Protein kinase Cε and development of squamous cell carcinoma, the nonmelanoma human skin cancer

Abstract Protein kinase C (PKC) represents a large family of phosphatidylserine (PS)‐dependent serine/threonine protein kinases. At least five PKC isoforms (α, δ, ε, η, and ζ) are expressed in epidermal keratinocytes. PKC isoforms are differentially expressed in proliferative (basal layer) and nonproliferative compartments (spinous, granular, cornified layers), which exhibit divergence in their roles in the regulation of epidermal cell proliferation, differentiation, and apoptosis. Immunocytochemical localization of PKC isoforms indicate that PKCα is found in the membranes of suprabasal cells in the spinous and granular layers. PKCε is mostly localized in the proliferative basal layers. PKCη is localized exclusively in the granular layer. PKCδ is detected throughout the epidermis. PKC isozymes exhibit specificities in their signals to the development of skin cancer. PKCε, a calcium‐insensitive PKC isoform mediates the induction of squamous cell carcinoma (SCC) elicited either by the DMBA‐TPA protocol or by repeated exposures to ultraviolet radiation (UVR). PKCε overexpression, which sensitizes skin to UVR‐induced carcinogenesis, suppresses UVR‐induced sunburn (apoptotic) cell formation, and enhances both UVR‐induced levels of TNFα and hyperplasia. UVR‐induced sunburn cell formation is mediated by Fas/Fas‐L and TNFα NFR1 extrinsic apoptotic pathways. The death adaptor protein termed Fas‐associated death domain (FADD) is a common adaptor protein for both of these apoptotic pathways. PKCε inhibits UVR‐induced expression of FADD leading to the inhibition of both apoptotic pathways. It appears that PKCε sensitizes skin to the development of SCC by UVR by transducting signals, which inhibit apoptosis on one hand, and enhances proliferation of preneoplastic cells on the other hand. © 2006 Wiley‐Liss, Inc.