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

DOI PDF 被引用文献24件
  • 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

書誌事項

公開日
2003-04-28
DOI
  • 10.1083/jcb.200208091
公開者
Rockefeller University Press

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説明

<jats:p>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.</jats:p>

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