Sunburn and p53 in the onset of skin cancer.
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.
Ziegler
A
A
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510.
Jonason
A S
AS
Leffell
D J
DJ
Simon
J A
JA
Sharma
H W
HW
Kimmelman
J
J
Remington
L
L
Jacks
T
T
Brash
D E
DE
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