Heterozygous DNA mismatch repair gene PMS2-knockout mice are susceptible to intestinal tumor induction with N-methyl-N-nitrosourea.
PMS2-deficient (PMS2(-/-)) mice are hypersensitive to N-methyl-N-nitrosourea (MNU)-induced thymic lymphomas based on the failure to initiate mismatch repair (MMR) at O(6)-methylguanine:T mismatches formed after MNU exposure. However, heterozygous PMS2 knockout (PMS2(+/-)) mice do not develop spontaneous tumors, suggesting that they have sufficient MMR function to prevent genomic instability. We hypothesized that in PMS2(+/-) mice, exogenous carcinogens may either mutationally knockout the remaining normal allele leading cells to develop tumors or introduce sufficient DNA adducts and mismatches to overload the lower capacity for MMR, leading in either case to an increased rate of tumor production. In the present study, PMS2(+/-) mice and their littermate PMS2(+/+) mice were monitored for tumor incidence following MNU treatment. Mice were given 50 mg MNU/kg i.p. when 5 weeks old. They demonstrated a similar incidence of thymic lymphomas, suggesting that expression of the single normal PMS2 allele is sufficient to protect the thymus and implying that a single dose of MNU may not efficiently knock out the remaining PMS2 allele in the thymus. Surprisingly, PMS2(+/-) mice were significantly more likely to develop intestinal tumors-both adenomas and adenocarcinomas-after MNU than were PMS2(+/+) mice (2.34 +/- 0.34 tumors per mouse versus 1.34 +/- 0.25 tumors per mouse; P < 0.05). The intestinal tumors were located mainly in the small intestine. However, these tumors in both the PMS2(+/-) mice and PMS2(+/+) mice did not show microsatellite instability characteristic of loss of MMR. These results suggest that a single normal PMS2 allele can protect thymus but not intestine from MNU carcinogenesis. Organ-specific factors might influence MMR- mediated resistance to methylating agents. Heterozygous PMS2 knockout mice may be used as a promising animal model for intestinal tumorigenesis studies involving environmental carcinogens.
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Division of Hematology/Oncology and Ireland Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106-4937, USA.
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Gerson
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D000251:Adenosine Triphosphatases; D000818:Animals; D020137:Base Pair Mismatch; D019175:DNA Methylation; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000139:chemically induced*; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D000070976:Mismatch Repair Endonuclease PMS2; D011506:Proteins / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D011506:Proteins; D008770:Methylnitrosourea; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes