Molecular Mechanisms of Cell Cycle Control

细胞周期控制的分子机制

• 批准号: 10797399
• 负责人: Jennifer A Benanti
• 金额: $ 20.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797399
• 关键词: Alleles; Award; Cell Cycle; Cell Cycle Arrest; Cell Cycle Proteins; Cell Cycle Regulation; Cell Proliferation; Cell division; Cells; Deubiquitinating Enzyme; Development; Disease; Ensure; Enzymes; Genetic; Genetic Transcription; Goals; Growth; Human; Laboratories; Malignant Neoplasms; Mediating; Molecular; Mutation; Organism; Pathway interactions; Phosphorylation; Production; Proliferating; Proteolysis; Regulator Genes; Saccharomycetales; Stress; System; Testing; Ubiquitin; Work; Yeasts; biological adaptation to stress; cell growth; environmental stressor; enzyme substrate; event cycle; genetic approach; in vivo; insight; protein degradation; response; transcription factor; ubiquitin isopeptidase

ABSTRACT Regulated progression through the cell division cycle is critical for cells to faithfully grow and divide. When cell cycle control is disrupted, cells can acquire mutations or proliferate uncontrollably, and this can lead to the development of diseases such as cancer. To ensure that cells replicate and divide accurately, multiple overlapping mechanisms function to coordinate and order cell cycle events. The focus of my laboratory is to understand how cell cycle-regulated transcription, phosphorylation and ubiquitin-mediated protein degradation are integrated to generate a robust cell cycle-regulatory network. To accomplish this we take advantage of high-throughput genetic approaches in budding yeast to uncover the systems-level consequences of perturbing cell cycle-regulatory genes. In this proposal we will focus on three key unanswered questions. First, how does phosphorylation of cell cycle-regulatory transcription factors (TFs) contribute to cell cycle control? We will utilize genetic interaction screens with phosphodeficient TF alleles to elucidate the importance of phosphorylation and test the hypothesis that TF phosphorylation is important to coordinate growth and energy production with the cell cycle. Second, how do stress response pathways cooperate to regulate the cell cycle in response to environmental stress? We will dissect the mechanism of crosstalk between conserved stress response pathways and investigate the importance of this crosstalk for cell cycle arrest and survival in response to distinct environmental stressors. Third, how do deubiquitinating enzymes (DUBs) regulate the stabilities of cell cycle-regulatory proteins? We will utilize an approach that we developed for identifying DUB substrates to investigate the in vivo functions of these enzymes and the mechanisms by which they control the cell cycle. By answering these questions, we will develop a network-level view of how transcription and proteolysis coordinate cell cycle events to ensure faithful cell division. Given the strong conservation between the cell cycle-regulatory mechanisms in yeast and human cells, we anticipate this work will provide insight into how disruptions in the cell cycle control network contribute to disease.

摘要 通过细胞分裂周期调节的进程对于细胞忠实地生长和分裂至关重要。当细胞 细胞周期控制被破坏，细胞可以获得突变或不受控制地增殖，这可能导致 疾病的发展，如癌症。为了确保细胞准确地复制和分裂， 重叠机制起协调和排序细胞周期事件的作用。我实验室的重点是 了解细胞周期如何调节转录，磷酸化和泛素介导的蛋白质降解 被整合以产生稳健的细胞周期调节网络。为了做到这一点，我们利用 芽殖酵母的高通量遗传方法，以揭示系统水平的后果， 扰乱细胞周期调控基因。在这份提案中，我们将重点关注三个关键的未回答的问题。第一、 细胞周期调节转录因子（TF）的磷酸化如何参与细胞周期控制？ 我们将利用与磷酸缺陷TF等位基因的遗传相互作用筛选来阐明 磷酸化和测试假设，TF磷酸化是重要的协调生长和能量 生产与细胞周期。第二，应激反应途径如何协同调节细胞周期， 应对环境压力？我们将剖析守恒应力之间串扰的机制 反应途径，并研究这种串扰对细胞周期停滞和存活的重要性， 对不同环境压力的反应。第三，去泛素化酶（DUBs）是如何调节 细胞周期调节蛋白的稳定性？我们将利用我们开发的识别DUB的方法 底物来研究这些酶的体内功能以及它们控制这些酶的机制。 细胞周期通过回答这些问题，我们将开发一个网络级的观点，如何转录和 蛋白水解协调细胞周期事件以确保忠实的细胞分裂。考虑到 酵母和人类细胞的细胞周期调控机制，我们预计这项工作将提供深入了解 细胞周期控制网络的中断如何导致疾病。