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Aurora-A Kinase Is Essential for Bipolar Spindle Formation and Early Development

2008; Taylor & Francis; Volume: 29; Issue: 4 Linguagem: Inglês

10.1128/mcb.01062-08

1098-5549

Dale O. Cowley, Jaime A. Rivera‐Pérez, Mark J. Schliekelman, Yizhou Joseph He, Trudy G. Oliver, Lucy Lu, Ryan O'Quinn, Edward D. Salmon, Terry Magnuson, Terry Van Dyke,

Cancer-related Molecular Pathways

Aurora-A is a conserved kinase implicated in mitotic regulation and carcinogenesis. Aurora-A was previously implicated in mitotic entry and spindle assembly, although contradictory results prevented a clear understanding of the roles of Aurora-A in mammals. We developed a conditional null mutation in the mouse Aurora-A gene to investigate Aurora-A functions in primary cells ex vivo and in vivo. We show here that conditional Aurora-A ablation in cultured embryonic fibroblasts causes impaired mitotic entry and mitotic arrest with a profound defect in bipolar spindle formation. Germ line Aurora-A deficiency causes embryonic death at the blastocyst stage with pronounced cell proliferation failure, mitotic arrest, and monopolar spindle formation. Aurora-A deletion in mid-gestation embryos causes an increase in mitotic and apoptotic cells. These results indicate that murine Aurora-A facilitates, but is not absolutely required for, mitotic entry in murine embryonic fibroblasts and is essential for centrosome separation and bipolar spindle formation in vitro and in vivo. Aurora-A deletion increases apoptosis, suggesting that molecular therapies targeting Aurora-A may be effective in inducing tumor cell apoptosis. Aurora-A conditional mutant mice provide a valuable system for further defining Aurora-A functions and for predicting effects of Aurora-A therapeutic intervention.