Dissection of the Inner Centromere Regulatory Network

内着丝粒调节网络的解剖

• 批准号: 7033270
• 负责人: P. TODD STUKENBERG
• 金额: $ 31.51万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033270
• 关键词: Xenopus; Xenopus oocyte; aneuploidy; biological signal transduction; cell cycle; cell cycle proteins; cell growth regulation; centromere; chromosome movement; cyclin dependent kinase; enzyme mechanism; phosphorylation; posttranslational modifications; protein binding; protein kinase; protein localization; protein protein interaction; protein purification; proteolysis

DESCRIPTION (provided by applicant): For each chromosome to properly segregate during mitosis, its kinetochores must bipolarly attach spindle microtubules. The failure of chromosomes to biorient is a major cause of cellular aneuploidy, a driving force in cancer and birth defects. Bipolar attachment is achieved because tension is produced between sister kinetochores, which both stabilizes microtubule attachments and turns off spindle checkpoint signals. The key to understanding how cells become aneuploid is to understand how chromosomes sense tension between sister kinetochores and use this to regulate microtubule attachment and spindle checkpoint signals. Recently we and others have implicated three components in this process-the Aurora B kinase complex, the MCAK microtubule depolymerase and the Polo kinase. We have published that the Aurora B regulates MCAK activity in centromeres presumably to release improperly attached microtubules, while Polo kinase phosphorylates proteins in the kinetochore in response to the lack of tension. We present new data that MCAK localization and activity is tightly controlled and the each chromosome regulates MCAK autonomously. Moreover we demonstrate that there is a network of interactions between five centromere proteins to regulate MCAK activity and localization including Aurora B and Polo kinases, the Gunanine Nucleotide Exchange Factor, TD-60, and the MCAK activator, ICIS. To elucidate the mechanisms that prevent aneuploidy, the experiments in this proposal dissect the molecular mechanisms of the centromere signaling network.

描述（由申请人提供）：每个染色体在有丝分裂过程中正确分离的每个染色体，其动力学必须双极固定纺锤体微管。染色体对生物的失败是细胞非整倍性的主要原因，癌症和先天缺陷的驱动力。之所以会达到双极附件，是因为姊妹动物学体之间会产生张力，这既可以稳定微管的附件并关闭主轴检查点信号。理解细胞如何变成非整倍体的关键是了解染色体如何感知姐妹动物之间的张力并使用它来调节微管附着和主轴检查点信号。最近，我们和其他人在此过程中牵涉到三个组成部分 - Aurora B激酶复合物，MCAK微管去聚合酶和polo激酶。我们已经发表了Aurora B调节centromeres中的MCAK活性，大概是释放不当附着的微管，而polo激酶会因缺乏张力而磷酸化动力学的蛋白质。我们介绍了MCAK定位和活动受到严格控制的新数据，并且每个染色体都会自动调节MCAK。此外，我们证明了五种Centromere蛋白之间存在相互作用网络，以调节MCAK活性和定位，包括Aurora B和Polo激酶，Gunanine核苷酸交换因子TD-60以及MCAK激活剂ICIS。为了阐明预防非整倍性的机制，该提案中的实验剖析了中心粒信号网络的分子机制。