Mechanisms that coordinate cell size and mitotic entry

协调细胞大小和有丝分裂进入的机制

• 批准号: 9419930
• 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
• 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/9419930
• 关键词: Address; 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 Assay; 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; 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

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.

多种细胞类型延迟细胞周期过渡，直到达到临界尺寸阈值， 但是测量大小并将此信息传输到核心细胞周期的机制 机械在很大程度上未知。保守的细胞周期调节器形成两个离散人群 裂变酵母细胞皮质中称为“淋巴结”的大型多蛋白结构之一。 节点的群体包含蛋白激酶CDR2，CDR1和WEE1，在A中起作用 线性，一般定义的途径，以调节有丝分裂进入。我们发现了第二人口 包含SKB1的节点，该节点通过与CDR1和WEE1结合而抑制有丝分裂进入。节点 组装是控制分裂处细胞尺寸所必需的，但我们不知道 节点内的组装或信号传输。我们将使用 强大的遗传，生化和定量成像方法。我们将专注于 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 控制信号转导的控制，因为高阶簇和节点样结构是 在整个细胞生物学中，出现是信号转移的关键位点。这个特定的目的 授予是：（1）定义CDR2组织节点和传输的分子机制 单元大小信号，（2）测试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抑制有丝分裂进入 CDR2-CDR1-WEE1节点。成功完成这些目标将提高科学知识 通过识别节点中的蛋白聚类如何协调细胞生长和分裂。而且， 我们发现的信号传导机制将为大小如何控制活动提供见解 其他生物系统。