Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.
Sunlight is a carcinogen to which everyone is exposed. Epidemiology indicates that most carcinogenic sunlight exposure takes place several decades before the tumor arises. Some of the early events have been identified by searching for genes having ultraviolet (UV)-specific mutations. Over 90% of squamous cell carcinomas and more than 50% of basal cell carcinomas from New England patients contain UV-like mutations in the p53 tumor suppressor gene. From the mutation pattern, it can be concluded that the carcinogenic DNA lesions were pyrimidine-cytosine photoproducts caused by the UVB portion of sunlight. Particular codons of the p53 gene are most susceptible, apparently because of slower DNA repair at specific sites. Sunlight is sufficiently mutagenic often to mutate both p53 alleles. These mutations are also found in the precancer for squamous cell carcinoma, actinic keratosis, implying an early role. The function of p53 in normal skin is indicated by the observation that inactivating p53 in mouse skin reduces the appearance of sunburn cells, apoptotic keratinocytes generated by UV overexposure. Skin thus appears to possess a p53-dependent "cellular proofreading" response to DNA damage in which precancerous cells self-destruct. If this response is reduced in a single cell by a prior p53 mutation, sunburn can thereafter select for clonal expansion of the p53-mutated cell into an actinic keratosis. Sunlight appears to act twice: as tumor initiator and as tumor promoter.
Brash
D E
DE
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA.
Ziegler
A
A
Jonason
A S
AS
Simon
J A
JA
Kunala
S
S
Leffell
D J
DJ
D000818:Animals; D017209:Apoptosis; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D051379:Mice; D009154:Mutation; D011230:Precancerous Conditions / Q000209:etiology; D012878:Skin Neoplasms / Q000209:etiology*; D013471:Sunburn / Q000150:complications*; D013472:Sunlight / Q000009:adverse effects*; D014466:Ultraviolet Rays / Q000009:adverse effects