Regulation of cell division is necessary to maintain genome integrity. Defective regulation leads to unequal chromosome segregation and aneuploidy, which is strongly associated with human cancer in mitotic divisions and pregnancy loss and developmental defects in meiosis. Much of the complex dynamics of cell division is controlled by a few key regulatory kinases. One of these kinases, Aurora B, localizes to the centromere until anaphase and regulates the attachments of chromosomes to the mitotic spindle. At anaphase onset Aurora B redistributes to the spindle midzone and controls anaphase microtubule dynamics and cytokinesis. Changes in kinase localization and interactions with other regulatory proteins suggest varying patterns of phosphorylation that would allow a single kinase to regulate multiple processes at different times and places. This proposal focuses on examining phosphorylation dynamics with high temporal and spatial resolution in living cells to test models for how these dynamics are controlled. A key role of Aurora B is to ensure that all chromosomes attach to spindle microtubule in the correct configuration, so that chromosomes segregate accurately in anaphase. Signals must be generated to distinguish correct and incorrect attachment, so that errors can be corrected. The first specific aim will test a model for differential Aurora B signaling at individual centromeres. Forces exerted by spindle microtubules create tension across the centromere, which may regulate phosphorylation of a kinetochore substrate by physically separating the substrate from the kinase, which is concentrated at the inner centromere. The second specific aim will examine the interplay between Aurora B and other mitotic kinases at the centromere. There is evidence for interactions between Aurora B, BubR1, Plk1, and Chk1. By combining quantitative measurements of phosphorylation dynamics in living cells with kinase inhibition, using small molecule inhibitors and RNAi, a model in which multiple kinases act in a signaling network at the centromere will be tested. Aurora B function and localization change dramatically in anaphase, suggesting that complex spatial and temporal phosphorylation patterns may allow a single a kinase to regulate a multiple cellular process. The third specific aim will determine how both Aurora B and opposing phosphatases contribute to a switch in site- specific phosphorylation dynamics in anaphase. These studies will contribute to an understanding of (1) basic mechanisms regulating cell division and (2) the effects of Aurora B inhibitors, which are in clinical trials for cancer therapy. Public Health Relevance: Proper regulation of cell division ensures that daughter cells inherit the correct genetic material. Errors during division lead to cells with genetic abnormalities that are strongly associated with human cancer, pregnancy loss, and developmental defects. The goal of this proposal is to understand the function of a key regulatory protein, which is a promising target for cancer therapy, in cell division.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Nuclear Dynamics and Transport (NDT)
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Hamlet, Michelle R
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University of Pennsylvania
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