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.
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28 April 2003
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April 28 2003
Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores
In Special Collection:
JCB65: Cell Division, Cell Cycle, and Polarity
Claire Ditchfield,
Claire Ditchfield
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
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Victoria L. Johnson,
Victoria L. Johnson
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
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Anthony Tighe,
Anthony Tighe
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
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Rebecca Ellston,
Rebecca Ellston
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
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Carolyn Haworth,
Carolyn Haworth
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
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Trevor Johnson,
Trevor Johnson
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
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Andrew Mortlock,
Andrew Mortlock
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
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Nicholas Keen,
Nicholas Keen
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
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Stephen S. Taylor
Stephen S. Taylor
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
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Claire Ditchfield
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
Victoria L. Johnson
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
Anthony Tighe
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
Rebecca Ellston
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
Carolyn Haworth
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
Trevor Johnson
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
Andrew Mortlock
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
Nicholas Keen
2Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Cheshire SK10 4TG, UK
Stephen S. Taylor
1School of Biological Sciences, University of Manchester, Manchester M13 9PT, 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: [email protected]
The online version of this article includes supplemental material.
*
Abbreviation used in this paper: RNAi, RNA interference.
Received:
August 15 2002
Revision Received:
February 24 2003
Accepted:
February 24 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 161 (2): 267–280.
Article history
Received:
August 15 2002
Revision Received:
February 24 2003
Accepted:
February 24 2003
Connected Content
Related
Demystifying Aurora B
Citation
Claire Ditchfield, Victoria L. Johnson, Anthony Tighe, Rebecca Ellston, Carolyn Haworth, Trevor Johnson, Andrew Mortlock, Nicholas Keen, Stephen S. Taylor; Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores . J Cell Biol 28 April 2003; 161 (2): 267–280. doi: https://doi.org/10.1083/jcb.200208091
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