Mechanisms that coordinate cell size with mitotic entry

协调细胞大小与有丝分裂进入的机制

• 批准号: 8997104
• 负责人: James B Moseley
• 金额: $ 29.89万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997104
• 关键词: Animal Model; Antimitotic Agents; Behavior; Biochemical; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Polarity; Cell Size; Cell division; Cells; Defect; Family; Fission Yeast; Genetic; Genomic Instability; Geometry; Goals; Growth; Human; Knowledge; Lead; Length; Ligands; Link; Malignant Neoplasms; Measurement; Measures; Mediating; Methyltransferase; Microscopy; Mitosis; Mitotic; Modeling; Molecular; Monitor; Mutation; Output; Pathway interactions; Pattern; Phosphorylation; Phosphotransferases; Positioning Attribute; Protein Kinase; Protein Methyltransferases; Proteins; Regulation; Regulatory Pathway; Role; Scientific Advances and Accomplishments; Shapes; Signal Pathway; Signal Transduction; Structure; System; Testing; Threonine; Width; Work; Yeasts; biological systems; cell cortex; cell growth; cell type; human disease; inhibitor/antagonist; insight; novel; prevent

DESCRIPTION (provided by applicant): 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. The protein kinase Cdr2 connects cell size measurement with mitotic entry in fission yeast, and is part of a conserved family of protein kinases that down- regulate the mitotic inhibitor Wee1 in yeast and human cells. To understand the function of Cdr2 in cell size checkpoints, it is important to define the upstream signals that control Cdr2 activity and localization. We are using combined genetic, biochemical, and microscopy approaches to identify Cdr2 regulatory circuits and to determine how their input-output behaviors depend on cell size. Our initial work implicates three molecular "input" signals to Cdr2: the polarity kinase Pom1, the methyltransferase Skb1, and phosphorylation in the Cdr2 activation loop by an unknown kinase. The specific aims of the project are to: (1) define how phosphorylation by Pom1 inhibits Cdr2 in cells, (2) identify the Skb1 signaling pathway that controls Cdr2, and (3) determine the role of Cdr2 activation loop phosphorylation in the mitotic size control system. Successful completion of these goals will advance scientific knowledge by identifying the mechanisms that coordinate cell growth and division through the activity of core cell cycle proteins. Moreover, the sizing mechanisms that we uncover will provide insights for how size controls the activity of other biological systems.

描述（由申请人提供）：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，但测量大小并将此信息传输到核心细胞周期机制的机制在很大程度上是未知的。蛋白激酶 Cdr2 将细胞大小测量与裂殖酵母中的有丝分裂进入联系起来，并且是蛋白激酶保守家族的一部分，可下调酵母和人类细胞中的有丝分裂抑制剂 Wee1。为了了解 Cdr2 在细胞大小检查点中的功能，定义控制 Cdr2 活性和定位的上游信号非常重要。我们正在使用遗传、生化和显微镜相结合的方法来识别 Cdr2 调节电路，并确定它们的输入输出行为如何依赖于细胞大小。我们最初的工作涉及 Cdr2 的三个分子“输入”信号：极性激酶 Pom1、甲基转移酶 Skb1 以及未知激酶在 Cdr2 激活环中的磷酸化。该项目的具体目标是：(1) 确定 Pom1 磷酸化如何抑制细胞中的 Cdr2，(2) 识别控制 Cdr2 的 Skb1 信号通路，以及 (3) 确定 Cdr2 激活环磷酸化在有丝分裂大小中的作用控制系统。成功完成这些目标将通过确定通过核心细胞周期蛋白的活性协调细胞生长和分裂的机制来推进科学知识。此外，我们发现的大小机制将为大小如何控制其他生物系统的活动提供见解。