A role of PP2A-Cdc55 in cell cycle

PP2A-Cdc55 在细胞周期中的作用

• 批准号: 10378659
• 负责人: Amy E Ikui
• 金额: $ 39.25万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378659
• 关键词: Affect; Animal Model; Binding; Biological Models; C-terminal; Cancer Patient; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell division; Cell model; Cell physiology; Cells; ChIP-seq; Chromosomal Instability; Chromosome Segregation; Complex; Consensus; Cyclin-Dependent Kinases; Cyclins; DNA biosynthesis; Dissociation; Ensure; Equilibrium; Eukaryota; Eukaryotic Cell; Event; Extramural Activities; Failure; Gel; Genome; Goals; Homologous Gene; Human; Knowledge; Learning; Licensing; Malignant Neoplasms; Mitosis; Mitotic spindle; N-terminal; PTTG1 gene; Pattern; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Process; Productivity; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Protein-Serine-Threonine Kinases; Proteins; Research; Research Project Grants; Role; Saccharomyces cerevisiae; Signal Transduction; Signal Transduction Pathway; Site; Testing; Threonine; Yeasts; cohesin; daughter cell; genome integrity; inhibitor; mutant; novel; novel anticancer drug; separase; targeted agent; therapeutic target; tumorigenesis

Project Summary The cell cycle is an ordered set of cellular processes that produces two identical daughter cells. This process involves DNA replication and chromosome segregation leading to cell division. Cyclin dependent kinase (Cdk1) drives eukaryotic cell cycle progression and cell proliferation. Cdk1 is a serine/threonine kinase whose activity depends on its binding partner, cyclin. The cyclin/Cdk1 complex phosphorylates various substrates at S/TP consensus motifs to trigger a downstream signaling cascade. The cell cycle is a unidirectional process which is regulated by temporal degradation of the cyclins. This Cdk1-dependent phosphorylation event is reversed by the phosphatases PP2A and Cdc14 in S. cerevisiae. PP2A is a heterotrimer with two possible regulatory subunits in yeast: Cdc55 or Rts1, which direct the complex to distinct targets. PP2A-Cdc55 preferentially dephosphorylates Cdk1 substrates at threonine residues in mitosis. Here we propose that PP2A-Cdc55 positively regulates DNA replication through Cdc6 and negatively regulates mitotic spindle elongation through Pds1 in S. cerevisiae. This mechanism ensures unidirectional cell cycle progression to maintain genome integrity. Aberrant cell cycle control leads to chromosome instability which is a hallmark of cancer. Our long-term goal is to understand the role of phosphatase in control of cell proliferation and tumorigenesis. In this proposal, two aims will test my hypothesis that PP2A-Cdc55 promotes origin licensing to initiate DNA replication and negatively regulates spindle elongation in S. cerevisiae. Aim1 will define the role of PP2A-Cdc55 in origin licensing. The general strategy of Aim1 is to study how Cdc6 and other DNA replication proteins are regulated by PP2A-Cdc55. Aim2 will determine how PP2A-Cdc55 dependent Pds1 dephosphorylation inhibits spindle elongation. We will test if PP2A-Cdc55 controls spindle elongation through Pds1-Esp1 and other downstream targets. The PP2A is frequently found to be inactivated in cancer patients making PP2A a potential therapeutic target. In this study, we will use a single cell model organism, S. cerevisiae, to understand the basic mechanism of how PP2A controls the cell cycle. DNA replication and mitosis are well conserved cellular events in eukaryotes. The yeast components focused on in this project are well conserved in humans. The results obtained from this study can be applied to understanding how PP2A functions in higher eukaryotes.

项目摘要 细胞周期是一组有序的细胞过程， 子细胞这一过程涉及DNA复制和染色体分离， 细胞分裂细胞周期蛋白依赖性激酶（Cdk 1）驱动真核细胞周期进程和细胞凋亡 增殖cdk 1是一种丝氨酸/苏氨酸激酶，其活性取决于其结合伴侣， 细胞周期蛋白。细胞周期蛋白/Cdk 1复合物磷酸化S/TP共有基序处的各种底物， 触发下游信号级联。细胞周期是一个单向的过程， 由细胞周期蛋白的时间降解调节。这种依赖Cdk 1的磷酸化事件是 在S.酿酒的。PP 2A是异源三聚体， 在酵母中有两种可能的调节亚基：Cdc 55或Rts 1，它们将复合物引导到不同的位置。 目标的PP 2A-Cdc 55优先使Cdk 1底物的苏氨酸残基去磷酸化， 分裂。在这里，我们提出PP 2A-Cdc 55通过Cdc 6正向调节DNA复制 并通过Pds 1负调控S.酿酒的。这 这种机制确保了细胞周期的单向进展，以维持基因组的完整性。异常 细胞周期控制导致染色体不稳定，这是癌症的标志。我们的长期 目的是了解磷酸酶在控制细胞增殖和肿瘤发生中的作用。 在这个提议中，两个目标将测试我的假设，PP 2A-Cdc 55促进起源 许可启动DNA复制和负调控纺锤体延伸在S。 酿酒的。 Aim 1将定义PP 2A-Cdc 55在原产地许可中的作用。目标1的总体战略是 研究Cdc 6和其他DNA复制蛋白如何受PP 2A-Cdc 55调控。 Aim 2将决定PP 2A-Cdc 55依赖性Pds 1去磷酸化如何抑制纺锤体 伸长率我们将测试PP 2A-Cdc 55是否通过Pds 1-Esp 1控制纺锤体伸长， 其他下游目标。 PP 2A在癌症患者中经常被发现失活，使得PP 2A成为潜在的 治疗靶点在本研究中，我们将使用单细胞模式生物，S。酿酒厂， 了解PP 2A如何控制细胞周期的基本机制。DNA复制和 有丝分裂是真核生物中非常保守的细胞事件。酵母成分集中在 这个项目在人类中保存得很好。本研究所得结果可应用于 了解PP 2A在高等真核生物中的功能。