Cooperation between Ha-ras and fos or transforming growth factor alpha overcomes a paradoxic tumor-inhibitory effect of p53 loss in transgenic mouse epidermis.

To investigate the role of loss of the p53 tumor suppressor gene in skin carcinogenesis, p53 knockout (p53(-/-)) mice were mated with transgenic mice coexpressing v-Ha-ras, v-fos, or human transforming growth factor alpha (TGFalpha) exclusively in the epidermis by using human keratin 1 (HK1)-based vectors (HK1.ras/fos, HK1.ras/alpha, and HK1.fos/alpha). HK1.ras/fos and HK1.ras/alpha mice displayed epidermal hyperplasia and autonomous benign papillomas to an identical degree between p53(+/+) and p53(+/-) genotypes. However, HK1.ras/fos mice with the p53(-/-) genotype were born with papillomatous skin and died soon after birth. HK1.ras/alpha-p53(-/-) mice also exhibited an increased epidermal hyperplasia, and, similar to HK1.ras/alpha mice with p53(+/+) and p53(+/-) genotypes, these mice rapidly developed spontaneous and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papillomas. These results are in contrast to our previous observation that, HK1.ras, HK1.fos, and HK1.TGFalpha transgenic mice with the p53(-/-) genotype display an unexpected delay in both spontaneous and TPA-promoted papilloma formation compared with mice with p53(+/+) and p53(+/-) genotypes. Taken collectively, our mating experiments between HK1 oncogenic transgenic mice and p53 knockout mice may identify a backup system that effectively compensates for p53 loss. Activation of multiple oncogenes not only partly overcomes such compensation but also synergizes with p53 loss. However, HK1.fos/alpha-p53(-/-) mice failed to exhibit either an increased newborn epidermal hyperplasia or an accelerated spontaneous or TPA-induced papillomas, suggesting that certain combinations of oncogenes, such as with activated Ha-ras, are required for this process. Because neither spontaneous nor TPA-elicited papillomas in p53(-/-) mice progressed to malignancy, additional genetic insults appear to be required for malignant progression.