Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis.
Mice deficient in the DNA mismatch repair (MMR) gene, PMS2, develop spontaneous thymic lymphomas and sarcomas. We have previously shown that PMS2(-/-) mice were hypersensitive to a single i.p. injection of 50 mg/kg of N-methyl-N-nitrosourea (MNU) for thymic lymphoma induction. We postulated that MNU sensitivity was due to formation of O(6)-methylguanine (O(6)-mG), which, if unrepaired by O(6)-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O(6)-mG:T mismatches in MMR deficient cells. Tumor induction is less in MMR(+/+) mice because cells with residual DNA adducts die, whereas mutagenized cells survive in MMR(-/-) mice. Overexpression of AGT (encoded by the methylguanine DNA methyltransferase-MGMT-gene) is known to block MNU induced tumorigenesis in mice with functional MMR. To further determine the sensitivity of PMS2(-/-) mice to MNU and the protective effect of hAGT overexpression, a low dose of MNU (25 mg/kg) was studied in PMS2(-/-) mice and PMS2(-/-)/hMGMT(+) mice. No thymic lymphomas were found in MNU-treated PMS2(+/+) and PMS2(+/-) mice. At 1 year, 46% of the MNU-treated PMS2(-/-) mice developed thymic lymphoma, compared with an incidence of 25% in both untreated PMS2(-/-) mice and MNU treated PMS2(-/-)/hMGMT(+) mice. In addition, a significantly shorter latency in the onset of thymic lymphomas was seen in MNU-treated PMS2(-/-) mice. K-ras mutations were detected almost equally in the thymic lymphomas induced by MNU in both PMS2(-/-) and PMS2(-/-)/hMGMT(+) mice, but not in the spontaneous lymphomas. These data suggest that PMS(-/-) mice are hypersensitive to MNU, that there are different pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2(-/-) mice, and that overexpression of hMGMT protects the mice by blocking non-K-ras pathways.
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Division of Hematology/Oncology and the Ireland Cancer Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA.
Zhou
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Liu
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Gerson
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D000251:Adenosine Triphosphatases; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004351:Drug Resistance; D011905:Genes, ras; D005816:Genetic Complementation Test; D006801:Humans; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics*; D008745:Methylation; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000070976:Mismatch Repair Endonuclease PMS2; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000235:genetics*
D002273:Carcinogens; D004268:DNA-Binding Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D008770:Methylnitrosourea; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes