Journal Article

Ionizing radiation up-regulates cyclooxygenase-2 in I407 cells through p38 mitogen-activated protein kinase

Teresa G. Tessner, Filipe Muhale, Suzanne Schloemann, Steven M. Cohn, Aubrey R. Morrison and William F. Stenson

in Carcinogenesis

Volume 25, issue 1, pages 37-45
Published in print January 2004 | ISSN: 0143-3334
Published online January 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg183
Ionizing radiation up-regulates cyclooxygenase-2 in I407 cells through p38 mitogen-activated protein kinase

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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 p38α (p38αWT) and dominant-negative p38α (p38αDN) 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 p38αWT clones with γ-radiation resulted in increased COX-2 protein levels and PGE2 synthesis similar to treated control-transfected cells. In contrast, the p38αDN clones failed to up-regulate COX-2 protein or increase PGE2 synthesis when irradiated. Exogenous arachidonate did not restore PGE2 synthesis by p38αDN 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 p38α 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.

Keywords: COX, cyclooxygenase; DRB, dichlorobenzimidazole; IL-1β, interleukin-1β; MAPK, mitogen-activated protein kinase; p38αDN, dominant-negative p38α; p38αWT, wild-type p38α; PGE2, prostaglandin E2

Journal Article.  7182 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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