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.
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Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas, for Cancer Research and for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan, Grants-in-Aid from the Ministry of Health and Welfare, Japan. We also thank K Katsuki and Y Ikeda for their excellent technical assistance and K Tsurui and T Kohyama for their help in maintaining the animals.
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Ise, K., Nakamura, K., Nakao, K. et al. Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 19, 2951–2956 (2000). https://doi.org/10.1038/sj.onc.1203600
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DOI: https://doi.org/10.1038/sj.onc.1203600
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