The functional role of UV irradiation, in combination with the E6 and E7 proteins of the cutaneous human papillomavirus (HPV) types in the malignant conversion of benign papillomatous lesions, has not been elucidated. Transgenic SKH-hr1 hairless mice expressing HPV-20 and HPV-27 E6 and E7 proteins in the suprabasal compartment were generated and exposed to chronic UV irradiation. UV irradiation is a major etiological factor in the development of nonmelanoma skin cancer, one of the most frequent cancers occurring among the Caucasian population worldwide (6, 38). These basal cell and squamous cell carcinomas (SCC) occur primarily on sun-exposed sites. Wild-type p53 protein is expressed at increased levels after UV irradiation, thereby shutting off DNA synthesis and cell replication and allowing for DNA repair and maintenance of genetic integrity after DNA damage. Severe UV irradiation induces not only acute inflammatory reactions but also DNA damage, which is reflected in the induction of p53 mutations (5,36,39,43,57). These p53 mutations are distributed as scattered cells or in clusters of p53-immunoreactive keratinocytes (4, 35).Papillomavirus infections have been implicated in the etiology of nonmelanoma skin cancer both in immunocompetent and in immunosuppressed individuals. This is evidenced in the malignant conversion of 30% to 60% of warts occurring on sun-exposed body sites in patients with the immune-impairing disease Epidermodysplasia verruciformis (37). Human papillomavirus (HPV) DNA has been demonstrated in the majority of premalignant lesions and SCC of the skin (12,21,23,52). The mechanism by which the high-risk mucosal HPV types participate in anogenital carcinogenesis has been elucidated. The expression of the E6 and E7 genes of the high-risk mucosal HPV types stimulates proliferation and is a precondition for immortalization and malignant growth (58, 59). Very little is known about the molecular pathways involved after infection with cutaneous papillomavirus types. The proinflammatory cytokines (interleukin-1␣ [IL-1␣], IL-1, IL-6, and IL-17 and alpha, beta, and gamma interferons) induced by UV irradiation either induce or inhibit the promoters of a number of HPV types associated with cutaneous lesions (13,14,48). The E6 proteins of certain cutaneous HPV types are unable to promote p53 degradation in vitro (18, 51, 53) but effectively inhibit UV-induced apoptosis by attenuating the transcription of p53-regulated proapoptotic genes as well as stimulating the degradation of the proapoptotic protein Bak (26). The ability of the E7 protein of cutaneous HPV types to bind to the pocket protein Rb is not a determinant for oncogenicity for the cutaneous HPV types tested as it has been demonstrated for the high-risk mucosal HPV types (8,58).A number of in vivo models using transgenic mice have been reported in which the E6 and E7 properties of high-risk mucosal HPV-16 or HPV-18 have been studied. Tumors developed in different organs, independent of the promoter used for expression (1,2,7,22,29,33). The in ...