title: Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors.
abstract: Aneuploidy, a chromosome content other than a multiple of the haploid number, is a common feature of cancer cells. Whole chromosomal aneuploidy accompanying ongoing chromosomal instability in mice resulting from reduced levels of the centromere-linked motor protein CENP-E has been reported to increase the incidence of spleen and lung tumors, but to suppress tumors in three other contexts. Exacerbating chromosome missegregation in CENP-E(+/-) mice by reducing levels of another mitotic checkpoint component, Mad2, is now shown to result in elevated cell death and decreased tumor formation compared with reduction of either protein alone. Furthermore, we determine that the additional contexts in which increased whole-chromosome missegregation resulting from reduced CENP-E suppresses tumor formation have a preexisting, elevated basal level of chromosome missegregation that is exacerbated by reduction of CENP-E. Tumors arising from primary causes that do not generate chromosomal instability, including loss of the INK4a tumor suppressor and microsatellite instability from reduction of the DNA mismatch repair protein MLH1, are unaffected by CENP-E-dependent chromosome missegregation. These findings support a model in which low rates of chromosome missegregation can promote tumorigenesis, whereas missegregation of high numbers of chromosomes leads to cell death and tumor suppression.
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Alain D
authors.initials: AD
authors.lastname: Silk
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Zasadil
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holland
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vitre
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Beth A
authors.initials: BA
authors.lastname: Weaver
mesh_terms: D000782:Aneuploidy; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D020090:Chromosome Segregation / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D064246:Mad2 Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics*; D059008:Time-Lapse Imaging
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C068688:centromere protein E
keywords: ARF; CIN; Mad2; spindle assembly checkpoint