A role of PP2A-Cdc55 in cell cycle

PP2A-Cdc55 在细胞周期中的作用

基本信息

批准号：
10171487
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
项目类别：
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/10171487
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 Cleaved cell 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/antagonist mutant novel novel anticancer drug separase targeted agent therapeutic target tumorigenesis

项目摘要

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，产生两个相同子细胞。此过程涉及DNA复制和染色体分离，导致细胞分裂。细胞周期蛋白依赖激酶（CDK1）驱动真核细胞周期进程和细胞增殖。 CDK1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。 Cyclin/cdk1复合物在S/TP共识基序中磷酸化各种底物触发下游信号级联。细胞周期是一个单向过程由细胞周期蛋白的时间降解调节。这个依赖CDK1的磷酸化事件是在酿酒酵母中，磷酸酶PP2A和CDC14逆转。 PP2A是一个异构体酵母中的两个可能的调节亚基：cdc55或rts1，将复合物引导到不同目标。 pp2a-cdc55优先将苏氨酸残基的cdk1底物脱磷酸化。有丝分裂。在这里，我们提出PP2A-CDC55通过CDC6积极调节DNA复制并通过在酿酒酵母中的PDS1进行负调节有丝分裂纺锤体的伸长。这机制确保单向细胞周期的进程以维持基因组完整性。异常细胞周期控制导致染色体不稳定性，这是癌症的标志。我们的长期目标是了解磷酸酶在控制细胞增殖和肿瘤发生中的作用。在此提案中，两个目标将检验我的假设，即PP2A-CDC55促进了起源许可以启动DNA复制和负调节S的主轴伸长。酿酒酵母。 AIM1将定义PP2A-CDC55在原点许可中的作用。 AIM1的一般策略是研究CDC6和其他DNA复制蛋白如何受PP2A-CDC55调节。 AIM2将确定PP2A-CDC55如何依赖PDS1去磷酸化抑制主轴伸长。我们将测试PP2A-CDC55是否通过PDS1-ESP1和其他下游目标。 PP2A经常被发现在癌症患者中失活，使PP2A成为潜力治疗靶标。在这项研究中，我们将使用单个细胞模型生物S. cerevisiae到了解PP2A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保守的细胞事件。酵母成分的重点是这个项目在人类中保存得很好。从这项研究中获得的结果可以应用了解PP2A如何在较高的真核生物中发挥作用。