Regulation of Microtubule Nucleation During Spindle Assembly

描述（由申请人提供）：有丝分裂的准确执行对于染色体分离和维持基因组稳定性至关重要。在有丝分裂过程中，其他细胞结构和信号分子的适当分配对细胞命运的决定和干细胞的维持也很重要。尽管过去的细胞周期研究已经揭示了有丝分裂的调控，但控制有丝分裂纺锤体正确组装的机制，驱动染色体分离和细胞分裂，仍然没有得到很好的理解。在当前的资助期（2002-2006），我们发现了一个由RanGTP介导的信号通路，导致Aurora a激酶的激活。这个通道对于主轴装配是必不可少的。我们计划利用我们已经开发的一些分析来了解纺锤体组装过程中微管成核是如何由这一重要的信号通路调节的。Aurora A激酶在调控有丝分裂的多个方面发挥重要作用。大量研究表明，Aurora A激酶是开发抗癌药物的一个有希望的靶点。我们对极光a在有丝分裂中调控微管成核机制的研究将有助于癌症治疗干预的发展。

DESCRIPTION (provided by applicant): Accurate execution of mitosis is essential for equal chromosome segregation and for the maintenance of genome stability. Proper partitioning of other cellular structures and signaling molecules into daughter cells during mitosis is also important for cell fate determination and stem cell maintenance. Although cell cycle research in the past has shed light on the regulation of mitosis, the mechanism that controls proper assembly of the mitotic spindle, which drives chromosome segregation and cell division, is still not well understood. In the current funding period (2002-2006), we have uncovered a signaling pathway mediated by RanGTP that leads to activation of the Aurora A kinase. This pathway is essential for spindle assembly. We plan to utilize a number of assays we have developed to understand how microtubule nucleation during spindle assembly is regulated by this important signaling pathway. Aurora A kinase plays an important role in regulating multiple aspects of mitosis. Extensive studies have suggested that Aurora A kinase is a promising target for developing anticancer drugs. Our study of the mechanism of Aurora A-regulated microtubule nucleation in mitosis should contribute the development of therapeutic interventions against cancer. PUBLIC HEALTH RELEVANCE: This proposal studies the mechanism of mitotic spindle assembly and cell division. The findings we make have direct relevance to human health as defects in cell division underlie many human diseases including cancer.