Human Papillomavirus-Induced Carcinogenesis with p53 Deficiency in Mouse: Novel Lymphomagenesis in HPV16E6E7 Transgenic Mice Mimicking p53 Defect

AbstractTo investigate the transforming activity of human papillomavirus (HPV) E6 and E7 genesin vivo, we previously established transgenic mouse lines containing HPV16E6E7, in which male mice develop a Leydig cell tumors with a very high incidence. Because HPV-induced carcinogenesis is highly related to p53, we changed the dose of p53 gene in the transgenic lines by the mice crossing with p53-disrupted mice. The transgenic mice with homozygous wild-type p53 alleles developed only the testicular tumor, whereas novel T cell lymphomagenesis occurred in the heterozygous p53–disrupted E6E7 (p53+/−E6E7) transgenic mice. In this tumor and even in the normal spleen, the absence of p53 protein was observed, whereas the p53 mRNA was expressed with a normal size, suggesting the degradation of p53 protein in these tissues. These results suggest that HPV16E6 could stimulate p53 protein degradation in mouse cells and induced the lymphomagenesis in a manner indistinguishable from p53 deficiency