
<ArticleTitle>Overexpression of human <prot>O6-alkylguanine DNA alkyltransferase</prot> (<prot>AGT</prot>) prevents MNU induced lymphomas in heterozygous <prot>p53</prot> deficient mice.</ArticleTitle>
<AbstractText><prot>O6-alkylguanine DNA alkyltransferase</prot> (<prot>AGT</prot>) is a key mechanism in the prevention against MNU induced malignant transformation by removal of O6 methyl guanine (O6mG) adducts. We asked whether heterozygous <prot>p53</prot> deficient mice (<prot>p53</prot>+/-) would be more susceptible to MNU induced lymphomas than wild type mice, and whether O6mG adducts were responsible for this susceptibility. To determine whether <prot>MGMT</prot> overexpression would be protective, <prot>p53</prot>+/- mice were bred to human <prot>MGMT</prot> transgenic mice (<prot>MGMT</prot>+) and treated with 50 mg/kg MNU. MNU increased the incidence of thymic lymphomas in non-transgenic <prot>p53</prot>+/- mice from 23% (n=13) to 68% (n=22) and decreased the mean latency from 433 to 106 days (P=0.01 compared to untreated mice). Wild type mice had an incidence of 30% (n=38) and a mean latency of 135 days after MNU. Overexpression of <prot>MGMT</prot> in the thymus of <prot>p53</prot>+/- mice significantly reduced the lymphoma incidence from 68 to 28% (n=17) and increased the latency from 106 to 167 days (P=0.003). Similarly, the lymphoma incidence in <prot>MGMT</prot>+/wild type mice decreased from 30 to 8% (n=12) and the latency increased to 297 days (P=0.2). Loss of the wild type allele was found in only 2/17 lymphomas occurring in <prot>p53</prot>+/- mice and there were no significant point mutations in exons 5-8 of <prot>p53</prot>. Furthermore, there was no loss of <prot>p53</prot> function in these mice. These data demonstrate that unrepaired O6mG lesions act cooperatively with the reduced <prot>p53</prot> dose and lead to lymphomagenesis in <prot>p53</prot>+/- mice, but <prot>AGT</prot> overexpression and rapid removal of O6mG adducts is protective.</AbstractText>
