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.

多种细胞类型会延迟细胞周期转变，直到达到临界大小阈值， 但测量大小并将信息传递给核心细胞周期的机制 机器在很大程度上未知。保守的细胞周期调节因子形成两个离散的群体 在分裂酵母细胞的皮层上有一种叫做“节点”的大型多蛋白质结构。一 节点群包含蛋白激酶Cdr 2、Cdr 1和Wee 1，它们在一个细胞中起作用。 线性的，遗传上确定的途径来调节有丝分裂进入。我们发现了第二个种群 包含Skb 1的节点，Skb 1通过与Cdr 1和Wee 1结合来抑制有丝分裂进入。节点 组装是控制分裂时细胞大小所必需的，但我们不知道组装的机制。 组装或信号转导。我们将使用以下方法解决关键的开放性问题： 强大的遗传、生物化学和定量成像方法。重点抓好 细胞周期调控的基本过程，但我们的工作具有广泛的影响，空间 控制信号转导，因为高阶簇和节点样结构是 在整个细胞生物学中作为信号转导的关键位点出现。具体目标是 授予是：（1）定义Cdr 2组织节点和传输的分子机制 细胞大小信号，（2）测试节点功能和组织响应的假设 环境变化，以及（3）确定Skb 1节点如何通过信号传导抑制有丝分裂进入， Cdr 2-Cdr 1-Wee 1节点。成功完成这些目标将推进科学知识 通过识别节点中的蛋白质集群如何协调细胞生长和分裂。此外，委员会认为， 我们揭示的信号机制将为规模如何控制活动提供见解 其他生物系统。