Targeted Deletion of the H-ras Gene Decreases Tumor Formation in Mouse Skin Carcinogenesis

Oncogene. 2000 Jun 15;19(26):2951-6. doi: 10.1038/sj.onc.1203600.

Abstract

To clarify the role of the H-Ras in vivo, we generated H-ras null mutant mice by gene targeting. In spite of the importance of the Ras in cell proliferation and differentiation, H-ras null mutant mice grew normally and were fertile. The oldest H-ras mutant mice grew to be more than 30 months old. We used the H-ras deficient mice to study the importance of the H-ras and other ras genes in the development of skin tumors induced by initiation with 7, 12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). We showed that H-ras null mutant mice develop approximately six times less papillomas compared with wild-type littermates after 20 weeks of TPA treatment. While all papillomas examined (17 out of 17) in wild-type mice have mutations of H-ras at codon 61, 13 (62%) out of 21 papillomas in H-ras null mutant mice have mutations of K-ras gene at codon 12, 13, or 61 and another eight (38%) papillomas have no mutations in these codons of K-ras or N-ras genes. This suggests that the activation of H-ras gene is critical in the wild-type mice, but the activation of K-ras gene can replace the H-ras activation in the initiation step of skin tumor development in the H-ras deficient mice. Oncogene (2000).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Division
  • DNA Primers
  • DNA, Neoplasm / genetics
  • Gene Deletion*
  • Genes, ras*
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology

Substances

  • DNA Primers
  • DNA, Neoplasm