Loss of mitotic spindle checkpoint activity predisposes to chromosomal instability at early stages of fibrosarcoma development.
Mice carrying the bovine papillomavirus type I genome develop dermal fibrosarcomas in a multiple step process characterized by distinctive proliferative stages. Chromosomal aberrations are identified early in this tumorigenic pathway, however, the mechanism that originates them is unknown. Using a functional assay, we investigated the status of the mitotic spindle cell cycle checkpoint (MSCCC) that regulates the metaphase to anaphase transition, in cells representing different stages of fibrosarcoma progression. Loss of MSCCC activity was apparent in mild fibromatosis and completely abolished in aggressive fibromatosis and fibrosarcoma lesions. This altered MSCCC status was confirmed biochemically by deregulated expression of Cks1 protein and unscheduled cyclin B metabolism. Immunoprecipitation and sequencing analyses indicated that mutation of p53 was not required for the abrogation of the MSCCC. These results demonstrate that loss of mitotic spindle checkpoint activity predisposes to chromosomal instability at early stages of fibrosarcoma development. To our knowledge, these studies constitute the first report of a transition in MSCCC activity in a tumorigenesis model.
The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Duncan M
DM
Gascoyne
Mary L
ML
Hixon
Antonio
A
Gualberto
Maria D M
MD
Vivanco
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D018450:Disease Progression; D005350:Fibroma / Q000235:genetics; D005354:Fibrosarcoma / Q000235:genetics*; D018816:Genes, cdc / Q000502:physiology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C081185:CKS1 protein, S cerevisiae; D018797:Cell Cycle Proteins; D019926:Cyclin B; D029701:Saccharomyces cerevisiae Proteins; D016159:Tumor Suppressor Protein p53