Microtubule Dynamics and Chromosome Segregation

微管动力学和染色体分离

• 批准号: 7102737
• 负责人: Linda Wordeman
• 金额: $ 30.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102737
• 关键词: RNA interference; cell cycle; centromere; centrosome; chromosome movement; conformation; cryoelectron microscopy; dimer; gene expression; gene mutation; genetic mapping; ionic bond; kinesin; microtubules; mitotic spindle apparatus; phosphoprotein phosphatase; phosphorylation; polymerization; protein kinase; protein structure function; tissue mosaicism; tubulin

DESCRIPTION (provided by applicant): During cell division the capture of dynamic microtubules by the centromere initiates chromosome movement and, ultimately, the segregation of chromosomes to each daughter cell with high fidelity.Chromosome movement involves the coordination of microtubule motor activity and microtubule polymerization dynamics. Many anti-cancer drugs disrupt cell division by suppressing microtubule dynamics. In cells, the dynamic behavior of microtubules is modulated by accessory factors such as the Kin I family of microtubule motors. These kinesin-related proteins have evolved the ability to depolymerize microtubules rather than walking along the surface lattice of the microtubule to transport cargo. The centromere is the engine for chromosome movement and is responsible for coordinating chromosome movement with microtubule dynamics. The long-term objective of this proposal is to determine how the centromere segregates chromosomes with high fidelity. The centromere is able to modulate the dynamic behavior of the microtubule ends to which it attaches. Previously we have identified a centromere-associated member of the Kin I family of microtubule motors, which is most likely to be responsible for modulating microtubule dynamics in conjunction with chromosome movement. Specifically we will test how the regulation and spatial localization of the ATP-dependent microtubule depolymerizing activity of Mitotic Centromere-associated Kinesin (MCAK) contributes to the accurate segregation of chromosomes during mitosis. To perform this study it is essential to (1) understand the mechanism by which MCAK depolymerizes microtubules, (2) determine if MCAK's microtubule depolymerizing activity is modulated by regulatory factors during cell division and, (3) determine the precise role that MCAK plays in ensuring chromosome segregation with high fidelity. By answering these questions regarding MCAK function and regulation we will make great strides in understanding how the stability of the genome is maintained over the lifetime of an organism. MCAK has been identified as a gene, which is up-regulated in certain kinds of proliferative tumors. Therefore, in the course of these studies we will uncover information and produce tools that may be important in the diagnosis or in understanding the etiology of these types of tumors.

描述（由申请人提供）：在细胞分裂期间，丝粒对动态微管的捕获启动染色体运动，最终，染色体对每个子细胞的隔离具有高富达式的运动。染色体运动涉及微管运动活性和微管聚合物聚合动力学的配位。许多抗癌药通过抑制微管动力学来破坏细胞分裂。在细胞中，微管的动态行为是由辅助因子（例如微管电动机的亲戚家族）调节的。这些与运动蛋白相关的蛋白已经发展出使微管解散的能力，而不是沿着微管的表面晶格行走以运输货物。 Centromere是染色体运动的发动机，负责与微管动力学协调染色体运动。该提议的长期目标是确定丝粒如何以高忠诚度分离染色体。 Centromere能够调节其附着的微管末端的动态行为。以前，我们已经确定了微管电动机的亲属I家族的丝粒相关成员，该家族最有可能负责调节微管动力学与染色体运动。具体而言，我们将测试有丝分裂centromere相关驱动蛋白（MCAK）在ATP依赖性微管解聚活性的调节和空间定位如何有助于有丝分裂过程中染色体的准确分离。要进行这项研究，必须（1）了解MCAK去聚合微管的机制，（2）（2）确定MCAK的微管解聚活性是否由细胞分裂过程中的调节因子调节，并且（（3）确定MCAK在确保染色体较高胎盘中的确切作用。通过回答有关MCAK功能和调节的这些问题，我们将在理解基因组的稳定性如何在生物体的一生中保持稳定方面取得了长足的进步。 MCAK已被确定为一种基因，该基因在某些类型的增殖性肿瘤中被上调。因此，在这些研究的过程中，我们将发现信息并生成在诊断或理解这些类型肿瘤的病因中可能很重要的工具。