Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinases, is not only the major intracellular receptor for the mouse skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) but also is activated by a variety of stress factors including ultraviolet radiation (UVR). PKCepsilon is among six isoforms (alpha, delta, epsilon, eta, mu and zeta) expressed in the mouse skin. To determine the in vivo functional specificity of PKCepsilon in mouse skin carcinogenesis, we generated PKCepsilon transgenic mouse (FVB/N) lines 224 and 215 that overexpress PKCepsilon protein approximately 8- and 18-fold, respectively, over endogenous levels in the basal epidermal cells and cells of the hair follicle. PKCepsilon transgenic mice were observed to be highly sensitive to the development of papilloma-independent metastatic squamous cell carcinoma (mSCC) elicited either by repeated exposure to UVR or by the 7,12-Dimethylbenzanthracene-TPA tumor promotion protocol. The development of squamous cell carcinoma (SCC) appears to be linked to the PKCepsilon-mediated induction of cytokine tumor necrosis factor-alpha(TNFalpha). Immunohistochemical analysis for the expression of PKCepsilon in the SCC of PKCepsilon transgenic mice revealed that PKCepsilon was not expressed in the tumor itself; however, the uninvolved tissue surrounding the SCC exhibited intense PKCepsilon expression. Also, human SCC, similar to mouse SCC, did not express PKCepsilon in the tumor, whereas the surrounding uninvolved epidermis revealed strong PKCepsilon expression. These findings in both the PKCepsilon mouse model and human SCC indicate that overexpression of PKCepsilon in epidermis may lead to a microenvironment, which is suitable for enhancing the development of mSCC by a paracrine mechanism involving specific cytokines including TNFalpha.