title: Sunburn and p53 in the onset of skin cancer.
abstract: Squamous cell carcinoma of the skin (SCC) can progress by stages: sun-damaged epidermis, with individual disordered keratinocytes; actinic keratosis (AK), spontaneously regressing keratinized patches having aberrant cell differentiation and proliferation; carcinoma in situ; SCC and metastasis. 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 SCCs were present in AKs. Inactivating p53 in mouse skin reduced the appearance of sunburn cells, 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.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: A
authors.initials: A
authors.lastname: Ziegler
authors.forename: A S
authors.initials: AS
authors.lastname: Jonason
authors.forename: D J
authors.initials: DJ
authors.lastname: Leffell
authors.forename: J A
authors.initials: JA
authors.lastname: Simon
authors.forename: H W
authors.initials: HW
authors.lastname: Sharma
authors.forename: J
authors.initials: J
authors.lastname: Kimmelman
authors.forename: L
authors.initials: L
authors.lastname: Remington
authors.forename: T
authors.initials: T
authors.lastname: Jacks
authors.forename: D E
authors.initials: DE
authors.lastname: Brash
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D016158:Genes, p53; D006801:Humans; D007642:Keratosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*; D013471:Sunburn / Q000235:genetics; D013472:Sunlight; D014466:Ultraviolet Rays