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: 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
• 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

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.

各种各样的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， 但测量大小并将信息传递给核心细胞周期的机制 机械设备在很大程度上是未知的。保守的细胞周期调节因子形成两个离散的种群 在分裂酵母细胞的大脑皮层上有一种叫做“节点”的大型多蛋白质结构。一 节点群包含蛋白激酶Cdr2、Cdr1和Wee1，它们在 线性的，基因定义的调节有丝分裂进入的途径。我们发现了第二个种群 含有Skb1的节点，Skb1通过与Cdr1和Wee1结合来抑制有丝分裂进入。节点 细胞分裂时需要组装来控制细胞大小，但我们不知道 节点内的组装或信号转导。我们将使用以下工具解决关键的公开问题 强大的遗传、生化和定量成像方法。我们将重点关注 细胞周期调控的基本过程，但我们的工作具有广泛的空间意义 信号转导的控制，因为更高阶簇和节点状结构 在整个细胞生物学中成为信号转导的关键部位。这样做的具体目的是 授权的目的是：(1)定义Cdr2组织节点和传输的分子机制 单元大小信号，(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节点如何通过信号转导抑制有丝分裂进入 Cdr2-Cdr1-Wee1节点。成功地完成这些目标将促进科学知识的发展 通过确定节点中的蛋白质集群如何协调细胞的生长和分裂。此外， 我们发现的信号机制将提供有关大小如何控制活动的见解 其他生物系统的。