Alkylation-induced colon tumorigenesis in mice deficient in the mgmt and msh6 proteins

ABSTRACT _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. Access through your institution Buy or subscribe This is a preview of subscription

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS MODERATE DNA HYPOMETHYLATION SUPPRESSES

INTESTINAL TUMORIGENESIS BY PROMOTING CASPASE-3 EXPRESSION AND APOPTOSIS Article Open access 04 May 2021 INHERITED _MUTYH_ MUTATIONS CAUSE ELEVATED SOMATIC MUTATION RATES AND DISTINCTIVE

MUTATIONAL SIGNATURES IN NORMAL HUMAN CELLS Article Open access 08 July 2022 BRAFV600E DRIVES DEDIFFERENTIATION IN SMALL INTESTINAL AND COLONIC ORGANOIDS AND COOPERATES WITH MUTANT P53 AND

APC LOSS IN TRANSFORMATION Article Open access 13 August 2020 ABBREVIATIONS * ACF: Aberrant crypt foci * AOM: Azoxymethane * DSS: Dextran sulfate sodium * Mgmt: _O_6-methylguanine-DNA

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Scholar  Download references ACKNOWLEDGEMENTS This research was supported by NIH Grants ES02109 and CA75576. We acknowledge the MIT CCR Histology facility (NCI Grant: CA14051), especially

Alicia Caron. LDS is an American Cancer Society Research Professor. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Biological Engineering Department and Center for Environmental Health

Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA J M Bugni, L B Meira & L D Samson Authors * J M Bugni View author publications You can also search for this author

inPubMed Google Scholar * L B Meira View author publications You can also search for this author inPubMed Google Scholar * L D Samson View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to L D Samson. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Bugni, J., Meira, L.

& Samson, L. Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins. _Oncogene_ 28, 734–741 (2009). https://doi.org/10.1038/onc.2008.426 Download citation

* Received: 22 July 2008 * Revised: 19 September 2008 * Accepted: 15 October 2008 * Published: 24 November 2008 * Issue Date: 05 February 2009 * DOI: https://doi.org/10.1038/onc.2008.426

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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * colorectal cancer * Mgmt * Msh6 * mismatch repair * azoxymethane