To develop an in vivo model for studying the role of the p53
tumor suppressor in skin
carcinogenesis, a murine p53(172H) mutant (equivalent to human p53(175H)) was expressed in the epidermis of transgenic mice, utilizing a targeting vector based on the human
keratin 1 gene (HK1.p53m). HK1.p53m mice developed normally and did not exhibit an obvious epidermal phenotype or develop spontaneous
tumors. However, these mice demonstrated an increased susceptibility to a two-stage chemical
carcinogenesis protocol, with the rate of formation and number of
papillomas being dramatically increased as compared to non-transgenic controls. The majority of
papillomas in control mice regressed after termination of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, whereas p53m
papillomas progressed to
carcinomas and
metastases. In addition, more advanced
malignancy, i.e., undifferentiated
spindle cell carcinomas, were exclusively observed in p53m mice. Increased
bromodeoxyuridine (
BrdU) labeling, accompanied by decreased expression of p21, was observed in HK1.p53m
papillomas. In situ examination of centrosomes in HK1.p53m
papillomas also revealed marked abnormalities, with 75% of the cells containing > or = 3 centrosomes/cell, whereas centrosome numbers in
papillomas from control animals remained normal. These data suggest that the accelerated
tumorigenesis observed in chemically-treated p53m mice is most likely due to increased
genomic instability resulting from an inhibition of G1 arrest and abnormal amplification of centrosomes.