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(申请人提供)：在细胞分裂过程中，着丝粒捕获动态微管，启动染色体运动，最终高保真地将染色体分离到每个子细胞。染色体运动涉及微管运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扰乱细胞分裂。在细胞中，微管的动态行为受到辅助因素的调节，如Kin I家族的微管发动机。这些与动蛋白相关的蛋白质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和微管动力学。这项提议的长期目标是确定着丝粒如何高保真地分离染色体。着丝粒能够调节它附着的微管末端的动态行为。以前，我们已经确定了Kin I微管电机家族中与着丝粒相关的成员，它最有可能与染色体运动一起调节微管的动力学。具体地说，我们将测试有丝分裂着丝粒相关激动素(MCAK)依赖于ATP的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。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控因素的调节，(3)确定MCAK在确保高保真染色体分离中所扮演的确切角色。通过回答这些关于MCAK功能和调控的问题，我们将在理解如何在生物体的整个生命周期中保持基因组的稳定性方面取得很大进展。MCAK是一种基因，在某些增生性肿瘤中表达上调。因此，在这些研究的过程中，我们将发现可能对诊断或了解这些类型的肿瘤的病因很重要的信息和工具。