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Molecular and Cellular Biology, June 2000, p. 4265-4274, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Regulation of Cyclooxygenase 2 mRNA Stability by the Mitogen-Activated Protein Kinase p38 Signaling Cascade

Marina Lasa,1 Kamal R. Mahtani,1 Andrew Finch,2 Gary Brewer,3 Jeremy Saklatvala,1 and Andrew R. Clark1,*

Kennedy Institute of Rheumatology, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom1; UCSF Cancer Center, San Francisco, California 94143-02182; and Department of Molecular Genetics and Microbiology, Robert Wood Johnson Medical School, University of Medicine and Dentistry---New Jersey, Piscataway, 088543 New Jersey

Received 24 January 2000/Returned for modification 6 March 2000/Accepted 20 March 2000

A tetracycline-regulated reporter system was used to investigate the regulation of cyclooxygenase 2 (Cox-2) mRNA stability by the mitogen-activated protein kinase (MAPK) p38 signaling cascade. The stable beta -globin mRNA was rendered unstable by insertion of the 2,500-nucleotide Cox-2 3' untranslated region (3' UTR). The chimeric transcript was stabilized by a constitutively active form of MAPK kinase 6, an activator of p38. This stabilization was blocked by SB203580, an inhibitor of p38, and by two different dominant negative forms of MAPK-activated protein kinase 2 (MAPKAPK-2), a kinase lying downstream of p38. Constitutively active MAPKAPK-2 was also able to stabilize chimeric beta -globin-Cox-2 transcripts. The MAPKAPK-2 substrate hsp27 may be involved in stabilization, as beta -globin-Cox-2 transcripts were partially stabilized by phosphomimetic mutant forms of hsp27. A short (123-nucleotide) fragment of the Cox-2 3' UTR was necessary and sufficient for the regulation of mRNA stability by the p38 cascade and interacted with a HeLa protein immunologically related to AU-rich element/poly(U) binding factor 1.

* Corresponding author. Mailing address: Kennedy Institute of Rheumatology, Imperial College School of Medicine, 1 Aspenlea Rd., Hammersmith, London W6 8LH, United Kingdom. Phone: (0044) 181 383 4430. Fax: (0044) 181 383 4499. E-mail: a.clark{at}cxwms.ac.uk.

Molecular and Cellular Biology, June 2000, p. 4265-4274, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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