Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint
- Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670
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Edited by Mark T. Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved April 22, 2004 (received for review February 17, 2004)
Abstract
A compromised mitotic checkpoint, the primary mechanism for ensuring that each new cell receives one copy of every chromosome, has been implicated as a contributor to carcinogenesis. However, a checkpoint response is shown here to be essential for cell survival, including that of chromosomally instable colorectal cancer cells. Reducing the levels of the checkpoint proteins BubR1 or Mad2 in human cancer cells or inhibiting BubR1 kinase activity provokes apoptotic cell death within six divisions except when cytokinesis is also inhibited. Thus, suppression of mitotic checkpoint signaling is invariably lethal as the consequence of massive chromosome loss, findings that have implications for inhibiting proliferation of tumor cells.
Footnotes
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↵ * To whom correspondence should be addressed at: Ludwig Institute for Cancer Research, 3080 CMM-East, 9500 Gilman Drive, La Jolla, CA 92093-0670. E-mail: dcleveland{at}ucsd.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: CIN, chromosome instability; MIN, microsatellite instability; siRNA, small interfering RNA.
- Copyright © 2004, The National Academy of Sciences
