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 model.
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-3beta 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.
Bachelor
Michael A
MA
Department of Cell Biology and Anatomy, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Room 4999, Tucson, AZ 85724, USA.
Cooper
Simon J
SJ
Sikorski
Ewa T
ET
Bowden
G Timothy
GT
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2; D004817:Epidermis / Q000201:enzymology / Q000528:radiation effects*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008812:Mice, Hairless; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D002867:Chromones; D017362:Cyclic AMP Response Element-Binding Protein; D051546:Cyclooxygenase 2; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole