Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis (original) (raw)

• Original Paper
• Published: 19 June 2000
• Kenji Nakamura1,
• Kazuki Nakao1,
• Seiichiro Shimizu3,
• Hosami Harada1,
• Taeko Ichise1,
• Jun Miyoshi5,
• Yoichi Gondo6,
• Takatoshi Ishikawa3,
• Atsu Aiba1 &
• …
• Motoya Katsuki1,2

Oncogene volume 19, pages 2951–2956 (2000)Cite this article

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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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Authors and Affiliations

1. Division of DNA Biology and Embryo Engineering, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan
   Kenji Nakamura, Kazuki Nakao, Hosami Harada, Taeko Ichise, Atsu Aiba & Motoya Katsuki
2. Core Research for Evolutional Science and Technology (CREST), Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan
   Motoya Katsuki
3. Department of Pathology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
   Seiichiro Shimizu & Takatoshi Ishikawa
4. Department of Cell Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
   Kazuhiro Ise
5. Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 537-8511, Japan
   Jun Miyoshi
6. RIKEN Genomic Sciences Center, Kanagawa, 244-0804, Japan
   Yoichi Gondo

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1. Kazuhiro Ise
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2. Kenji Nakamura
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3. Kazuki Nakao
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4. Seiichiro Shimizu
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5. Hosami Harada
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6. Taeko Ichise
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7. Jun Miyoshi
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8. Yoichi Gondo
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9. Takatoshi Ishikawa
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10. Atsu Aiba
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11. Motoya Katsuki
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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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• Received: 14 January 2000
• Revised: 13 March 2000
• Accepted: 28 March 2000
• Published: 19 June 2000
• Issue Date: 15 June 2000
• DOI: https://doi.org/10.1038/sj.onc.1203600

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