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Published 28 April 2003. doi:10.1083/jcb.200208091
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© The Rockefeller University Press, 0021-9525/2003/4/267 $5.00
The Journal of Cell Biology, Volume 161, Number 2, 267-280

Article

 Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores

Claire Ditchfield1, Victoria L. Johnson1, Anthony Tighe1, Rebecca Ellston2, Carolyn Haworth2, Trevor Johnson2, Andrew Mortlock2, Nicholas Keen2 and Stephen S. Taylor1

1 School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
2 Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK

Address correspondence to Stephen S. Taylor, School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Rd., Manchester M13 9PT, UK. Tel.: 44-161-275-5100. Fax: 44-161-275-5763. E-mail: stephen.taylor{at}man.ac.uk

The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.

Key Words: mitosis; spindle checkpoint; chemical biology; aneuploidy; ZM447439

The online version of this article includes supplemental material.

* Abbreviation used in this paper: RNAi, RNA interference.


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