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Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

Oncogene volume 24, pages 7055–7063 (2005)Cite this article

Abstract

Chronic exposure to ultraviolet (UV) radiation causes skin cancer in humans and mice. We have previously shown that in hairless SKH-hr1 mice, UVB-induced p53 mutations arise very early, well before tumor development. In this study, we investigated whether discontinuation of UVB exposure before the onset of skin tumors results in the disappearance of p53 mutations in the skin of hairless SKH-hr1 mice. Irradiation of mice at a dose of 2.5 kJ/m2 three times a week for 8 weeks induced p53 mutations in the epidermal keratinocytes of 100% of the mice. UVB irradiation was discontinued after 8 weeks, but p53 mutations at most hotspot codons were still present even 22 weeks later. During that period, the percent of mice carrying p53V154A/R155C, p53H175H/H176Y, and p53R275C mutant alleles remained at or near 100%, whereas the percentage of mice with p53R270C mutation decreased by 45%. As expected, discontinuation of UVB after 8 weeks resulted in a delay in tumor development. A 100% of tumors carried p53V154A/R155C mutant alleles, 76% carried p53H175H/H176Y mutants, and 24 and 19% carried p53R270C and p53R275C mutants, respectively. These results suggest that different UVB-induced p53 mutants may provide different survival advantages to keratinocytes in the absence of further UVB exposure and that skin cancer development can be delayed but not prevented by avoidance of further exposure to UVB radiation.

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Acknowledgements

We thank Alexander Gorny for technical assistance and Dawn Chalaire for editorial assistance. This work was supported by National Cancer INSTITUTE Grant CA 46523 and U01 CA105345, National Institute of Environmental Health Sciences Center Grant ES07784, and The University of Texas MD Anderson Cancer Center institutional core grant CA 16672.

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Author notes

  1. Alessia Pacifico

    Present address: Department of Dermatology, The University of l'Aquila, L'Aquila, Italy

  2. Vladislava O Melnikova and Alessia Pacifico: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, PO Box 301402, Unit 902, Houston, 77030, TX, USA

    Vladislava O Melnikova, Alessia Pacifico & Honnavara N Ananthaswamy

  2. Department of Dermatology, The University of Rome ‘tor Vergata’, Rome, Italy

    Sergio Chimenti

  3. Department of Dermatology, The University of l'Aquila, L'Aquila, 67100, Italy

    Ketty Peris

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  1. Vladislava O Melnikova
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  3. Sergio Chimenti
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  5. Honnavara N Ananthaswamy
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Correspondence to Honnavara N Ananthaswamy.

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Melnikova, V., Pacifico, A., Chimenti, S. et al. Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development. Oncogene 24, 7055–7063 (2005). https://doi.org/10.1038/sj.onc.1208863

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