Regulation of microtubule dynamics during cell division

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。在有丝分裂期间，微管组织成称为有丝分裂纺锤体的双侧对称装置，其作用是将复制的染色体分离成两个相等的组。干扰有丝分裂纺锤体功能的化疗药物可有效根除癌细胞。更好地了解细胞分裂过程可能会确定其他药物靶点，这些靶点在癌症疾病管理中很有用。染色体通过称为动粒的特殊结构与有丝分裂纺锤体中的微管结合。着丝粒微管的生长和缩短产生了驱动染色体运动的力量。动粒-微管动力学必须被调节以产生协调的姐妹动粒运动，但对其潜在机制知之甚少。在这项研究中，我们将探讨一个kinetochore定位马达蛋白影响微管聚合动力学的生化机制。我们还将讨论如何有丝分裂的一个主调节因子，波罗样激酶1，使用纺锤体力作为线索来支配染色体运动。我们的工作将推进我们对细胞分裂机制的认识，并与正在进行的探索波罗激酶作为癌症药物靶点的适用性的研究直接相关。

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.