Expression of the PMLRARalpha fusion dominant-negative oncogene in the epidermis of transgenic mice resulted in spontaneous skin tumors attributed to changes in both the PML and RAR pathways [Hansen et al., Cancer Res 2003; 63:5257-5265]. To determine the contribution of PML to skin tumor susceptibility, transgenic mice were generated on an FVB/N background, that overexpressed the human PML protein in epidermis and hair follicles under the control of the bovine keratin 5 promoter. PML was highly expressed in the epidermis and hair follicles of these mice and was also increased in cultured keratinocytes where it was confined to nuclear bodies. While an overt skin phenotype was not detected in young transgenic mice, expression of keratin 10 (K10) was increased in epidermis and hair follicles and cultured keratinocytes. As mice aged, they exhibited extensive alopecia that was accentuated on the C57BL/6J background. Following skin tumor induction with 7, 12-dimethylbenz[a]anthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter, papilloma multiplicity and size were decreased in the transgenic mice by 35%, and the conversion of papillomas to carcinomas was delayed. Cultured transgenic keratinocytes underwent premature senescence and upregulated transcripts for p16 and Rb but not p19 and p53. Together, these changes suggest that PML participates in regulating the growth and differentiation of keratinocytes that likely influence its activity as a suppressor for tumor development.