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Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis

Oncogene volume 18, pages 7395–7398 (1999)Cite this article

Abstract

Like xeroderma pigmentosum (XP) patients, transgenic mice lacking nucleotide excision repair (NER) genes such as XPA and XPC are extremely susceptible to ultraviolet (UV)-induced skin cancer. Because the p53 gene is an important target for UV carcinogenesis and because the p53 protein modulates NER, we investigated the consequences of NER deficiency on UV-induced p53 mutations in XPC−/− mouse skin tumors. Thirty-eight (76%) of 50 UV-induced XPC−/− skin tumor analysed displayed C→T or CC→TT transitions at dipyrimidine sites on the untranscribed strand of the p53 gene. A major hot spot for p53 mutation occurred at codon 270, which is also a hot spot in UV-induced skin tumors from NER-proficient C3H and SKH-hr 1 mice. Interestingly, codon 270 mutations were induced in both XPC−/− and +/+ mouse skin after 1 week of UV irradiation, but the mutations persisted only in XPC−/− mouse skin after 3 – 4 weeks of chronic UV. The persistence of UV-induced p53 mutations in XPC−/− mouse skin was associated with decreased apoptosis and increased proliferation of keratinocytes, suggesting that these events may contribute to the accelerated development of UV-induced skin tumors in XPC−/− mice.

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Acknowledgements

Supported by National Cancer Institute grants CA 46523 (to HN Ananthaswamy), CA 42157 (to CJ Conti), Institutional core grant CA 16672, and by 5-P30 ES07784-04 from the National Institute of Environmental Health Sciences, NIH). A Ouhtit is the recipient of a McCarthy postdoctoral fellowship.

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Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, 77030, Texas, TX, USA

    Honnavara N Ananthaswamy, Allal Ouhtit, Randall L Evans, Alexander Gorny & Polina Khaskina

  2. Lexicon Genetics, 4000 Research Forest Drive, The Woodlands, 77381, Texas, TX, USA

    Arthur T Sands

  3. Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, PO Box 309, 78957, Smithville, Texas, TX, USA

    Claudio J Conti

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  1. Honnavara N Ananthaswamy
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Ananthaswamy, H., Ouhtit, A., Evans, R. et al. Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis. Oncogene 18, 7395–7398 (1999). https://doi.org/10.1038/sj.onc.1203147

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