A role of PP2A-Cdc55 in cell cycle

项目摘要 细胞周期是一组有序的细胞过程，它产生两个相同的 子代细胞。这一过程涉及DNA复制和染色体分离，导致 细胞分裂。细胞周期蛋白依赖性激酶(CDK1)驱动真核细胞周期进程和细胞 扩散。CDK1是一种丝氨酸/苏氨酸激酶，其活性依赖于其结合伙伴， 循环系统。Cyclin/CDK1复合体使S/TP共有基序上的各种底物磷酸化，以 触发下行信令级联。细胞周期是一个单向过程，它是 受周期蛋白在时间上的降解调节。这种依赖于CDK1的磷酸化事件是 在酿酒酵母中被磷酸酶PP2A和CDC14逆转。PP2A是一种杂三聚体，具有 酵母中两个可能的调节亚基：CDC55或RTS1，它们将复合体引导到不同的 目标。PP2A-CDC55优先使CDK1底物在苏氨酸残基上脱磷 有丝分裂。我们认为PP2A-CDC55通过CDC6正向调节DNA复制 并通过Pds1负向调节酿酒酵母有丝分裂纺锤体的伸长。这 机制确保单向细胞周期进程，以保持基因组的完整性。反常的 细胞周期控制导致染色体不稳定，这是癌症的一个标志。我们的长期合作 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，有两个目标将检验我的假设，即PP2A-CDC55促进起源 许可启动DNA复制并负向调节S. 酿酒。 AIM1将定义PP2A-CDC55在原产地许可中的作用。Aim1的总体战略是 研究PP2A-CDC55是如何调控CDC6和其他DNA复制蛋白的。 AIM2将确定依赖PP2A-CDC55的Pds1去磷酸化如何抑制纺锤体 伸长率。我们将测试PP2A-CDC55是否通过Pds1-ESP1和Pds1-ESP1控制心轴伸长 其他下游目标。 PP2A在癌症患者中经常被发现失活，使PP2A成为潜在的 治疗靶点。在这项研究中，我们将使用单细胞模式生物，酿酒酵母，来 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。中重点介绍的酵母成分 这个项目在人类身上保存得很好。本研究的成果具有一定的应用价值。 以了解PP2A如何在高等真核生物中发挥作用。

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.