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：
10551218
负责人：
James B Moseley
金额：
$ 33.78万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551218
关键词：
Area Biochemical Biological Assay Cell Cycle Cell Cycle Regulation Cell Nucleus Cell Shape Cell Size Cell Volumes Cell division Cell model Cell physiology Cell surface Cells Cellular biology Cytosol Data Defect Ensure Fission Yeast Funding Genetic Genetic Screening Genomic Instability Geometry Goals Grant Guanosine Triphosphate Phosphohydrolases Homeostasis Human In Vitro Incubated Knowledge Link Lipid Bilayers Malignant Neoplasms Measures Membrane Methods Mitosis Mitotic Modeling Molecular Monitor Mutation Nuclear Pathway interactions Phosphorylation Phosphotransferases Protein Kinase Publishing Recombinants Reproducibility Research Rod Role Scientific Advances and Accomplishments Series Signal Pathway Signal Transduction Signaling Protein Site Structure Surface System Testing Time Work Yeasts biochemical model biological systems cdc25 Phosphatase cell cortex cell growth cell type computerized tools dosage experimental study human disease imaging approach insight live cell imaging model organism monomer mutant nucleocytoplasmic transport prevent programs protein purification protein structure quantitative imaging reconstitution recruit sensor trafficking transmission process

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. Fission yeast cells divide at a specific surface area due to signaling by large, multi-protein structures called “nodes” at the cortex. Nodes contain conserved cell cycle regulators including the protein kinases Cdr2, Cdr1, and Wee1, which function in a linear, genetically defined pathway to regulate mitotic entry. Recently, we discovered that nodes also contain the conserved GTPase Arf6 and found that Arf6 promotes mitotic entry through the Cdr2- Cdr1-Wee1 pathway. 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. Mutations that abolish node signaling cause cells to divide at a specific volume, as opposed to surface area. Based on several lines of evidence, we hypothesize that regulated accumulation of Cdc25 in the cell nucleus represents the volume sensor. We will test the model that cell size control emerges from different pathways, each monitoring distinct aspects of cell geometry. 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 of Cdr2 node assembly and function, (2) determine how Arf6 GTPase regulates Cdr2 nodes and cell size at division, and (3) test the model that Cdc25 and Cdr2 pathways monitor distinct aspects of cell geometry. Successful completion of these goals will advance scientific knowledge by identifying how defined signaling pathways respond to different aspects of cell growth. 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机制的机制裂变酵母细胞由于大的信号传导而在特定的表面积上分裂，目前尚不清楚。皮质上称为“节点”的多蛋白质结构节点包含保守的细胞周期。调节因子包括蛋白激酶 Cdr2、Cdr1 和 Wee1，它们以线性、最近，我们发现节点也调节有丝分裂进入。含有保守的 GTPase Arf6，发现 Arf6 通过 Cdr2- 促进有丝分裂进入我们不知道 Cdr1-Wee1 通路的组装或信号转导机制。我们将利用强大的遗传、生化和定量技术来解决关键的开放性问题。消除节点信号传导的突变导致细胞在特定的时间分裂。根据几条证据，我们得出了体积，而不是表面积。我们将测试细胞核中 Cdc25 的调节积累代表体积传感器。该模型认为细胞大小控制来自不同的途径，每个途径监测不同的方面我们将重点关注细胞周期调控的基本过程，但我们的工作对信号转导的空间控制具有广泛的影响，因为高阶簇和节点状结构正在成为整个细胞生物学中信号转导的关键位点。本次资助的具体目的是：（1）明确Cdr2节点组装的分子机制和功能，(2) 确定 Arf6 GTPase 在分裂时如何调节 Cdr2 节点和细胞大小，以及 (3) 测试 Cdc25 和 Cdr2 通路监测细胞几何形状不同方面的模型。成功完成这些目标将通过确定如何定义来推进科学知识信号通路对细胞生长的不同方面作出反应。我们发现的机制将为尺寸如何控制其他物体的活动提供见解生物系统。