title: A mutation in separase causes genome instability and increased susceptibility to epithelial cancer.
abstract: Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis.
authors.affiliation: Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Shepard
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: James
authors.initials: J
authors.lastname: Ziai
authors.forename: K Rose
authors.initials: KR
authors.lastname: Finley
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Ken
authors.initials: K
authors.lastname: Chiang
authors.forename: Candace
authors.initials: C
authors.lastname: Hersey
authors.forename: Bruce
authors.initials: B
authors.lastname: Barut
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Freeman
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics*; D042822:Genomic Instability; D006579:Heterozygote; D006720:Homozygote; D007414:Intestinal Neoplasms / Q000209:etiology / Q000473:pathology; D008938:Mitosis; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology* / Q000473:pathology; D011003:Ploidies; D064247:Separase; D008941:Spindle Apparatus / Q000235:genetics / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D010450:Endopeptidases; D064247:Separase; D001973:Bromodeoxyuridine