Generating chromosome instability through the simultaneous deletion of Mad2 and p53
- *Department of Biology, Center for Cancer Research, and ‡Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139
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Communicated by Stephen C. Harrison, Harvard Medical School, Boston, MA, June 22, 2005 (received for review December 10, 2004)
Abstract
Cancer cells exhibit high levels of chromosome instability (CIN), and considerable interest surrounds the possibility that inactivation of the spindle checkpoint is involved. However, homozygous disruption of Mad and Bub checkpoint genes in metazoans causes cell death rather than CIN. We now report the isolation and characterization of blastocysts and two independent mouse embryonic fibroblast lines carrying deletions in Mad2 and p53. These cells lack a functional spindle checkpoint, undergo anaphase prematurely, and exhibit an extraordinarily high level of CIN. We conclude that the mitotic checkpoint is not essential for viability per se and that a CIN phenotype can be established in culture through the inactivation of both the Mad2- and p53-dependent checkpoint pathways.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: psorger{at}mit.edu.
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↵ † A.A.B. and A.S.L. contributed equally to this work.
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Author contributions: A.A.B., A.S.L., and P.K.S. designed research; A.A.B. and A.S.L. performed research; A.A.B., A.S.L., and P.K.S. analyzed data; and A.A.B., A.S.L., and P.K.S. wrote the paper.
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Abbreviations: CIN, chromosome instability; MEF, mouse embryonic fibroblast; En, embryonic day n; ICM, inner cell mass; NBD, nuclear envelope breakdown.
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Freely available online through the PNAS open access option.
- Copyright © 2005, The National Academy of Sciences
