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Orienting Chromosomes on the Meiotic Spindle

减数分裂纺锤体上染色体的定向

基本信息

批准号：
9309513
负责人：
DEAN S DAWSON
金额：
$ 34.25万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
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：
2017-09-20 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309513
关键词：
Alleles Aneuploidy Behavior Biological Assay Biology Breast Cancer Cell Candidate Disease Gene Cell Cycle Cell Cycle Progression Cell division Cells Centromere Chromosome Segregation Chromosomes Collaborations Collection Complex Congenital Abnormality Defect Development Ensure Future Genes Genetic study Germ Cells Growth Human Kinetochores Lateral Lead Light Location Maintenance Malignant Neoplasms Maps Mediating Meiosis Mental Retardation Microtubules Minor Mitosis Mitotic Mitotic Chromosome Molecular Molecular Genetics Monitor Mutation Organism Phenotype Phosphorylation Phosphotransferases Plus End of the Microtubule Positioning Attribute Process Proteins Proteome RPS27 gene Research Personnel Role Side Site Suppressor Mutations System Testing Therapeutic Yeasts anti-cancer therapeutic antitumor drug aurora B kinase cancer therapy chromosome movement daughter cell experimental study imaging approach imaging study improved insight live cell imaging loss of function mutant overexpression prevent tumor

项目摘要

PROJECT SUMMARY MPS1 encodes a conserved kinase that is essential for multiple cell cycle related functions. One critical role for Mps1 is to promote the formation of force-generating associations of kinetochores with microtubules in meiosis. These connections are critical for chromosomes to become properly oriented on the meiotic spindle, but the molecular mechanisms by which Mps1 forms these associations is a mystery. Errors in meiotic chromosome bi-orientation lead to gametes with the wrong number of chromosomes, referred to as aneuploidy, which in humans is the leading cause of birth defects and mental retardation. Mps1 is necessary to prevent this aneuploidy, as loss of Mps1 leads to high levels of aneuploid gametes. Mps1 is also implicated in human cancer. Many human cancers are aneuploid, with very high chromosome numbers, and over-express Mps1. Aneuploid breast tumor cells are especially dependent upon Mps1 – presumably because of the demands placed upon the bi-orientation machinery by the high chromosome numbers in these cells. These results have led to the pursuit of anti-Mps1 compounds that might act as anti-tumor drugs. Determining the mechanism-of-action of Mps1 in bi-orientation would clarify the specific Mps1 protein interactions that might be the best targets for the development of refined anti-tumor therapeutics. This project seeks determine the mechanisms used to form force-generating kinetochore-microtubule attachments in yeast meiosis, and the role of Mps1 in that process. The project has four Aims. The first will use imaging approaches to monitor the interactions between a centromere and a single microtubule, to pinpoint the step in developing kinetochore-microtubule attachments that is defective in mps1 mutants. A second Aim will explore the roles of known phosphorylation targets of Mps1 that reside at the kinetochore-microtubule interface, in the formation of productive kinetochore-microtubule attachments. This aim will be supported by a collaboration with investigators who will uncover new phosphorylation targets of Mps1 by mapping the Mps1 phospho-proteome. A third Aim is to characterize a collection of strains that carry suppressor mutations that improve chromosome segregation in mps1-R170S mutants – these suppressor mutations likely map to genes that are involved in kinetochore-microtubule interactions and their analysis will shed light on how Mps1 is regulating this process. The final objective is to determine whether Mps1 contributes to mitotic chromosome segregation in the same way that it promotes proper chromosome segregation in meiosis. Because the proteins being examined in this proposal are for the most part shared between yeast and humans, the insights gained in the yeast system could have important implications for better understanding the origins aneuploidy and treatment of cancer in humans.

项目摘要 MPS 1编码一种保守的激酶，对多种细胞周期相关功能至关重要。一个关键的作用， mps 1是促进形成的力产生协会的动粒与微管，减数分裂这些连接对于染色体在减数分裂纺锤体上正确定向至关重要，但Mps 1形成这些关联的分子机制仍是一个谜。减数分裂错误染色体双取向导致配子的染色体数目错误，称为非整倍体，这在人类中是出生缺陷和智力迟钝的主要原因。MPS 1必须防止这种非整倍性，因为Mps 1的丢失导致高水平的非整倍性配子。MPS 1还与人类癌症许多人类癌症是非整倍体，具有非常高的染色体数目，并且过度表达 Mps1.非整倍体乳腺肿瘤细胞特别依赖于Mps 1-可能是因为Mps 1的表达。这些细胞中的高染色体数目对双向定位机制提出了要求。这些这些结果促使人们寻求可能作为抗肿瘤药物的抗Mps 1化合物。确定 Mps 1双向作用的机制将阐明Mps 1蛋白的特异性相互作用，是开发精细抗肿瘤疗法的最佳靶点。本项目旨在确定用于形成产生力的运动编排微管的机制酵母减数分裂中的附件，以及Mps 1在该过程中的作用。该项目有四个目标。第一个将使用成像方法来监测着丝粒和单个微管之间的相互作用，在MPS 1突变体中有缺陷的运动编排-微管附着的发展步骤。第二个目标将探索Mps 1已知磷酸化靶点的作用，这些靶点位于运动舞蹈微管上界面，在生产性的kinetochore-microtubule附件的形成。这一目标将得到一个与研究人员合作，他们将通过绘制Mps 1的图谱来发现Mps 1的新磷酸化靶点。磷酸化蛋白质组第三个目的是表征携带抑制突变的菌株的集合， mps 1-R170 S突变体染色体分离改善--这些抑制突变可能定位于基因它们参与了运动舞蹈-微管的相互作用，对它们的分析将有助于阐明Mps 1是如何与微管相互作用的。规范这个过程。最终目标是确定Mps 1是否对有丝分裂染色体有贡献在减数分裂中，它以同样的方式促进适当的染色体分离。因为在这个提议中被检查的蛋白质大部分是酵母和人类共有的，在酵母系统中获得的结果可能对更好地理解非整倍体的起源具有重要意义。和治疗人类癌症。