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平等的染色体分离和保持基因组的稳定性是必不可少的。在有丝分裂过程中，适当地将其他细胞结构和信号分子划分为子细胞，对于细胞命运的决定和干细胞的维持也是重要的。尽管过去的细胞周期研究已经阐明了有丝分裂的调控，但控制有丝分裂纺锤体正确组装的机制仍然不太清楚，有丝分裂纺锤体驱动染色体分离和细胞分裂。在目前的资助期间(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。这条通路对纺锤体的组装是必不可少的。我们计划利用我们开发的一些分析方法来了解纺锤体组装过程中微管成核是如何受到这一重要信号通路的调控的。极光A激酶在有丝分裂的多个方面起着重要的调节作用。广泛的研究表明，Aurora A激酶是开发抗癌药物的一个有前途的靶点。我们对Aurora A调控的有丝分裂中微管成核机制的研究将有助于癌症治疗干预的发展。 公共卫生相关性：这项建议研究有丝分裂纺锤体组装和细胞分裂的机制。我们的发现与人类健康直接相关，因为细胞分裂缺陷是包括癌症在内的许多人类疾病的基础。

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.