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Signaling and Regulation

Inhibition of p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Decreases UVB-Induced Activator Protein-1 and Cyclooxygenase-2 in a SKH-1 Hairless Mouse Model¹

Department of Cell Biology and Anatomy, Arizona Cancer Center, University of Arizona, Tucson, Arizona

Requests for reprints: G. Timothy Bowden, Department of Cell Biology and Anatomy, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Room 4999, Tucson, AZ 85724. Phone: 520-626-6006; Fax: 520-626-4979. E-mail: tbowden{at}azcc.arizona.edu

Activation of activator protein-1 (AP-1) and increased expression of cyclooxygenase-2 (COX-2) have been clearly shown to play a functional role in UVB-induced skin tumor promotion. In this study, we examined UVB-induced signal transduction pathways in SKH-1 mouse epidermis leading to increases in COX-2 expression and AP-1 activity. We observed rapid increases in p38 mitogen-activated protein kinase (MAPK) signaling through activation of p38 MAPK and its downstream target, MAPK activated protein kinase-2. UVB also increased phosphatidylinositol 3-kinase (PI3K) signaling as observed through increases in AKT and GSK-3ß phosphorylation. Activation of the p38 MAPK and PI3K pathways results in the phosphorylation of cyclic AMP–responsive element binding protein, which was also observed in UVB-irradiated SKH-1 mice. Topical treatment with SB202190 (a specific inhibitor of p38 MAPK) or LY294002 (a specific inhibitor of PI3K) significantly decreased UVB-induced AP-1 activation by 84% and 68%, respectively, as well as COX-2 expression. Our data show that in mouse epidermis, UVB activation of the p38 MAPK and PI3K pathways leads to AP-1 activation and COX-2 expression.

Key Words: UVB • SKH-1 • AP-1 • COX-2 • p38 MAPK • PI3-kinase

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