The major etiological agent contributing to human nonmelanoma
skin cancer is sunlight. The p53 tumor suppressor gene is usually mutated in these
tumors, and the mutations are "UV signature" single or tandem transitions at dipyrimidine sequences in the
DNA-binding domain (DBD). Cells that harbor these characteristic mutations are already present in sun-exposed skin areas of healthy individuals, and small epidermal patches that are immunoreactive to anti-p53 antibody accrue as exposure increases. To explore
carcinogen-specific human p53 mutation patterns experimentally, we generated a knock-in (Hupki) mouse in which the murine DBD of the p53 gene has been replaced by the homologous human p53 DBD segment; thus, the precise base sequence context frequently targeted by
mutagens or endogenous mutagenic processes in human
carcinogenesis is present in this strain (J. L. Luo et al., Oncogene, 20: 320-328, 2001). Here we show that when epidermal cells of Hupki mice (p53(ki/ki)) are irradiated in vivo with a single acute dose of UVB light, they accumulate UV photoproducts at the same locations of the p53 gene as human cells. Chronic exposure of Hupki mice (4.5 kJ/m(2) 5x/week for 4 weeks) results in the appearance of cell patches that
stain intensely with the anti-p53 antiserum CM1.
DNA preparations from 2 cm(2) sections of chronically irradiated Hupki epidermis harbor C to T and CC to TT mutations at two mutation hotspots identified in human
skin cancer, one at
codons 278-279, and one at
codons 247-248; the latter is the most frequent UVB-associated mutation site in humans but not in p53 wild-type mice. Thus, Hupki keratinocytes with these p53 mutations encode an aberrant DBD identical in amino acid sequence to the mutant p53 molecules in human UV-induced
tumors. The Hupki mouse model offers a new experimental tool in molecular epidemiology and biomedical research.