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Carcinogenesis Advance Access published online on July 5, 2007
Carcinogenesis, doi:10.1093/carcin/bgm153
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Associated Contributions of p53 and the DNA Mismatch Repair Protein Msh6 to Spontaneous Tumorigenesis

Leah C. Young*, Angela M. Keuling*, Raymond Lai§,¥, Patrick N. Nation{ddagger}, Victor A. Tron§,¥ and Susan E. Andrew*,§

* Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
§ Department of Experimental Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
{ddagger} Department of Health Sciences Laboratory Animal Services, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
¥ Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

Address correspondence and reprint requests to: Susan E. Andrew, Department of Medical Genetics, 8-33 MSB, University of Alberta, Edmonton Alberta Canada T6G 2H7, Office: (780) 492-1127 Lab: (780) 492-1128 Fax: (780) 492-1998, email: susan.andrew{at}ualberta.ca

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 (MSI) 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.

Key Words: Msh6 • p53 • tumorigenesis • apoptosis • microsatellite instability • loss of heterozygosity • DNA mismatch repair

Received March 26, 2007; revised May 29, 2007; accepted June 22, 2007.


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