The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice
| Autor: | R. J. W. Berg, A. De Vries, F.R. de Gruijl, C. F. Van Kreijl, Nicolas Dumaz, P. W. Wester, H.J. van Kranen, Leela Daya-Grosjean, Alain Sarasin |
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| Rok vydání: | 1997 |
| Předmět: |
Cancer Research
Neoplasms Radiation-Induced Skin Neoplasms Tumor suppressor gene Ultraviolet Rays Mice Inbred Strains Human skin Biology medicine.disease_cause Mice medicine Animals Humans Point Mutation Missense mutation Polymorphism Single-Stranded Conformational Genetics Mutation Spectra integumentary system General Medicine Genes p53 Hairless CpG site Epidermoid carcinoma Mutagenesis Carcinoma Squamous Cell Cancer research Carcinogenesis |
| Zdroj: | Carcinogenesis. 18:897-904 |
| ISSN: | 1460-2180 |
| DOI: | 10.1093/carcin/18.5.897 |
| Popis: | Mutation spectra of the p53 gene from human skin carcin- process that involves many modifications including proto-omas have been connected to solar UV radiation. For oncogenes and tumor suppressor genes. Among these, the p53comparison we have characterized the mutation spectrum tumor suppressor gene has all the characteristics required forof the p53 gene in a very large sample of squamous analyzing mutation spectra in tumors and enables elucidationcell carcinomas from hairless mice induced with UV of of the events involved in the initiation of cancers (5). It is bywavelength 280–320 nm (UV-B), which have substantiated far one of the most frequently mutated genes found in humanthe mutagenic effects of UV-B radiation in vivo. Tumors cancers and can be functionally altered at more than a hundredfrom hairless mice, random bred SKH:HR1 as well as different codons, which code for the amino acids clustered ininbred SKH:HRAstrains, which areanalyzed for mutations the central hydrophobic region of the protein. Although allin the conserved domains of the p53 protein present a possible typesof mutationshave been documented,the majorityvery specific mutation spectrum. The observed mutation consists of missense mutations. Moreover, the large databasefrequency after chronic UV-B radiation in the p53 gene containing .4500 mutations of the p53 gene in human cancersranged from 54% (SKH-HRA) to 73% (SKH-HR1) among (6) has allowed the comparison of mutation spectra amongthe 160 tumors analyzed. Over 95% of the mutations were different classes of human tumors.found at dipyrimidine sites located in the non-transcribed It has already been shown that the p53 mutation spectrumstrand, the majority were C→T transitions and 5% were in human skin cancers is significantly different from thoseCC→TT tandem double mutations. Four distinct UV-B observed in other human cancers but very similar to thosemutation hot spots have been identified for the first time: observed in UV-treated target genes in model systems (2,3).two major ones at codons 267 (33%) and 272 (19%) and In human skin carcinomas, p53 mutations are mainly C→Ttwo minor ones at codons 146 (10%) and 173 (4%). The transitions located on dipyrimidine sites that are specific UVcodon 267 hot spot consists of a CpG preceded by a targets, whereas in internal cancers C→T are mainly located atpyrimidine, which confirms in vivo an important role for CpG sites. Moreover CC→TT tandem substitutions, generallythis UV-B mutable site in UV-B-induced skin tumors that recognized as being the characteristic fingerprint of UV lesions,is not found in other types of mouse tumors. Comparison are frequently found in human skin carcinomas (7–11).with mutation spectra from human skin carcinomas fully Skin carcinogenesis experiments with animal models, par-validatesthemeritsofthehairlessmousemodelforstudying ticularly the mouse, have already yielded a lot of data on howthe molecular mechanisms of skin carcinogenesis. For skin tumor development depends on dose, time and wavelengthexample, the murine hot spot at codon 272 does have a of the UV-radiation (12). Indeed, murine skin cancers inducedfull equivalent in human skin carcinomas. In contrast, the by repeated exposure to UV radiation provide an excellenthuman equivalent of the murine codon 267 lacks the model system for investigating the molecular mechanisms ofdipyrimidine site and therefore fails to be a pronounced UV carcinogenesis, since UV radiation is the only carcinogenichot spot in human skin carcinomas; however, this site is agent known once other known risk factors are carefullyone of the major hot spots in human internal cancers controlled for or eliminated. In particular, studies on hairless(evidently not induced by UV radiation but probably by mice have demonstrated that wavelengths in the UV-B (280–deamination of the 5 methyl cytosine). 320 nm) region of the solar spectrum are the most carcino-genic (13).Therefore, in the present study we were particularly interes-Introduction ted in looking for p53 alterations in UV-B-induced murineThe carcinogenicity of sunlight to the skin has been recognized skin cancers in order to investigate whether the relationshipfor nearly a century and various experimental studies have between oncogenetic changes and the UV radiation describedfor human non-melanoma skin cancers could be confirmed inthe hairless murine model. Up to now, the data from various |
| Databáze: | OpenAIRE |
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