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© The Rockefeller University Press, 0021-9525/2003/8/551 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 551-563

Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss

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: dcleveland{at}ucsd.edu

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.

Key Words: kinetochore; mitosis; cell cycle; LENP-E; BubR1

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