Journal Article

Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis

Nakao, Kazuki, Gondo, Yoichi, Ishikawa, Takatoshi, Ise, Kazuhiro, Shimizu, Seiichiro, Harada, Hosami, Miyoshi, Jun, Ichise, Taeko, Katsuki, Motoya, Nakamura, Kenji, Aiba, Atsu

2000

Overview

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).

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: 12-O-Tetradecanoylphorbol-13-acetate / 9,10-Dimethyl-1,2-benzanthracene / Acetic acid / Animals / Anthracene / Base Sequence / Biological and medical sciences / Biology / Carcinogenesis / Carcinogens / Cell differentiation / Cell Division / Cell physiology / Cell proliferation / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Codons / DNA Primers / DNA, Neoplasm - genetics / Fundamental and applied biological sciences. Psychology / Gene Deletion / Gene targeting / Genes / Genes, ras / H-ras gene / H-Ras protein / Hras gene / K-ras gene / K-Ras protein / Male / Medicine / Mice / Mice, Knockout / Molecular and cellular biology / Mutants / Mutation / Proteins / Ras protein / Rodents / Science / Skin / Skin Neoplasms - genetics / Skin Neoplasms - pathology / Tumorigenesis / Tumors