The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis.
DNA mismatch repair (MMR) is a highly conserved system that repairs DNA adducts acquired during replication, as well as some forms of exogenous/endogenous DNA damage. Additionally, MMR proteins bind to DNA adducts that are not removed by MMR and influence damage-response mechanisms other than repair. Hereditary non-polyposis colorectal cancer, as well as mouse models for MMR deficiency, illustrate that MMR proteins are required for maintenance of genetic stability and tumor suppression. In both humans and mice, the phenotype associated with Msh6-associated tumorigenesis is distinct from that of Msh2. In this study, we hypothesized that Msh6-/-;p53+/- mice would display earlier tumor onset than their Msh6-/- or p53+/- counterparts, indicating that concomitant loss of these two tumor suppressors contributes to tumorigenesis via mechanisms that are only partially interrelated. We generated a Msh6-/-;p53+/- mouse model which succumbed to malignant disease at an accelerated rate and with a tumor spectrum distinct from both Msh6-/- and p53+/- models. Alteration of tumor phenotype in the Msh6-/-;p53+/- mice included a marked increase in microsatellite instability that was associated with loss of heterozygosity of the remaining p53 allele. Also, genetic instability was inversely correlated with survival. This manuscript marks the first in vivo investigation into the association between Msh6 and p53, and their combined role in the suppression of spontaneous tumorigenesis, cell survival and genomic stability. Our results support the hypothesis that p53 and Msh6 are functionally interrelated and that, with concomitant mutation, these tumor suppressors act together to accelerate tumorigenesis.
Young
Leah C
LC
Department of Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Keuling
Angela M
AM
Lai
Raymond
R
Nation
Patrick N
PN
Tron
Victor A
VA
Andrew
Susan E
SE
D000818:Animals; D043171:Chromosomal Instability; D017124:Conserved Sequence; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003643:Death; D016158:Genes, p53; D005838:Genotype; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D013160:Splenic Neoplasms / Q000235:genetics / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; D016159:Tumor Suppressor Protein p53