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Originally published as MBC in Press, 10.1091/mbc.E08-08-0885 on February 18, 2009

Vol. 20, Issue 8, 2218-2228, April 15, 2009

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Aurora B Kinase Regulates the Postmitotic 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

Submitted August 28, 2008; Revised February 3, 2009; Accepted February 6, 2009
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 pseudo G1 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 postmitotic checkpoint to prevent endoreduplication after an aberrant mitosis. Thus, we propose for the first time that Aurora B determines cellular fate after an aberrant mitosis by directly regulating the Rb tumor suppressor protein.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-08-0885) on February 18, 2009.

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






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