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（申请人提供）：在细胞分裂过程中，着丝粒捕获动态微管会启动染色体运动，最终将染色体高保真地分离到每个子细胞。染色体运动涉及微管运动活动和微管聚合动力学的协调。许多抗癌药物通过抑制微管动力学来破坏细胞分裂。在细胞中，微管的动力学行为是由辅助因子如微管马达的Kin I家族调节的。这些驱动蛋白相关的蛋白质已经进化出了使微管解聚的能力，而不是沿着微管的表面晶格行走来运输货物。着丝粒是染色体运动的引擎，负责协调染色体运动与微管动力学。这项建议的长期目标是确定着丝粒如何以高保真度分离染色体。着丝粒能够调节它所附着的微管末端的动态行为。以前，我们已经确定了一个着丝粒相关的Kin I家族的微管马达，这是最有可能负责调节微管动力学与染色体运动。具体来说，我们将测试如何有丝分裂着丝粒相关驱动蛋白（MCAK）的ATP依赖性微管解聚活性的调节和空间定位有助于在有丝分裂过程中染色体的准确分离。为了进行这项研究，有必要（1）了解MCAK解聚微管的机制，（2）确定MCAK的微管解聚活性是否受细胞分裂过程中的调节因子调节，（3）确定MCAK在确保染色体分离中的精确作用。通过回答这些关于MCAK功能和调节的问题，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方面取得重大进展。 MCAK已被鉴定为在某些类型的增殖性肿瘤中上调的基因。因此，在这些研究的过程中，我们将发现信息，并产生可能在诊断或理解这些类型的肿瘤的病因重要的工具。