Microtubule Dynamics and Chromosome Segregation

微管动力学和染色体分离

• 批准号: 7269991
• 负责人: Linda Wordeman
• 金额: $ 29.47万
• 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/7269991
• 关键词: Amino Acids; Antineoplastic Agents; Behavior; Binding; Biological Assay; Cell division; Cells; Centromere; Centrosome; Charge; Chimera organism; Chromosome Segregation; Chromosomes; Decompression Sickness; Diagnosis; Dominant-Negative Mutation; Electrostatics; Ensure; Etiology; Family; Genes; Genome Stability; In Vitro; Interphase; Kinesin; Knock-out; Maps; Microtubule Depolymerization; Microtubule Polymerization; Microtubules; Mitosis; Mitotic; Mitotic Activity; Mitotic spindle; Molecular Conformation; Motor; Motor Activity; Movement; Neck; Organism; Peptide antibodies; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Proteins; RNA Interference; Regulation; Research; Role; Site; Surface; Temperature; Testing; Tubulin; Walking; cell motility; chromosome movement; daughter cell; depolymerization; dimer; in vivo; member; programs; tool; tumor

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）：在细胞分裂过程中，着丝粒捕获动态微管会启动染色体运动，并最终将染色体以高保真度分离到每个子细胞。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，微管的动态行为受到微管马达 Kin I 家族等辅助因素的调节。这些驱动蛋白相关蛋白已经进化出解聚微管的能力，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。该提案的长期目标是确定着丝粒如何高保真度地分离染色体。着丝粒能够调节其所附着的微管末端的动态行为。此前，我们已经鉴定出微管马达 Kin I 家族的一个与着丝粒相关的成员，它最有可能负责调节与染色体运动相关的微管动力学。具体来说，我们将测试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如何有助于有丝分裂期间染色体的准确分离。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到细胞分裂过程中调节因子的调节，(3) 确定 MCAK 在确保染色体高保真分离中所起的精确作用。通过回答有关 MCAK 功能和调节的这些问题，我们将在理解如何在生物体的整个生命周期中维持基因组的稳定性方面取得重大进展。 MCAK 已被确定为一种在某些类型的增殖性肿瘤中表达上调的基因。因此，在这些研究过程中，我们将发现信息并产生对于诊断或了解这些类型肿瘤的病因可能很重要的工具。