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Cooperation between Ha‐ ras and fos or transforming growth factor α overcomes a paradoxic tumor‐inhibitory effect of p53 loss in transgenic mouse epidermis
Author(s) -
Wang XiaoJing,
Greenhalgh David A.,
Donehower Lawrence A.,
Roop Dennis R.
Publication year - 2000
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/1098-2744(200010)29:2<67::aid-mc3>3.0.co;2-2
Subject(s) - biology , genetically modified mouse , tgf alpha , transgene , carcinogenesis , epidermal growth factor , p14arf , cancer research , hyperplasia , epidermis (zoology) , endocrinology , tumor suppressor gene , gene , cell culture , genetics , anatomy
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 α ( TGFα ) exclusively in the epidermis by using human keratin 1 (HK1)–based vectors (HK1.ras/fos, HK1.ras/α, and HK1.fos/α). HK1.ras/fos and HK1.ras/α 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/α‐p53 −/− mice also exhibited an increased epidermal hyperplasia, and, similar to HK1.ras/α 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.TGFα 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/α‐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. Mol. Carcinog. 29:67–75, 2000. © 2000 Wiley‐Liss, Inc.