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. p53 m). HK1. p53 m 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 p53 m papillomas progressed to carcinomas and metastases. In addition, more advanced malignancy, ie, undifferentiated spindle cell carcinomas, were exclusively observed in p53 m mice. Increased bromodeoxyuridine (BrdU) labeling, accompanied by decreased expression of p21, was observed in HK1. p53 m papillomas. In situ examination of centrosomes in HK1. p53 m papillomas also revealed marked abnormalities, with 75% of the cells containing⩾ 3 centrosomes/cell, whereas centrosome numbers in papillomas from control animals remained normal. These data suggest that the accelerated tumorigenesis observed in chemically-treated p53 m mice is most likely due to increased genomic instability resulting from an inhibition of G1 arrest and abnormal amplification of centrosomes.