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Mutant mouse p53 transgene elevates the chemical induction of tumors that respond to gene silencing with siRNA

Cancer Gene Therapy volume 17, pages 1–10 (2010)Cite this article

A Corrigendum to this article was published on 16 December 2009

Abstract

To study the role of mutant p53 in the induction and cure of tumors, we generated transgenic mice carrying mutant p53 (mp53) containing a 9 bp deletion in exon 6 in addition to wild-type p53, expressing both p53 and mp53. The mp53 cDNA was cloned from a radiation-induced mouse tumor and ligated to the chicken β-actin promoter/CMV-IE enhancer in the expression vector. The presence of mp53 suppressed p21 expression in primary fibroblasts after ionizing irradiation, indicating the dominant-negative activity of mp53 in the mice. These mice developed fibrosarcomas after the subcutaneous injection of 3-methylcholanthrene with an incidence 1.7-fold higher than that of wild-type mice (42% excess). The tumors were then treated via a potent atelocollagen delivery system with small interfering RNA (siRNA), that targeted the promoter/enhancer of the expression vector, resulting in the suppression of tumor growth in 30% of 44 autochthonous tumors, including four cures, and their transplants, the total fraction corresponding to the tumor excess. This suppressive effect involved the induction of apoptosis. These results indicate that mp53 activity causes tumors that can be suppressed by subsequent silencing of mp53 in the presence of wild-type p53 alleles.

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Acknowledgements

We thank Dr S Kondo for his continuous encouragement and critical comments, Dr S Takahashi for his support of this study, Dr M Katsuki for useful suggestions, Dr K Hirai and Dr K Maruyama for technical advice and support, and Dr S Kito and Ms Y Oota for preparing frozen transgenic mouse embryos. This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan, a Special Grant for the Project Research ‘Genetic Control of Biodefense Mechanisms against Radiation’ (KT), a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (KT), a Grant-in-Aid for the Third-Term Comprehensive 10-Year Strategy for Cancer Control (TO) and the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (TO).

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Authors and Affiliations

  1. Biological Effects Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan

    H Tanooka, K Tatsumi, H Tsuji, Y Noda, T Katsube & H Ishii

  2. Department of Radiation Biology and Health, University of Occupational and Environmental Health, Kita-Kyushu, Japan

    A Ootsuyama

  3. Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo, Japan

    F Takeshita & T Ochiya

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  1. H Tanooka
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Correspondence to H Tanooka.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt)

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Tanooka, H., Tatsumi, K., Tsuji, H. et al. Mutant mouse p53 transgene elevates the chemical induction of tumors that respond to gene silencing with siRNA. Cancer Gene Ther 17, 1–10 (2010). https://doi.org/10.1038/cgt.2009.43

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