title: Protein kinase C delta overexpressing transgenic mice are resistant to chemically but not to UV radiation-induced development of squamous cell carcinomas: a possible link to specific cytokines and cyclooxygenase-2.
abstract: Protein kinase C delta (PKCdelta), a Ca(2+)-independent, phospholipid-dependent serine/threonine kinase, is among the novel PKCs (delta, epsilon, and eta) expressed in mouse epidermis. We reported that FVB/N transgenic mice that overexpress ( approximately 8-fold) PKCdelta protein in basal epidermal cells and cells of the hair follicle are resistant to the development of both skin papillomas and squamous cell carcinoma (SCC) elicited by 7,12-dimethylbenz(a)anthracene initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion protocol. We now present that PKCdelta overexpression in transgenic mice failed to suppress the induction of SCC developed by repeated exposures to UV radiation (UVR), the environmental carcinogen linked to the development of human SCC. Both TPA and UVR treatment of wild-type mice (a) increased the expression of proliferating cell nuclear antigen (PCNA) and apoptosis; (b) stimulated the expression of cytokines tumor necrosis factor-alpha (TNF-alpha), granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte CSF (G-CSF); and (c) increased cyclooxygenase-2 (COX-2) expression and expression of phosphorylated Akt (p-Akt), p38, extracellular signal-regulated kinase-1 (ERK1), and ERK2. PKCdelta overexpression in transgenic mice enhanced TPA-induced but not UVR-induced apoptosis and suppressed TPA-stimulated but not UVR-stimulated levels of cell PCNA, cytokines (TNF-alpha, G-CSF, and GM-CSF), and the expression of COX-2, p-Akt, and p38. The results indicate that UVR-mediated signal transduction pathway to the induction of SCC does not seem to be sensitive to PKCdelta overexpression. The proapoptotic activity of PKCdelta coupled with its ability to suppress TPA-induced expression of proinflammatory cytokines, COX-2 expression, and the phosphorylation of Akt and p38 may play roles in the suppression of TPA-promoted development of SCC.
authors.affiliation: Department of Human Oncology, Medical School, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Moammir H
authors.initials: MH
authors.lastname: Aziz
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
authors.forename: Bhushan
authors.initials: B
authors.lastname: Bhamb
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D020869:Gene Expression Profiling; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000096:biosynthesis* / Q000502:physiology; D011725:Pyridines / Q000633:toxicity; D012878:Skin Neoplasms / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D014466:Ultraviolet Rays / Q000009:adverse effects; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002273:Carcinogens; D016207:Cytokines; D011725:Pyridines; C431843:tris(2-pyridylmethyl)amine; D051546:Cyclooxygenase 2; D051058:Oncogene Protein v-akt; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases