Proliferation-quiescence control by integration of stress and mitogen signaling

通过整合应激和有丝分裂原信号传导来控制增殖-静止

• 批准号: 8766464
• 负责人: Sabrina Leigh Spencer
• 金额: $ 18.43万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766464
• 关键词: Activity Cycles; Affect; Biochemistry; Buffers; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Regulation; Cell division; Cells; Commit; DNA Damage; DNA biosynthesis; Data; Dominant-Negative Mutation; Event; G0 Phase; Goals; Growth Factor; Incidence; Interphase; Lead; Life; Light; Link; MAP Kinase Gene; Malignant Neoplasms; Mediating; Metabolic; Mitogen-Activated Protein Kinase Inhibitor; Mitogens; Mitosis; Molecular; Monitor; Normal Cell; Outcome; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Proliferating; Recovery; Regulation; Research; Signal Transduction; Somatic Cell; Stress; Testing; Therapeutic Intervention; Time; Uncertainty; Up-Regulation; Work; cancer cell; cancer type; cellular imaging; human CDK2 protein; inhibitor/antagonist; insight; interest; oncoprotein p21; public health relevance; repaired; sensor; small molecule; tumorigenic; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Entry into the cell cycle is deregulated in nearly all types of cancer, demonstrating the importance of the cellular decision to proliferate or remain quiescent. Despite this, the molecular events involved in a cell's committing to another round of cell division are not well defined. The overall goal of this proposal is to build a quantitative, dynamic, and mechanistic understanding of the proliferation-quiescence decision in normal, somatic cells. Specifically, I am interested in how cells integrate stress and growth factor signaling inputs at the end of the previous cell cycle to control the proliferative or quiescent fae after mitosis. Key to achieving this goal is my ability to monitor cell cycle events at the moleculr level in single, asynchronously cycling cells. I will make use of a new live-cell sensor that I developed that monitors Cyclin-dependent kinase 2 (CDK2) activity, a key driver of cell cycle progression. Cell cycle commitment is marked by a buildup of CDK2 activity, whereas quiescent cells lack CDK2 activity. My first aim will be to determine how the CDK inhibitor, p21, controls whether, after mitosis, cells immediately build up CDK2 activity and choose a proliferative fate or turn CDK2 activity off and choose a quiescent fate. My second aim will explore the dynamics with which DNA damage causes cell cycle arrest, how cells recover from this damage and resume cycling, and how DNA damage in one cell cycle affects the proliferation-quiescence decision in the next cycle. In my third aim, I seek to understand how growth factor signaling regulates the cell cycle machinery to drive proliferation and how mitogenic signals are integrated in G2/M of the previous cell cycle to influence the proliferative or quiescent fate of a cell. My ability to link upstream signal transduction events to the proliferation-quiescence outcome in single cells will provide valuable insight into this critical control point and may identify new targets that be exploited therapeutically for treating cancer.

描述（由申请人提供）：几乎所有类型的癌症中细胞周期的进入都是失调的，这表明细胞决定增殖或保持静止的重要性。尽管如此，参与细胞进入另一轮细胞分裂的分子事件还没有得到很好的定义。这个建议的总体目标是建立一个定量的，动态的，和机械的理解正常的体细胞的增殖-静止的决定。具体来说，我感兴趣的是细胞如何整合压力和生长因子信号输入在前一个细胞周期结束时，以控制有丝分裂后的增殖或静止。实现这一目标的关键是我能够在分子水平上监测单个异步循环细胞的细胞周期事件。我将使用我开发的一种新的活细胞传感器，该传感器监测细胞周期蛋白依赖性激酶2（CDK 2）的活性，这是细胞周期进程的关键驱动因素。细胞周期定型以CDK 2活性的积累为标志，而静止细胞缺乏CDK 2活性。我的第一个目标将是确定CDK抑制剂p21如何控制有丝分裂后细胞是否立即建立CDK 2活性并选择增殖命运或关闭CDK 2活性并选择静止命运。我的第二个目标是探索DNA损伤导致细胞周期停滞的动力学，细胞如何从这种损伤中恢复并恢复循环，以及一个细胞周期中的DNA损伤如何影响下一个周期中的增殖-静止决定。在我的第三个目标中，我试图了解生长因子信号如何调节细胞周期机制以驱动增殖，以及促有丝分裂信号如何整合在先前细胞周期的G2/M中以影响细胞的增殖或静止命运。我将上游信号转导事件与单细胞中的增殖-静止结果联系起来的能力将为这个关键控制点提供有价值的见解，并可能确定用于治疗癌症的新靶点。