Cell Cycle Regulatory Mechanisms of Aurora/Ipl1Kinases

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The long-term goal of this project is to dissect the mechanism that regulates vertebrate chromosome segregation. This process is regulated by three kinases: Cdc2, plkl and Aurora/Ipll. Our approach is to determine how these kinases are themselves regulated and then determine how they control chromosome segregation. Aurora/Ipll kinases regulate four different events in chromosome segregation: centrosome separation, chromatin assembly, kinetochore attachment and cytogenesis. When Aurora kinases are misexpressed they can promote anuploidy and transformation, suggesting that the regulation of Aurora kinases regulation. We provide evidence that Aurora kinases are cell cycle regulated by multiple mechanisms and present a powerful in vitro system to dissect these regulatory pathways. The experiments in this proposal will 1) identify the role of Aurora/Ipll cell cycle phosphorylation; 20 identify the cell regulator (s0 of Aurora/Ipll activity; 30 identify the regulators of Aurora/Ipll proteolysis. An emerging programming transformation is that defects in chromosome segregation can cause anuploidy and promote cancer. By focusing on the spatial and temporal control of chromosome segregation, this work should identify both mechanisms of cancer progression and new targets for cancer therapies.