Source:http://linkedlifedata.com/resource/pubmed/id/10469609
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
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| pubmed:dateCreated |
1999-9-30
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| pubmed:abstractText |
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 O(6)-methylguanine (O(6)-mG), which, if unrepaired by O(6)-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O(6)-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.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Carcinogens,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Repair Enzymes,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Methylnitrosourea,
http://linkedlifedata.com/resource/pubmed/chemical/O(6)-Methylguanine-DNA...,
http://linkedlifedata.com/resource/pubmed/chemical/PMS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Pms2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins
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| pubmed:status |
MEDLINE
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| pubmed:month |
Sep
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| pubmed:issn |
0143-3334
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
20
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1667-73
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:10469609-Adenosine Triphosphatases,
pubmed-meshheading:10469609-Animals,
pubmed-meshheading:10469609-Carcinogens,
pubmed-meshheading:10469609-DNA,
pubmed-meshheading:10469609-DNA Damage,
pubmed-meshheading:10469609-DNA Repair,
pubmed-meshheading:10469609-DNA Repair Enzymes,
pubmed-meshheading:10469609-DNA-Binding Proteins,
pubmed-meshheading:10469609-Drug Resistance,
pubmed-meshheading:10469609-Genes, ras,
pubmed-meshheading:10469609-Genetic Complementation Test,
pubmed-meshheading:10469609-Humans,
pubmed-meshheading:10469609-Lymphoma,
pubmed-meshheading:10469609-Methylation,
pubmed-meshheading:10469609-Methylnitrosourea,
pubmed-meshheading:10469609-Mice,
pubmed-meshheading:10469609-Mice, Knockout,
pubmed-meshheading:10469609-Mice, Transgenic,
pubmed-meshheading:10469609-O(6)-Methylguanine-DNA Methyltransferase,
pubmed-meshheading:10469609-Proteins,
pubmed-meshheading:10469609-Recombinant Fusion Proteins,
pubmed-meshheading:10469609-Thymus Neoplasms
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| pubmed:year |
1999
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| pubmed:articleTitle |
Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis.
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| pubmed:affiliation |
Division of Hematology/Oncology and the Ireland Cancer Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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