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Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins

Bugni, JM, Meira, LB and Samson, LD (2009) Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins ONCOGENE, 28 (5). pp. 734-741.

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Abstract

O6-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 ApcMin 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 ApcMin/+ 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 ApcMin/+ mice.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Biochemical Sciences
Authors :
AuthorsEmailORCID
Bugni, JMUNSPECIFIEDUNSPECIFIED
Meira, LBUNSPECIFIEDUNSPECIFIED
Samson, LDUNSPECIFIEDUNSPECIFIED
Date : 5 February 2009
Identification Number : 10.1038/onc.2008.426
Uncontrolled Keywords : Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Oncology, Cell Biology, Genetics & Heredity, BIOCHEMISTRY & MOLECULAR BIOLOGY, CELL BIOLOGY, GENETICS & HEREDITY, ONCOLOGY, colorectal cancer, Mgmt, Msh6, mismatch repair, azoxymethane, INVITRO DNA-REPLICATION, MISMATCH-REPAIR, O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE, INTESTINAL TUMORIGENESIS, METHYLTRANSFERASE GENE, MUTATION FREQUENCY, KNOCKOUT MICE, APOPTOSIS, CANCER, DAMAGE
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 06 Oct 2015 09:53
Last Modified : 06 Oct 2015 09:53
URI: http://epubs.surrey.ac.uk/id/eprint/808674

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