| First Author | Bugni JM | Year | 2009 |
| Journal | Oncogene | Volume | 28 |
| Issue | 5 | Pages | 734-41 |
| PubMed ID | 19029948 | Mgi Jnum | J:145871 |
| Mgi Id | MGI:3836219 | Doi | 10.1038/onc.2008.426 |
| Citation | Bugni JM, et al. (2009) Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins. Oncogene 28(5):734-41 |
| abstractText | O(6)-methylguanine DNA methyltransferase (MGMT) suppresses mutations and cell death that result from alkylation damage. MGMT expression is lost by epigenetic silencing in a variety of human cancers including nearly half of sporadic colorectal cancers, suggesting that this loss maybe causal. Using mice with a targeted disruption of the Mgmt gene, we tested whether Mgmt protects against azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), against AOM and dextran sulfate sodium (DSS)-induced colorectal adenomas and against spontaneous intestinal adenomas in Apc(Min) mice. We also examined the genetic interaction of the Mgmt null gene with a DNA mismatch repair null gene, namely Msh6. Both Mgmt and Msh6 independently suppress AOM-induced ACF, and combination of the two mutant alleles had a multiplicative effect. This synergism can be explained entirely by the suppression of alkylation-induced apoptosis when Msh6 is absent. In addition, following AOM+DSS treatment Mgmt protected against adenoma formation to the same degree as it protected against AOM-induced ACF formation. Finally, Mgmt deficiency did not affect spontaneous intestinal adenoma development in Apc(Min/+) mice, suggesting that Mgmt suppresses intestinal cancer associated with exogenous alkylating agents, and that endogenous alkylation does not contribute to the rapid tumor development seen in Apc(Min/+) mice. |
