2) test the hypothesis that node function and organization respond to environmental changes, and (3) determine how Skb1 nodes inhibit mitotic entry by signaling to Cdr2-Cdr1-Wee1 nodes. Successful completion of these goals will advance scientific knowledge by identifying how protein clustering in nodes coordinates cell growth and division. Moreover, the signaling mechanisms that we uncover will provide insights for how size controls the activity of other biological systems.

多种细胞类型会延迟细胞周期转变，直到它们达到临界大小阈值，但是测量大小并将此信息传输到核心细胞周期的机制保守的细胞周期调节因子形成两个离散的群体，但在很大程度上是未知的。裂殖酵母细胞皮层上称为“节点”的大型多蛋白质结构。节点群包含蛋白激酶 Cdr2、Cdr1 和 Wee1，它们以我们发现了调节有丝分裂进入的线性、基因定义的途径。含有 Skb1 的节点，它通过与 Cdr1 和 Wee1 结合来抑制有丝分裂进入。分裂时控制细胞大小需要组装，但我们不知道其机制我们将使用节点内的组装或信号转导来解决关键的开放问题。我们将重点关注强大的遗传、生化和定量成像方法。细胞周期调节的基本过程，但我们的工作对空间具有广泛的影响信号转导的控制，因为高阶簇和节点状结构是成为整个细胞生物学中信号转导的关键位点。授予的目的是：（1）定义Cdr2组织节点和传输的分子机制细胞大小信号，（2）检验节点功能和组织响应的假设环境变化，以及 (3) 确定 Skb1 节点如何通过信号传导来抑制有丝分裂进入 Cdr2-Cdr1-Wee1 节点的成功完成将促进科学知识的发展。通过确定节点中的蛋白质聚集如何协调细胞生长和分裂。我们将揭示的信号机制将为尺寸如何控制活动提供见解其他生物系统。