Roles of Akt and glycogen synthase kinase 3beta in the ultraviolet B induction of cyclooxygenase-2 transcription in human keratinocytes.
Ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) expression plays an important role in UVB tumor promotion. We examined whether Akt and glycogen synthase kinase 3beta (GSK-3beta), components of the phosphatidylinositol 3'-kinase pathway, are involved in UVB induction of COX-2 transcription. UVB caused Akt phosphorylation at both Thr-308 and Ser-473 that was inhibited by LY294002, a phosphatidylinositol 3'-kinase inhibitor. LY294002 also decreased the expression of endogenous COX-2 protein and a luciferase construct driven by COX-2 promoter. Similarly, UVB caused phosphorylation of GSK-3beta (Ser-9) and presumably inactivation of GSK-3beta. Inhibition of GSK-3beta by lithium induced endogenous COX-2 protein expression and COX-2 promoter activity. Finally, overexpression of a dominant-negative Akt mutant or wild-type GSK-3beta suppressed UVB-mediated induction of COX-2 promoter. These studies suggest that inactivation of GSK-3beta through activation of Akt plays an important role in the UVB induction of COX-2 transcription.
Tang
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Department of Radiation Oncology, Arizona Cancer Center, The University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
Gonzales
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Inoue
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Bowden
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D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D015603:Keratinocytes / Q000201:enzymology* / Q000502:physiology / Q000528:radiation effects; D008094:Lithium / Q000494:pharmacology; D008565:Membrane Proteins; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000528:radiation effects; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D014162:Transfection; D014466:Ultraviolet Rays
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007527:Isoenzymes; D008094:Lithium; D008565:Membrane Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496540:PTGS2 protein, human; C494918:AKT1 protein, human