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

To clarify the role of the H-Ras in vivo, we generated H-ras null mutant mi ce by gene targeting. In spite of the importance of the Ras in cell prolife ration and differentiation, H-ras null mutant mice grew normally and were f ertile. 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 oth er ras genes in the development of skin tumors induced by initiation with 7 ,12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetrad ecanoylphorbol-13-acetate (TPA), We showed that H-ras null mutant mice deve lop approximately six times less papillomas compared with wild-type litterm ates 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-vas gene at codon 12, 13, or 61 and another eight (38%) papillomas have no mutations i n these codons of K-ras or N-ras genes. This suggests that the activation o f 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.