Regulation of microtubule dynamics during cell division

描述(申请人提供)：微管是一种不稳定的细丝，通过亚基的增加和丢失而生长和收缩。在有丝分裂期间，微管组织成一个双边对称的装置，称为有丝分裂纺锤体，它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在根除癌细胞方面有效。更好地了解细胞分裂过程可能会确定更多在癌症疾病管理中有用的药物靶点。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触。动粒微管的生长和缩短产生了推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，但对其潜在的机制知之甚少。在这项资助中，我们将研究动粒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者之一，Polo Like Kinase 1如何使用纺锤力作为指示染色体运动的线索。我们的工作将促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宜性的研究直接相关。 公共卫生相关性：在细胞分裂过程中，复制的染色体通过一种名为有丝分裂纺锤体的微管装置的作用在两个子细胞中分离。染色体的运动是由微管和附着在动粒上的末端的聚合动力学提供动力的。动粒-微管动力学受到广泛的调节，在本应用中，我们将确定两个蛋白质因子如何调节微管动力学，以决定有丝分裂染色体运动的速度和方向性。

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.