title: Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis.
abstract: Like xeroderma pigmentosum (XP) patients, transgenic mice lacking nucleotide excision repair (NER) genes such as XPA and XPC are extremely susceptible to ultraviolet (UV)-induced skin cancer. Because the p53 gene is an important target for UV carcinogenesis and because the p53 protein modulates NER, we investigated the consequences of NER deficiency on UV-induced p53 mutations in XPC-/- mouse skin tumors. Thirty-eight (76%) of 50 UV-induced XPC-/- skin tumor analysed displayed C-->T or CC-->TT transitions at dipyrimidine sites on the untranscribed strand of the p53 gene. A major hot spot for p53 mutation occurred at codon 270, which is also a hot spot in UV-induced skin tumors from NER-proficient C3H and SKH-hr 1 mice. Interestingly, codon 270 mutations were induced in both XPC-/- and +/+ mouse skin after 1 week of UV irradiation, but the mutations persisted only in XPC-/- mouse skin after 3 - 4 weeks of chronic UV. The persistence of UV-induced p53 mutations in XPC-/- mouse skin was associated with decreased apoptosis and increased proliferation of keratinocytes, suggesting that these events may contribute to the accelerated development of UV-induced skin tumors in XPC-/- mice.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas, TX 77030, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Ananthaswamy
authors.forename: A
authors.initials: A
authors.lastname: Ouhtit
authors.forename: R L
authors.initials: RL
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Gorny
authors.forename: P
authors.initials: P
authors.lastname: Khaskina
authors.forename: A T
authors.initials: AT
authors.lastname: Sands
authors.forename: C J
authors.initials: CJ
authors.lastname: Conti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D015603:Keratinocytes / Q000473:pathology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C501002:Xpc protein, mouse