title: Ultraviolet radiation and 12-O-tetradecanoylphorbol-13-acetate-induced interaction of mouse epidermal protein kinase Cε with Stat3 involve integration with ERK1/2.
abstract: We have reported that protein kinase C epsilon (PKCε) expression level in epidermis dictates the susceptibility of mice to the development of squamous cell carcinomas (SCC) elicited either by repeated exposure to ultraviolet radiation (UVR) or by the DMBA-TPA tumor promotion protocol. To find clues about the mechanism by which PKCε mediates susceptibility to UVR-induced development of SCC, we found that PKCε-over-expressing transgenic mice, as compared to their wild-type littermates, when exposed to UVR, elicit enhanced phosphorylation of Stat3 at Ser727 residues. Stat3 is constitutively activated in SCC and UVR fails to induce SCC in Stat3 mutant mice. Stat3Ser727 phosphorylation is essential for Stat3 transcriptional activity (Cancer Res. 67: 1385, 2007). We now present several novel findings including that PKCε integrates with its downstream partner ERK1/2 to phosphorylate Stat3Ser727. In these experiments, mice were either exposed to UVR (2 kJ/m(2)/dose) emitted by Kodacel-filtered FS-40 sun lamps or treated with TPA (5 nmol). Both UVR and TPA treatment stimulated PKCε-Stat3 interaction, Stat3Ser727 phosphorylation and Stat3-regulated gene COX-2 expression. PKCε-Stat3 interaction and Stat3Ser727 phosphorylation was also observed in SCC elicited by repeated UVR exposures of mice. PKCε-Stat3 interaction was PKCε specific. UVR or TPA-stimulated Stat3Ser727 phosphorylation accompanied interaction of PKCε with ERK1/2 in intact mouse skin in vivo. Deletion of PKCε in wild-type mice attenuated both TPA and UVR-induced expression of phosphoforms of ERK1/2 and Stat3Ser727. These results indicate that PKCε integrates with ERK1/2 to mediate both TPA and UVR-induced epidermal Stat3Ser727 phosphorylation. PKCε and Stat3 may be potential molecular targets for SCC prevention.
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin 53705; Department of Molecular and Environmental Toxicology Center, Wisconsin Institutes for Medical Research, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin 53705.
authors.forename: Jordan Marshall
authors.initials: JM
authors.lastname: Sand
authors.forename: Bilal
authors.initials: B
authors.lastname: Bin Hafeez
authors.forename: Moammir Hasan
authors.initials: MH
authors.lastname: Aziz
authors.forename: Emily Marie
authors.initials: EM
authors.lastname: Siebers
authors.forename: Nancy Ellen
authors.initials: NE
authors.lastname: Dreckschmidt
authors.forename: Ajit Kumar
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004817:Epidermis / Q000201:enzymology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017353:Gene Deletion; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011485:Protein Binding; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry*; D014466:Ultraviolet Rays
chemical_list: D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate