1. ¹Biological Effects Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan
2. ²Department of Radiation Biology and Health, University of Occupational and Environmental Health, Kita-Kyushu, Japan
3. ³Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo, Japan

Correspondence: Dr H Tanooka, Biological Effects Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. E-mail: tanooka-h@wind.ocn.ne.jp; tnk@nirs.go.jp

Received 3 August 2008; Revised 3 February 2009; Accepted 22 March 2009; Published online 26 June 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 -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.