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AuroraA overexpression overrides the mitotic spindle checkpoint triggered by nocodazole, a microtubule destabilizer

Oncogene volume 22, pages 8293–8301 (2003)Cite this article

Abstract

AuroraA, a mitotic kinase, is reported to be amplified and overexpressed in a variety of human tumors. Active mutants of AuroraA can transform mouse fibroblasts and form tumors in nude mice. However, the mechanism behind this oncogenic potential remains elusive. In this study, we investigated the consequences of AuroraA overexpression and showed that increased AuroraA levels compromise the mitotic spindle checkpoint triggered by nocodazole, a microtubule polymerization inhibitor. This is accomplished by disrupting the proper assembly of the mitotic checkpoint complex at the level of the Cdc20-BubR1 interaction. As a result, the spindle checkpoint complex fails to form and cells progress through mitosis without proper arrest in response to nocodazole. This ability to override the mitotic spindle checkpoint was found to be independent of AuroraA kinase activity. We conclude that maintenance of a functional balance between AuroraA and mitotic checkpoint proteins is essential for the proper progression through mitosis. This study therefore offers a possible explanation of how deregulation of AuroraA can contribute to genetic instability and tumorigenesis.

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Acknowledgements

We thank Wouter Korver for the initial cloning of AuroraA and Shireen Khan for suggestions. We also thank David Parry, Ronald Herbst and Xiaomin Schebye for suggestions and critical review of the manuscript. The DNAX Research Institute is funded by the Schering-Plough Corporation.

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  1. Ying Jiang and Yongke Zhang: Contributed equally to the work

Authors and Affiliations

  1. DNAX Research Inc., Palo Alto, 94304, CA, USA

    Ying Jiang, Emma Lees & Wolfgang Seghezzi

  2. Protein Design Labs, Inc., Fremont, 94555, CA, USA

    Yongke Zhang

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  1. Ying Jiang
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Correspondence to Wolfgang Seghezzi.

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Jiang, Y., Zhang, Y., Lees, E. et al. AuroraA overexpression overrides the mitotic spindle checkpoint triggered by nocodazole, a microtubule destabilizer. Oncogene 22, 8293–8301 (2003). https://doi.org/10.1038/sj.onc.1206873

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