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A more recent version of this article appeared on April 1, 2007 Originally published as MBC in Press, 10.1091/mbc.E06-05-0409 on February 7, 2007
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Submitted on May 10, 2006
Revised on January 10, 2007
Accepted on January 29, 2007
*MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom; Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom
Monitoring Editor: Gerard Evan
Despite the fact that the chromosomal passenger complex is well known to regulate kinetochore behavior in mitosis, no functional link has yet been established between the complex and kinetochore structure. In addition, remarkably little is known about how the complex targets to centromeres. Here, in a study of caspase-8 activation during death receptor-induced apoptosis in MCF-7 cells, we have found that cleaved caspase-8 rapidly translocates to the nucleus and that this is correlated with loss of the centromeric protein, CENP-C, resulting in extensive disruption of centromeres. Caspase-8 activates cytoplasmic caspase-7, which is likely to be the primary caspase responsible for cleavage of CENP-C and INCENP, a key chromosomal passenger protein. Caspase-mediated cleavage of CENP-C and INCENP results in their mislocalization and the subsequent mislocalization of Aurora B kinase. Our results demonstrate that the chromosomal passenger complex is displaced from centromeres as a result of caspase activation. Furthermore, mutation of the primary caspase cleavage sites of INCENP and CENP-C and expression of noncleavable CENP-C or INCENP prevents the mislocalization of the passenger complex following caspase activation. Our studies provide the first evidence for a functional interplay between the passenger complex and CENP-C.
These authors contributed equally to this work.
Address correspondence to:
William C. Earnshaw (Bill.Earnshaw{at}ed.ac.uk) or Gerald M. Cohen (gmc2{at}le.ac.uk)
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