title: Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents.
abstract: Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents that damage DNA. This process is facilitated by defects in the G1 and G2 checkpoints of the cell cycle that are apparent in most cancer cells and which allow the cells to enter mitosis with DNA damage. We have now characterized the dynamics of mitotic catastrophe induced by DNA-damaging agents in p53-deficient cancer cells. Cells that entered mitosis with DNA damage transiently arrested at metaphase for more than 10 h without segregation of chromosomes and subsequently died directly from metaphase. In those metaphase arrested precatastrophic cells, anaphase-promoting complex appeared to be inactivated and BubR1 was persistently localized at kinetochores, suggesting that spindle checkpoint is activated after the DNA damage. Furthermore, suppression of spindle checkpoint function by BubR1 or Mad2 RNA interference in the DNA damaged cells led to escape from catastrophic death and to subsequent abnormal mitosis. Dysfunction of the spindle checkpoint in p53-deficient cancer cells is thus likely a critical factor in resistance to DNA-damaging therapeutic agents.
authors.affiliation: Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, University of Kumamoto, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nitta
authors.forename: Osamu
authors.initials: O
authors.lastname: Kobayashi
authors.forename: Shinobu
authors.initials: S
authors.lastname: Honda
authors.forename: Toru
authors.initials: T
authors.lastname: Hirota
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.forename: Tomotoshi
authors.initials: T
authors.lastname: Marumoto
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Ushio
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D017931:DNA Primers; D016159:Tumor Suppressor Protein p53