Investigate the Molecular Basis that Controls the Timing of Spindle Elongation

研究控制纺锤体伸长时间的分子基础

基本信息

批准号：
8083720
负责人：
Yanchang Wang
金额：
$ 28.09万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8083720
关键词：
Anaphase Binding Proteins Biochemical Genetics Biomedical Research Cell Cycle Cell Nucleolus Cells Characteristics Chromosome Segregation Chromosomes Congenital Abnormality Cyclin A Cyclin-Dependent Kinases Cyclins Data Defect Ensure Equilibrium Exhibits Hereditary Disease Investigation Kinetics Knowledge Lead Malignant Neoplasms Mammals Mitosis Mitotic Mitotic Activity Molecular Morphology Outcome Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Play Plus End of the Microtubule Protein Dephosphorylation Regulation Research Role S Phase Saccharomycetales Students Substrate Specificity Temperature Testing Time Time Study Training Work base cancer cell cancer diagnosis cancer therapy daughter cell expectation human PLK1 protein innovation mutant overexpression premature prevent segregation spindle pole body tumor progression

项目摘要

DESCRIPTION (provided by applicant): Chromosome mis-segregation is a common cause of genetic disorders, including birth defects and cancer. Spindle elongation is essential for chromosome segregation and premature spindle elongation leads to abnormal chromosome segregation. Thus, the timing of spindle elongation must be rightly regulated. The objective of this application is to determine how cells ensure that spindle elongation occurs at the right time. The central hypothesis of the application is that, in budding yeast, the balance of mitotic CDK (cyclin dependent kinase) vs. S-phase CDK controls the timing of spindle elongation. S- phase CDK plays a negative role in spindle elongation by phosphorylating the S-phase CDK-specific substrates, whereas mitotic CDK promotes spindle elongation by indirectly stimulating the dephosphorylation of S-phase CDK substrates. The Cdc14 phosphatase is responsible for the dephosphorylation of S-phase CDK substrates and mitotic CDK allows this to happen by activating the FEAR (Cdc Fourteen Early Anaphase Release), a mitotic exit pathway that frees Cdc14 from the nucleolus during early anaphase. We further propose that S-phase CDK inhibits spindle elongation through the phosphorylation of Spc110, a component of the spindle pole body (SPB). We will take a comprehensive biochemical, genetic, and functional approach to study the timing control of spindle elongation in budding yeast. The objective of the application will be accomplished by pursuing three specific aims. 1) Test the hypothesis that S-phase and mitotic CDKs antagonistically regulate spindle elongation. 2) Test the hypothesis that mitotic CDK activates the FEAR pathway to counteract the negative effect of S-phase CDK on spindle elongation. 3) We hypothesize that S-phase CDK inhibits spindle elongation by phosphorylating Spc110, a component of the spindle pole body. The proposed work is innovative because it will reveal the molecular basis that controls the timing of spindle elongation. It is our expectation that the tightly regulated activities of mitotic and S-phase CDK during cell cycle ensure the correct timing of spindle elongation. Such outcomes will be significant because new knowledge will suggest new targets for preventing genetic disorders, such as cancer. Moreover, the support of this R15 proposal will enable the training of undergraduate students and expose them to biomedical research. PUBLIC HEALTH RELEVANCE: During mitosis, spindle elongation segregates duplicated chromosomes into two daughter cells. Premature spindle elongation leads to abnormal chromosome segregation, a characteristic of many cancer cells. This proposal aims to understand the molecular basis that controls the timing of spindle elongation. Therefore, this research will potentially uncover new targets for cancer diagnosis and treatment. Moreover, many undergraduate students will receive training in biomedical research by working on this project.

描述（由申请人提供）：染色体错误分离是遗传疾病的常见原因，包括先天缺陷和癌症。纺锤体伸长对于染色体分离至关重要，并且纺锤体伸长伸长导致异常的染色体分离。因此，必须正确调节主轴伸长的时间。该应用的目的是确定细胞如何确保在正确的时间发生纺锤体伸长。该应用的中心假设是，在萌芽的酵母中，有丝分裂CDK（细胞周期蛋白依赖激酶）与S期CDK的平衡控制纺锤体伸长的时间。 S期CDK通过磷酸化S期CDK特异性底物在主轴伸长中起负面作用，而有丝分裂CDK通过间接刺激S阶段CDK底物的去磷酸化来促进纺锤延伸。 CDC14磷酸酶负责S阶段CDK底物的去磷酸化，有丝分裂CDK可以通过激活恐惧（CDC 14个早期后期释放），这是一种有丝分裂的出口途径，这是一种有丝分裂的出口途径，这是一种有丝分裂的出口途径，该途径在后期早期的核仁中释放了CDC14。我们进一步提出，S期CDK通过SPC110的磷酸化（SPB）的磷酸化（SPB）抑制纺锤体伸长。我们将采用一种全面的生化，遗传和功能方法来研究萌芽酵母中纺锤体伸长的时间控制。该应用程序的目的将通过追求三个具体目标来实现。 1）检验以下假设：S期和有丝分裂CDK拮抗纺锤体伸长。 2）测试丝裂CDK激活恐惧途径的假设，以抵消S期CDK对纺锤体伸长的负面影响。 3）我们假设S期CDK通过磷酸化SPC110（纺锤体体的一个成分）抑制纺锤体伸长。提出的工作具有创新性，因为它将揭示控制纺锤伸长时机的分子基础。我们期望在细胞周期中有丝分裂和S期CDK的严格调节活性可确保纺锤伸长的正确时机。这样的结果将是重要的，因为新知识将提出预防遗传疾病（例如癌症）的新目标。此外，该R15提案的支持将使本科生的培训能够接受生物医学研究。公共卫生相关性：在有丝分裂期间，主轴伸长率将重复的染色体分离为两个子细胞。过早的纺锤伸长导致异常的染色体分离，这是许多癌细胞的特征。该建议旨在了解控制主轴伸长时机的分子基础。因此，这项研究可能会发现用于癌症诊断和治疗的新靶标。此外，许多本科生将通过从事该项目来接受生物医学研究的培训。