Protein kinase Cε, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3

Chronic exposure to UV radiation (UVR) is the major etiologic factor in the development of human skin cancers including squamous cell carcinoma (SCC). We have shown that protein kinase C epsilon (PKC epsilon), a Ca2+-independent, phospholipid-dependent serine/threonine kinase, is an endogenous photosensitizer. PKC epsilon is among the six isoforms (alpha, delta, epsilon, eta, mu, and zeta) expressed in both mouse and human skin. PKC epsilon transgenic mice, which overexpress PKC epsilon in the basal epidermal cells and cells of the hair follicle, are highly sensitive to UVR-induced cutaneous damage and development of SCC. We now present that PKC epsilon-overexpressing, but not PKC delta-overexpressing, transgenic mice, when exposed to a single (4 kJ/m(2)) or repeated (four doses, 2 kJ/m(2)/dose, thrice weekly) UVR, emitted by Kodacel-filtered FS-40 sun lamps, elicit constitutive phosphorylation of signal transducers and activators of transcriptions 3 (Stat3) at both Tyr705 and Ser727 residues. UVR-induced phosphorylation of Stat3 accompanied increased expression of Stat3-regulated genes (c-myc, cyclin D1, cdc25A, and COX-2). In reciprocal immunoprecipitation/blotting experiments, phosphorylated Stat3 coimmunoprecipitated with PKC epsilon. As observed in, vivo using PKC epsilon knockout mice and in vitro in an immunocomplex kinase assay, PKC epsilon phosphorylated Stat3 at Ser727 residue. These results indicate for the first time that (a) PKC epsilon is a Stat3Ser727 kinase; (b) PKC epsilon-mediated phosphorylation of StatSer727 may be essential for transcriptional activity of Stat3; and (c) UVR-induced phosphorylation of Ser727 may be a key component of the mechanism by which PKCe imparts sensitivity to UVR-induced development of SCC.