Dexamethasone Destabilizes Cyclooxygenase 2 mRNA by Inhibiting Mitogen-Activated Protein Kinase p38

doi:10.1128/MCB.21.3.771-780.2001

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Molecular and Cellular Biology, February 2001, p. 771-780, Vol. 21, No. 3
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.3.771-780.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dexamethasone Destabilizes Cyclooxygenase 2 mRNA by Inhibiting Mitogen-Activated Protein Kinase p38

Marina Lasa, Matthew Brook, Jeremy Saklatvala, and Andrew R. Clark^*

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom

Received 24 August 2000/Returned for modification 12 October 2000/Accepted 8 November 2000

The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activatedprotein kinase (MAPK) p38 and negatively by anti-inflammatoryglucocorticoids such as dexamethasone. A tetracycline-regulatedreporter system was used to investigate mechanisms of regulationof Cox-2 mRNA stability. Dexamethasone was found to destabilize $beta$ -globin-Cox-2 reporter mRNAs by inhibiting p38. This inhibitionoccurred at the level of p38 itself: stabilization of reportermRNA by a kinase upstream of p38 was blocked by dexamethasone,while stabilization by a kinase downstream of p38 was insensitiveto dexamethasone. Inhibition of p38 activity by dexamethasonewas observed in a variety of cell types treated with differentactivating stimuli. Furthermore, inhibition of p38 was antagonizedby the anti-glucocorticoid RU486 and was delayed and actinomycinD sensitive, suggesting that ongoing glucocorticoid receptor-dependenttranscription isrequired.

^* Corresponding author. Mailing address: Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1Aspenlea Rd., Hammersmith, London W6 8LH, United Kingdom. Phone:(0044) 20 8383 4430. Fax: (0044) 20 8383 4499. E-mail: andy.clark{at}ic.ac.uk.

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