Regulation of microtubule dynamics during cell division

细胞分裂过程中微管动力学的调节

• 批准号: 7887170
• 负责人: Ryoma Ohi
• 金额: $ 30.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887170
• 关键词: Address; Affect; Anaphase; Antineoplastic Agents; Biochemical; CENP-E protein; Cell Division Process; Cell division; Cells; Cellular Structures; Chromosome Positioning; Chromosomes; Complex Mixtures; Cues; Cytoskeleton; Data; Disease Management; Drosophila polo protein; Drug Delivery Systems; Electron Microscopy; Eukaryota; Excision; Exhibits; Filament; Fission Yeast; Goals; Grant; Growth; Human; In Vitro; Kinesin; Kinetochores; Knowledge; Laboratories; Life; Location; Malignant Neoplasms; Meiosis; Metaphase; Metaphase Plate; Microscopy; Microtubule Polymerization; Microtubules; Mitosis; Mitotic; Mitotic Chromosome; Mitotic spindle; Molecular; Motor; Movement; Phosphorylation; Phosphotransferases; Plus End of the Microtubule; Polymers; Positioning Attribute; Proteins; RNA Interference; Regulation; Role; Sister; Speed; Structure; Tail; Testing; Tubulin; Work; base; cancer cell; cell motility; chemotherapeutic agent; chromosome movement; daughter cell; design; human PLK1 protein; in vitro Assay; monomer; mutant; novel; polymerization; prevent; public health relevance; segregation

DESCRIPTION (provided by applicant): Microtubules are unstable filaments that grow and shrink by subunit addition and loss. During mitosis, microtubules organize into a bilaterally symmetric apparatus termed the mitotic spindle which acts to segregate replicated chromosomes into two equal sets. Chemotherapeutic agents that interfere with mitotic spindle function are effective at eradicating cancer cells. Better understanding of the cell division process is likely to identify additional drug targets that are useful in cancer disease management. Chromosomes engage microtubules in the mitotic spindle through specialized structures called kinetochores. Growth and shortening of kinetochore-microtubules generate forces that power chromosome movement. Kinetochore-microtubule dynamics must be modulated to produce coordinated sister kinetochore movements, but little is known about the underlying mechanisms. In this grant, we will investigate the biochemical mechanism by which a kinetochore-localized motor protein affects microtubule polymerization dynamics. We will also address how one master regulator of mitosis, Polo like kinase 1, uses spindle forces as a cue to dictate chromosome movements. Our work will advance our knowledge of cell division mechanisms, and have immediate relevance to ongoing studies exploring the suitability of Polo kinases as cancer drug targets. PUBLIC HEALTH RELEVANCE: During cell division, replicated chromosomes are segregated among two daughter cells through the action of a microtubule-based apparatus termed the mitotic spindle. Chromosome motility is powered by the polymerization dynamics of microtubule plus ends attached to kinetochores. Kinetochore-microtubule dynamics are subject to extensive regulation, and in this application, we will determine how two protein factors modulate microtubule dynamics to dictate the speed and directionality of mitotic chromosome movements.

描述（由申请人提供）：微管是不稳定的细丝，通过亚基的增加和损失而生长和收缩。在有丝分裂过程中，微管组织成一个称为有丝分裂纺锤体的双边对称装置，其作用是将复制的染色体分离成两组相等的染色体。干扰有丝分裂纺锤体功能的化疗药物对根除癌细胞是有效的。更好地了解细胞分裂过程可能会确定在癌症疾病管理中有用的其他药物靶点。染色体通过称为着丝点的特殊结构与有丝分裂纺锤体中的微管接合。着丝点微管的生长和缩短产生动力，为染色体运动提供动力。着丝点-微管动力学必须被调节以产生协调的姐妹着丝点运动，但对其潜在机制知之甚少。在这项资助中，我们将研究着丝点定位的马达蛋白影响微管聚合动力学的生化机制。我们还将讨论有丝分裂的主要调节因子Polo激酶1如何使用纺锤体力作为指示染色体运动的线索。我们的工作将推进我们对细胞分裂机制的了解，并与正在进行的探索Polo激酶作为癌症药物靶点的适用性的研究直接相关。