Site-specific mutation of the human c-Ha-ras transgene induced by dimethylbenzanthracene causes tissue-specific tumors in mice.
Forestomach squamous cell carcinomas, lung adenocarcinomas and spleen angiosarcomas were induced by dimethylbenzanthracene (DMBA) in the rasH2 transgenic mouse line carrying human c-Ha-ras genes with their own promoter, encoding the prototype p21 gene product. Fifteen out of 21 mice (71%) developed forestomach squamous cell carcinomas, while 15 out of 21 (71%) had lung adenocarcinomas and 3 out of 21 (14%) showed spleen angiosarcomas within 8 weeks after a single administration of 50 mg/kg DMBA intraperitoneally. Somatic mutation at the 61st codon of the transgenes, from CAG(Gln) to CTG(Leu), was detected in all these newly developed tumors. However, non-transgenic littermates demonstrated no tumors at all. These findings provide strong evidence that the somatic mutational activation of human c-Ha-ras genes is a critical event in tumorigenesis and a close relationship is therefore strongly suggested between the tissue-specific development of tumors and the somatic mutation of human c-Ha-ras genes in these rasH2 transgenic mice.
Doi
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Laboratory of Immunology, Aichi Cancer Center Research Institute, Nagoya.
Kimura
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Katsuki
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D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D003062:Codon / Q000235:genetics; D011905:Genes, ras; D006394:Hemangiosarcoma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D015345:Oligonucleotide Probes; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D013160:Splenic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology
D003062:Codon; D015345:Oligonucleotide Probes; D015127:9,10-Dimethyl-1,2-benzanthracene; D008770:Methylnitrosourea