Regulation of Microtubule Nucleation During Spindle Assembly

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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.