IngentaConnect Transgenic expression of human MGMT blocks the hypersensitivity o...

Abstract:

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 O⁶-methylguanine (O⁶-mG), which, if unrepaired by O⁶-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O⁶-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.

The full text electronic article is available for purchase. You will be able to download the full text electronic article after payment.

$40.19 plus tax Refund Policy

Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis