Ionizing radiation up-regulates cyclooxygenase-2 in I407 cells through p38 mitogen-activated protein kinase.
The epithelial cell line I407 up-regulates cyclooxygenase-2 (COX-2) mRNA and protein expression following ionizing radiation exposure. Prostaglandin E2 (PGE2) production is concomitantly up-regulated. Irradiation of I407 cells also results in phosphorylation of the p38 mitogen-activated protein kinase and the p38 inhibitor SB203580 abrogates radiation-induced PGE2 synthesis. Wild-type p38alpha (p38alphaWT) and dominant-negative p38alpha (p38alphaDN) stable-transfectant clones of I407 cells were used to examine the role of the p38 mitogen-activated protein kinase pathway in the events controlling PGE2 synthesis after ionizing radiation. Treatment of p38alphaWT clones with gamma-radiation resulted in increased COX-2 protein levels and PGE2 synthesis similar to treated control-transfected cells. In contrast, the p38alphaDN clones failed to up-regulate COX-2 protein or increase PGE2 synthesis when irradiated. Exogenous arachidonate did not restore PGE2 synthesis by p38alphaDN cells. Radiation increased COX-2 mRNA stability and the p38 inhibitor SB203580 attenuated COX-2 mRNA stability in irradiated I407 cells. In contrast, irradiation had no effect on transcription from a COX-2 promoter/luciferase reporter plasmid in the presence or absence of SB203580. The data demonstrate a crucial role for p38alpha in COX-2 expression and PGE2 synthesis in an irradiated transformed epithelial cell line. Furthermore, they indicate that p38 activity is required at a step distal to arachidonate release, most probably COX-2 up-regulation, since exogenous arachidonate did not restore PGE2 synthesis.
D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004847:Epithelial Cells / Q000201:enzymology / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone