p53 Mutations in Hairless SKH-hr1 Mouse Skin Tumors Induced by a Solar Simulator

Abstract

In this study, we investigated whether the spectrum of p53 mutations in skin tumors induced in hairless SKH-hr1 mice by a solar simulator (290-400 nm) are similar to those found in skin tumors induced in C3H mice by UV radiation from unfiltered (250-400 nm) and Kodacel-filtered (290-400 nm) FS40 sunlamps. Analysis of tumor DNA for p53 mutations revealed that 14 of 16 (87.5%) SkH-hr1 skin tumors induced by the solar simulator contained mutations. Single C-->T transitions at dipyrimidine sequences located on the nontranscribed DNA strand were the most predominant type of p53 mutation. Remarkably, 52% of all p53 mutations in solar simulator-induced SKH-hr1 skin tumors occurred at codon 270, which is also a hotspot in C3H skin tumors induced by unfiltered and Kodacel-filtered FS40 sunlamps. However, T-->G transversions, which are hallmarks of UVA-induced mutations, were not detected in any of the solar simulator-induced skin tumors analyzed. These results demonstrate that the p53 mutation spectra seen in solar simulator-induced SKH-hr1 skin tumors are similar to those present in -unfiltered and Kodacel-filtered FS40 sunlamp-induced C3H skin tumors. In addition, our data indicate that the UVA present in solar simulator radiation does not play a role in the induction of p53 mutations that contribute to skin cancer development.

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H‐ras gene, but not p53, in SKH‐1 hairless mouse skin

“…18 For detection of p53 mutations, we targeted exons 5 and 8 since they possess hot spots for UV-induced mutations. 19 Mutated homozygous p53 DNA for ras12-1 TG GGC GCT GGA GGC GTG GGA 60 ras12-2 TG GGC GCT GAA GGC GTG GGA 58 ras12-3 TG GGC GCT GTA GGC GTG GGA 58 ras12-4 TGG GCG CT GCA GGC GTG GGA 60 ras12-5 TG GGC GCT CGA GGC GTG GGA 60 ras12-6 TGG GGC GCT AGA GGC GTG GGA 58…”

p53 protects against skin cancer induction by UV-B radiation

“…As shown in Table 2, of the 13 tumors with mutations, three occurred in exon 5, one was in exon 6, and nine were in exon 8 (69%). All mutations in exon 8 were C?T point mutations at codon 270, which is a mutational hotspot, resulting in an Arg?Cys substitution (Kanjilal et al, 1993;Ananthaswamy et al, 1998). The tumor with an alteration in exon 6 had a silent point mutation in codon 212, as well as a deletion of codon 213.…”

“…Exon 5 of the p53 gene was ampli®ed by PCR using primers that spanned the intron-exon junctions, as described previously (Kanjilal et al, 1993;Ananthaswamy et al, 1998). For the ampli®cation of exons 6 ± 8, one primer was anchored in exons that were deleted in the targeted allele was used, along with a primer that spanned in the intronexon junctions of the desired exon.…”

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

“…It is interesting that 35 of 42 mutations occurred at codon 270, which is also a hot spot in UV-induced skin cancers in C3H and SKH-hr-1 mice (Kanjilal et al, 1993;van Kranen et al, 1995;Dumaz et al, 1997;Ananthaswamy et al, 1998). Interestingly, more than 90% of the mutations occurred at dipyrimidine sites on the untranscribed strand of the p53 gene, similar to that of UV-induced skin tumors in NER-pro®cient C3H and SKH-hr1 mice (Kress et al, 1992;Kanjilal et al, 1993;van Kranen et al, 1995;Dumaz et al, 1997;Ananthaswamy et al, 1998). These results suggest that even though XPC7/7 mice are much more sensitive to UV-induced skin carcinogenesis than NER-pro®cient mice, the p53 mutation spectrum, hotspots and strand bias in skin tumors are quite similar to those found in UV-induced skin tumors from NER-pro®cient mice.…”

“…Alternatively, Figure 1 UV-induced XPC7/7 mouse skin tumors contain UV signature p53 mutations. Genomic DNA was analysed for p53 mutations as described previously (Ananthaswamy et al, 1998). Tumor 9.4C contains both mutant (tandem CC?TT) and wildtype sequences at codons 245-246.…”