title: Death receptor-induced apoptosis reveals a novel interplay between the chromosomal passenger complex and CENP-C during interphase.
abstract: 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 translocation is correlated with loss of the centromere 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 prevent the mislocalization of the passenger complex after caspase activation. Our studies provide the first evidence for a functional interplay between the passenger complex and CENP-C.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Faragher
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Sun
authors.forename: Michael
authors.initials: M
authors.lastname: Butterworth
authors.forename: Nick
authors.initials: N
authors.lastname: Harper
authors.forename: Mike
authors.initials: M
authors.lastname: Mulheran
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ruchaud
authors.forename: William C
authors.initials: WC
authors.lastname: Earnshaw
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000473:pathology; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007399:Interphase / Q000502:physiology*; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; D046912:Multiprotein Complexes; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C060905:centromere protein C; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D053179:Caspase 7; D053181:Caspase 8