Work over the past 15 years has revealed how cyclin-dependent kinases control the cell division cycle and how their activity is, in turn, controlled by several checkpoint pathways. By contrast, we know much less about the roles of, and molecular mechanisms that regulate, several other kinases that have important mitotic roles. One of these is Aurora-A (AurA), a 46 kDa serlthr kinase that is required for formation of An functional bipolar spindle and accurate chromosome segregation. Studies from several labs, including my own, show that overexpression of AurA is oncogenic. Even slight increases in Aura protein levels rapidly generate aneuploid ceils with multiple spindle poles, and sustained overexpression results in transformation and tumor formation in mice. An increasing number of genetic studies reveal a growing correlation between Aura gene amplification or overexpression and certain types of cancers in humans The goals of this project are to understand the basic molecular mechanisms by which AurA regulates accurate progression through mitosis, and how AurA itself is regulated during normal embryonic and somatic cell cycles. We also want to understand the roles that AurA plays in surveillance (checkpoint) systems that detect DNA damage, incomplete DNA replication, or mitotic spindle damage, and delay or block cell cycle progression to prevent the production of daughter ceils carrying mutated DNA or an incorrect complement of chromosomes. To do this, we will investigate the following questions. 1. What is the timing, order and dependency of AurA activation and inactivation during the normal cell cycle 2. How does AurA function to establish and/or maintain checkpoint arrests? 3. How is Aur-A activation, inactivation, and destruction spatially regulated in somatic cells?
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