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MBC in Press, published online ahead of print February 18, 2009
Mol. Biol. Cell 10.1091/mbc.E08-08-0885

A more recent version of this article appeared on April 15, 2009
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Submitted on August 28, 2008
Revised on February 3, 2009
Accepted on February 6, 2009

Aurora B Kinase Regulates the Post-mitotic Endoreduplication Checkpoint via Phosphorylation of the Retinoblastoma Protein at Serine 780

Jayasree S. Nair,* Alan L. Ho,* Archie N. Tse,* Jesse Coward,* Haider Cheema,* Grazia Ambrosini,* Nicholas Keen,{dagger} and Gary K. Schwartz*

*Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and {dagger}Astra-Zeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Monitoring Editor: Mark J. Solomon

The phenotypic change characteristic of Aurora B inhibition is the induction of polyploidy. Utilizing specific siRNA duplexes and a selective small molecule inhibitor (AZD1152) to inhibit Aurora B activity in tumor cells, we sought to elucidate the mechanism by which Aurora B inhibition results in polyploidy. Cells treated with AZD1152 progressed through mitosis with misaligned chromosomes and exited without cytokinesis and subsequently underwent endoreduplication of DNA despite activation of a p53-dependent pseudoG1 checkpoint. Concomitant with polyploid cell formation, we observed the appearance of Rb hypophosphorylation, an event that occurred independently of cyclin dependent kinase inhibition. We went on to discover that Aurora B directly phosphorylates Rb at serine 780 both in vitro and in vivo. This novel interaction plays a critical role in regulating the post-mitotic checkpoint to prevent endoreduplication following an aberrant mitosis. Thus, we propose for the first time that Aurora B determines cellular fate following an aberrant mitosis by directly regulating the Rb tumor suppressor protein.

Address correspondence to: Gary K. Schwartz (schwartg{at}mskcc.org)






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