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Regulation and function of the Clp 1p protein phosphatase

Clp 1p 蛋白磷酸酶的调节和功能

基本信息

批准号：
7470556
负责人：
DANNEL MCCOLLUM
金额：
$ 30.76万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-19 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470556
关键词：
Actomyosin Anaphase Authorship Cassia Cell Cycle Cell Cycle Progression Cells Chromosome Segregation Collaborations Cyclin-Dependent Kinases Cytokinesis Elements Enzymes Equilibrium Event Failure Family Fission Yeast Funding Future Genome Genome Stability Genomic Instability Grant Homologous Gene Journals Knowledge Lead Malignant Neoplasms Methods Mitosis Mitotic Modeling Molecular Names Paper Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Polyploidy Productivity Protein Dephosphorylation Protein phosphatase Publications Publishing Reagent Regulation Research Research Personnel Research Support Role Students Testing Training Universities Wages Week Work Yeasts anaphase-promoting complex cdc25 Phosphatase cost daughter cell design inner centromere protein mutant programs rad24 protein research study survivin telophase

项目摘要

DESCRIPTION (provided by applicant): Timely activation and inactivation of Cyclin dependent kinases (CDKs) regulate most cell cycle transitions. Precise coordination of each cell cycle step with the others is essential for cells to correctly transmit an intact genome to each daughter cell. Failure to do so can lead to polyploidy, genomic instability and cancer. The function of phosphatases which reverse the action of CDKs is less well understood. The highly conserved Cdc14-family phosphatases act to reverse Cdk phosphorylation events. Most of our knowledge about Cdc14 phosphatases has come from yeast. Key unanswered questions about this family of phosphatases are how they are regulated, what are their targets, and how does the phosphatase regulate these targets to promote key steps of mitosis and cytokinesis? We have been studying the fission yeast Cdc14 homolog, known as Clp1. Our work previous work showed that Clp1 activity is closely integrated with the activities of other key cell cycle regulators. In addition, we found that Clp1 is required to promote proper chromosome segregation, cytokinesis, and inactivation of Cdk1 at the end of mitosis. These studies have identified potential targets for Clp1 involved in each of these important steps. In this proposal we will exploit these results to define in molecular terms how Clp1 is regulated, and how it acts to promote chromosome segregation, cytokinesis, and Cdk1 inactivation. The involvement of Clp1 in these various steps in cell cycle progression makes Clp1 a central regulator for controlling key cell cycle events and promoting genomic stability. Our specific aims are: 1) To test the model that proper chromosome segregation requires a carefully regulated equilibrium between Cdk1 phosphorylation and Clp1 dephosphorylation of Survivin and INCENP. 2) To test a hypothesis for how the Sid2 kinase and the 14-3-3 protein, Rad24, maintain elevated Clp1 activity until cytokinesis is complete. 3) To test a hypothesis that Clp1 promotes actomyosin ring stability through effects on Cdc15. 4) To determine how Clp1 and the anaphase promoting complex promote Cdc25 inactivation in late mitosis.

描述（由申请人提供）：细胞周期蛋白依赖性激酶（CDKs）的及时激活和失活调节大多数细胞周期转变。每个细胞周期步骤与其他步骤的精确协调对于细胞正确地将完整的基因组传递给每个子细胞至关重要。如果不这样做，可能会导致多倍体、基因组不稳定和癌症。逆转CDKs作用的磷酸酶的功能尚不清楚。高度保守的cdc14家族磷酸酶可以逆转Cdk磷酸化事件。我们对Cdc14磷酸酶的大部分知识来自酵母。关于这个磷酸酶家族的关键悬而未决的问题是它们是如何被调节的，它们的靶点是什么，以及磷酸酶如何调节这些靶点来促进有丝分裂和细胞分裂的关键步骤？我们一直在研究分裂酵母的Cdc14同源物，也就是Clp1。我们之前的研究表明，Clp1的活性与其他关键细胞周期调节因子的活性密切相关。此外，我们发现Clp1在有丝分裂结束时促进适当的染色体分离、细胞分裂和Cdk1失活是必需的。这些研究已经确定了参与这些重要步骤的Clp1的潜在靶点。在本提案中，我们将利用这些结果从分子角度定义Clp1是如何被调节的，以及它如何促进染色体分离、细胞分裂和Cdk1失活。Clp1参与细胞周期进程的这些不同步骤，使Clp1成为控制关键细胞周期事件和促进基因组稳定性的中心调节因子。我们的具体目标是：1)测试适当的染色体分离需要在Cdk1磷酸化和Clp1去磷酸化的Survivin和INCENP之间仔细调节平衡的模型。2)为了验证关于Sid2激酶和14-3-3蛋白Rad24如何在细胞分裂完成之前维持升高的Clp1活性的假设。3)验证Clp1通过影响Cdc15促进肌动球蛋白环稳定性的假设。4)确定Clp1和后期促进复合体在有丝分裂后期如何促进Cdc25失活。