Site-specific mutation of the human c-Ha-ras transgene induced by dimethylbenzanthracene causes tissue-specific tumors in mice

Jpn J Cancer Res. 1994 Aug;85(8):801-7. doi: 10.1111/j.1349-7006.1994.tb02951.x.

Abstract

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.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity*
  • Adenocarcinoma / chemically induced*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Carcinoma, Squamous Cell / chemically induced*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Codon / genetics
  • Genes, ras*
  • Hemangiosarcoma / chemically induced*
  • Hemangiosarcoma / genetics
  • Hemangiosarcoma / pathology
  • Humans
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Methylnitrosourea / toxicity
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed*
  • Oligonucleotide Probes
  • Point Mutation*
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic
  • Splenic Neoplasms / chemically induced*
  • Splenic Neoplasms / genetics
  • Splenic Neoplasms / pathology
  • Stomach Neoplasms / chemically induced*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / pathology

Substances

  • Codon
  • Oligonucleotide Probes
  • 9,10-Dimethyl-1,2-benzanthracene
  • Methylnitrosourea