Centromere-associated protein-E (CENP-E) is an essential mitotic kinesin that is required for efficient, stable microtubule capture at kinetochores. It also directly binds to BubR1, a kinetochore-associated kinase implicated in the mitotic checkpoint, the major cell cycle control pathway in which unattached kinetochores prevent anaphase onset. Here, we show that single unattached kinetochores depleted of CENP-E cannot block entry into anaphase, resulting in aneuploidy in 25% of divisions in primary mouse fibroblasts in vitro and in 95% of regenerating hepatocytes in vivo. Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal.
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18 August 2003
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August 18 2003
Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss
Beth A.A. Weaver,
Beth A.A. Weaver
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
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Zahid Q. Bonday,
Zahid Q. Bonday
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
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Frances R. Putkey,
Frances R. Putkey
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
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Geert J.P.L. Kops,
Geert J.P.L. Kops
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
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Alain D. Silk,
Alain D. Silk
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
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Don W. Cleveland
Don W. Cleveland
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
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Beth A.A. Weaver
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
Zahid Q. Bonday
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
Frances R. Putkey
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
Geert J.P.L. Kops
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
Alain D. Silk
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
Don W. Cleveland
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
Address correspondence to Don W. Cleveland, Ludwig Institute for Cancer Research, 3080 CMM-East, 9500 Gilman Drive, La Jolla, CA 92093-0670. Tel.: (858) 534-7811. Fax: (858) 534-7659. email: [email protected]
Abbreviations used in this paper: AdCre, adenovirus expressing the Cre recombinase; APC/C, anaphase-promoting complex/cyclosome; CENP-E, centromere-associated protein-E; MEF, mouse embryonic fibroblast.
Received:
March 28 2003
Accepted:
June 19 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 162 (4): 551–563.
Article history
Received:
March 28 2003
Accepted:
June 19 2003
Citation
Beth A.A. Weaver, Zahid Q. Bonday, Frances R. Putkey, Geert J.P.L. Kops, Alain D. Silk, Don W. Cleveland; Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss . J Cell Biol 18 August 2003; 162 (4): 551–563. doi: https://doi.org/10.1083/jcb.200303167
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