¹Division of DNA Biology and Embryo Engineering, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 Japan

²Core Research for Evolutional Science and Technology (CREST), Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 Japan

³Department of Pathology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

⁴Department of Cell Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

⁵Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan

⁶RIKEN Genomic Sciences Center, Kanagawa 244-0804, Japan

Correspondence to: M Katsuki, Division of DNA Biology and Embryo Engineering, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8638, Japan

^aCurrent address: Center of Medical Information Science, Kochi Medical School, Kochi 783-8505, Japan

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) 19, 2951-2956

H-ras mutant; skin papilloma; chemical carcinogenesis