Chronic exposure to UV radiation (UVR), especially in the UVA (315-400 nm) and UVB (280 -315 nm) spectrum of sunlight, is the major risk factor for the development of nonmelanoma skin cancer. UVR is a complete carcinogen, which both initiates and promotes carcinogenesis. We found that protein kinase C ⑀ (PKC⑀), a member of the phospholipiddependent threonine/serine kinase family, is an endogenous photosensitizer, the overexpression of which in the epidermis increases the susceptibility of mice to UVR-induced cutaneous damage and development of squamous cell carcinoma. The PKC⑀ transgenic mouse (FVB/N) lines 224 and 215 overexpressed 8-and 18-fold PKC⑀ protein, respectively, over endogenous levels in basal epidermal cells. UVR exposure (1 kJ/m 2 three times weekly) induced irreparable skin damage in high PKC⑀-overexpressing mouse line 215. However, the PKC⑀ transgenic mouse line 224, when exposed to UVR (2 kJ/m 2 three times weekly), exhibited minimum cutaneous damage but increased squamous cell carcinoma multiplicity by 3-fold and decreased tumor latency by 12 weeks. UVR exposure of PKC⑀ transgenic mice compared with wild-type littermates (1) elevated the levels of neither cyclobutane pyrimidine dimer nor pyrimidine (6-4) pyrimidone dimer, (2) reduced the appearance of sunburn cells, (3) induced extensive hyperplasia and increased the levels of mouse skin tumor promoter marker ornithine decarboxylase, and (4) elevated the levels of tumor necrosis factor ␣ (TNF␣) and other growth stimulatory cytokines, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor. The role of TNF␣ in UVR-induced cutaneous damage was evaluated using PKC⑀ transgenic mice deficient in TNF␣. UVR treatment three times weekly for 13 weeks at 2 kJ/m 2 induced severe cutaneous damage in PKC⑀ transgenic mice (line 215), which was partially prevented in PKC⑀-transgenic TNF␣-knockout mice. Taken together, the results indicate that PKC⑀ signals UVR-induced TNF␣ release that is linked, at least in part, to the photosensitivity of PKC⑀ transgenic mice.