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 ca rcinogenesis, p53 knockout (p53(-/-)) mice were mated with transgenic mice coexpressing v-Ha-ras, v-fos, or human transforming growth factor alpha (TG F alpha) 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 HK 1.ras/alpha mice displayed epidermal hyperplasia and autonomous benign papi llomas to an identical degree between p53(+/+) and p53(+/-) genotypes. Howe ver, HK1.ras/fos mice with the p53(-/-) genotype were born with papillomato us skin and died soon after birth. HK1.ras/alpha -p53(-/-) mice also exhibi ted an increased epidermal hyperplasia, and, similar to HK1.ras/alpha mice with p53(+/+) and p53(+/-) genotypes, these mice rapidly developed spontane ous and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papillomas. Thes e results are in contrast to our previous observation that, HK1.ras, HK1.fo s, and HK1.TGF alpha transgenic mice with the p53(-/-)genotype display an u nexpected delay in both spontaneous and TPA-promoted papilloma formation co mpared with mice with p53(+/+) and p53(+/-)genotypes. Taken collectively, o ur mating experiments between HK1 oncogenic transgenic mice and p53 knockou t mice may identify a backup system that effectively compensates for p53 lo ss. Activation of multiple oncogenes not only partly overcomes such compens ation but also synergizes with p53 loss. However, HK1.fos/alpha -p53(-/-) m ice failed to exhibit either an increased newborn epidermal hyperplasia or an accelerated spontaneous or TPA-induced papillomas, suggesting that certa in combinations of oncogenes, such as with activated Ha-ras, are required f or 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. Mol. Carcinog. 29:67-75, 2000. (C ) 2000 Wiley-Liss, Inc.