Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice.
The spindle assembly checkpoint (SAC) guards against chromosomal missegregation during mitosis. To investigate the role of SAC in tumor development, mice heterozygously knocked out for the mitotic arrest deficient (Mad) genes Mad1 and/or Mad2 were mated with p53(+/) (-) mice. Increased tumor frequencies were reproducibly observed in Mad2(+/) (-)p53(+/) (-) (88.2%) and Mad1(+/) (-)Mad2(+/) (-)p53(+/) (-) (95.0%) mice compared with p53(+/) (-) (66.7%) mice. Moreover, 53% of Mad2(+/) (-)p53(+/) (-) mice developed lymphomas compared with 11% of p53(+/) (-) mice. By examining chromosome content, increased loss in diploidy was seen in cells from Mad2(+/) (-)p53(+/) (-) versus p53(+/) (-) mice, correlating loss of SAC function, in a p53(+/) (-) context, with increased aneuploidy and tumorigenesis. The findings here provide evidence for a cooperative role of Mad1/Mad2 and p53 genes in preventing tumor development.
Chi
Ya-Hui
YH
Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Ward
Jerrold M
JM
Cheng
Lily I
LI
Yasunaga
Junichiro
J
Jeang
Kuan-Teh
KT
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D003433:Crosses, Genetic; D005260:Female; D016193:G1 Phase / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D008098:Litter Size; D064246:Mad2 Proteins; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D016196:S Phase / Q000235:genetics; D008941:Spindle Apparatus / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D018797:Cell Cycle Proteins; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D016159:Tumor Suppressor Protein p53; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases