This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aziz, M. H. Articles by Verma, A. K. Search for Related Content PubMed PubMed Citation Articles by Aziz, M. H. Articles by Verma, A. K. Related Collections Oncogenesis Oncogenesis: Animal Models

Protein Kinase C, which Sensitizes Skin to Sun's UV Radiation–Induced Cutaneous Damage and Development of Squamous Cell Carcinomas, Associates with Stat3

Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin

Requests for reprints: Ajit K. Verma, Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792. Phone: 608-263-9136; Fax: 608-262-6654; E-mail: akverma{at}facstaff.wisc.edu.

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 (PKC), a Ca²⁺-independent, phospholipid-dependent serine/threonine kinase, is an endogenous photosensitizer. PKC is among the six isoforms (, , , , µ, and ) expressed in both mouse and human skin. PKC transgenic mice, which overexpress PKC 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-overexpressing, but not PKC-overexpressing, transgenic mice, when exposed to a single (4 kJ/m²) or repeated (four doses, 2 kJ/m²/dose, thrice weekly) UVR, emitted by Kodacel-filtered FS-40 sun lamps, elicit constitutive phosphorylation of signal transducers and activators of transcription 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. As observed in vivo using PKC knockout mice and in vitro in an immunocomplex kinase assay, PKC phosphorylated Stat3 at Ser727 residue. These results indicate for the first time that (a) PKC is a Stat3Ser727 kinase; (b) PKC-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 PKC imparts sensitivity to UVR-induced development of SCC. [Cancer Res 2007;67(3):1385–94]

This article has been cited by other articles:

				C. J. Clarke, J. M. Guthrie, and Y. A. Hannun Regulation of Neutral Sphingomyelinase-2 (nSMase2) by Tumor Necrosis Factor-{alpha} Involves Protein Kinase C-{delta} in Lung Epithelial Cells Mol. Pharmacol., October 1, 2008; 74(4): 1022 - 1032. [Abstract] [Full Text] [PDF]

				M. H. Aziz, H. T. Manoharan, D. R. Church, N. E. Dreckschmidt, W. Zhong, T. D. Oberley, G. Wilding, and A. K. Verma Protein Kinase C{varepsilon} Interacts with Signal Transducers and Activators of Transcription 3 (Stat3), Phosphorylates Stat3Ser727, and Regulates Its Constitutive Activation in Prostate Cancer Cancer Res., September 15, 2007; 67(18): 8828 - 8838. [Abstract] [Full Text] [PDF]