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p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases

Oncogene volume 33, pages 3550–3560 (2014)Cite this article

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Abstract

A number of small-molecule inhibitors of Aurora kinases have been developed and are undergoing clinical trials for anti-cancer therapies. Different Aurora kinases, however, behave as very different targets: while inhibition of Aurora A (AURKA) induces a delay in mitotic exit, inhibition of Aurora B (AURKB) triggers mitotic slippage. Furthermore, while it is evident that p53 is regulated by Aurora kinase-dependent phosphorylation, how p53 may in turn regulate Aurora kinases remains mysterious. To address these issues, isogenic p53-containing and -negative cells were exposed to classic inhibitors that target both AURKA and AURKB (Alisertib and ZM447439), as well as to new generation of inhibitors that target AURKA (MK-5108), AURKB (Barasertib) individually. The fate of individual cells was then tracked with time-lapse microscopy. Remarkably, loss of p53, either by gene disruption or small interfering RNA-mediated depletion, sensitized cells to inhibition of both AURKA and AURKB, promoting mitotic arrest and slippage respectively. As the p53-dependent post-mitotic checkpoint is also important for preventing genome reduplication after mitotic slippage, these studies indicate that the loss of p53 in cancer cells represents a major opportunity for anti-cancer drugs targeting the Aurora kinases.

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Acknowledgements

Many thanks are due to Michelle Chen, Nelson Lee and Kenji Nishiura for technical assistance. This work was supported in part by the Research Grants Council grant HKU7/CRG/09 to RYCP.

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  1. Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China

    M Marxer, H T Ma, W Y Man & R Y C Poon

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  1. M Marxer
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Correspondence to R Y C Poon.

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Marxer, M., Ma, H., Man, W. et al. p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases. Oncogene 33, 3550–3560 (2014). https://doi.org/10.1038/onc.2013.325

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