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: 8420538
• 负责人: James B Moseley
• 金额: $ 28.77万
• 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/8420538
• 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; 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）：多种细胞类型延迟细胞周期过渡直至达到临界大小阈值，但是测量大小并将此信息传输到核心细胞周期机械的机制在很大程度上是未知的。蛋白激酶CDR2将细胞尺寸测量与裂变酵母中的有丝分裂进入连接，并且是保守的蛋白激酶家族的一部分，该蛋白激酶会下调酵母和人类细胞中有丝分裂抑制剂WEE1。要了解CDR2在单元尺寸检查点中的功能，定义控制CDR2活动和本地化的上游信号很重要。我们使用遗传，生化和显微镜方法来识别CDR2调节电路，并确定其输入输出行为如何取决于细胞的大小。我们的最初工作暗示了CDR2的三个分子“输入”信号：极性激酶POM1，甲基转移酶SKB1和通过未知激酶在CDR2激活环中的磷酸化。该项目的具体目的是：（1）定义POM1的磷酸化如何抑制细胞中的CDR2，（2）确定控制CDR2的SKB1信号传导途径，（3）确定CDR2激活Loop磷酸化在有丝分裂大小控制系统中的作用。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来协调细胞生长和分裂的机制来提高科学知识。此外，我们发现的尺寸机制将为大小如何控制其他生物系统的活性提供见解。