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：
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
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/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

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.

项目概要细胞周期是一组有序的细胞过程，产生两个相同的细胞子细胞。这个过程涉及 DNA 复制和染色体分离，从而导致细胞分裂。细胞周期蛋白依赖性激酶 (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伙伴，细胞周期蛋白。细胞周期蛋白/Cdk1 复合物磷酸化 S/TP 共有基序上的各种底物，触发下游信号级联。细胞周期是一个单向过程受细胞周期蛋白的暂时降解调节。这种 Cdk1 依赖性磷酸化事件是酿酒酵母中的磷酸酶 PP2A 和 Cdc14 可以逆转这种情况。 PP2A 是一种异源三聚体酵母中两个可能的调节亚基：Cdc55 或 Rts1，它们将复合物引导至不同的区域目标。 PP2A-Cdc55 优先将 Cdk1 底物的苏氨酸残基去磷酸化有丝分裂。在此我们提出PP2A-Cdc55通过Cdc6正向调节DNA复制并通过酿酒酵母中的 Pds1 负向调节有丝分裂纺锤体的伸长。这机制确保单向细胞周期进展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，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。在这个提案中，两个目标将检验我的假设：PP2A-Cdc55 促进起源许可启动 DNA 复制并负向调节 S 中的纺锤体伸长。酿酒酵母。 Aim1 将定义 PP2A-Cdc55 在原产地许可中的作用。 Aim1 的总体策略是研究 PP2A-Cdc55 如何调节 Cdc6 和其他 DNA 复制蛋白。 Aim2 将确定 PP2A-Cdc55 依赖性 Pds1 去磷酸化如何抑制纺锤体伸长。我们将测试 PP2A-Cdc55 是否通过 Pds1-Esp1 控制纺锤体伸长，其他下游目标。经常发现 PP2A 在癌症患者体内失活，这使得 PP2A 成为一种潜在的药物治疗目标。在这项研究中，我们将使用单细胞模型生物，酿酒酵母，了解 PP2A 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高度保守的细胞事件。酵母成分集中在该项目在人类中保存完好。本研究所得结果可应用了解 PP2A 在高等真核生物中的功能。