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Sunburn and p53 in the onset of skin cancer

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Abstract

SQUAMOUS cell carcinoma of the skin (SCC) can progress by stages: sun-damaged epidermis, with individual disordered keratin-ocytes; actinic keratosis (AK), spontaneously regressing keratin-ized patches having aberrant cell differentiation and proliferation; carcinoma in situ; SCC and metastasis1–3. To understand how sunlight acts as a carcinogen, we determined the stage at which sunlight mutates the p53 tumour-suppressor gene and identified a function for p53 in skin. The p53 mutations induced by ultraviolet radiation and found in >90% of human SCCs4,5 were present in AKs. Inactivating p53 in mouse skin reduced the appearance of sunburn cells6, apoptotic keratinocytes generated by overexposure to ultraviolet. Skin thus appears to possess a p53-dependent 'guardian-of-the-tissue' response to DNA damage which aborts precancerous cells. If this response is reduced in a single cell by a prior p53 mutation, sunburn can select for clonal expansion of the p53-mutated cell into the AK. Sunlight can act twice: as tumour initiator and tumour promoter.

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Author information

Author notes

  1. Annemarie Ziegler

    Present address: Department of Internal Medicine, University Hospital of Zurich, Zurich, 8044, Switzerland

  2. Jeffrey A. Simon

    Present address: Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregon, 97201, USA

  3. Harsh W. Sharma

    Present address: Division of Oncology, Hoffmann-LaRoche Inc., Nutley, New Jersey, 07110, USA

Authors and Affiliations

  1. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    Annemarie Ziegler, Alan S. Jonason, Jeffrey A. Simon, Harsh W. Sharma, Jonathan Kimmelman & Douglas E. Brash

  2. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    David J. Leffellt

  3. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    Douglas E. Brash

  4. Department of Biology, Center for Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Lee Remington & Tyler Jacks

Authors
  1. Annemarie Ziegler
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  2. Alan S. Jonason
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  3. David J. Leffellt
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  4. Jeffrey A. Simon
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  5. Harsh W. Sharma
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  6. Jonathan Kimmelman
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  7. Lee Remington
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  8. Tyler Jacks
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  9. Douglas E. Brash
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Ziegler, A., Jonason, A., Leffellt, D. et al. Sunburn and p53 in the onset of skin cancer. Nature 372, 773–776 (1994). https://doi.org/10.1038/372773a0

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  • DOI: https://doi.org/10.1038/372773a0

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