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COX-2 (cyclo-oxygenase-2) mRNA is degraded rapidly in resting cells, but is stabilized by the mitogen-activated protein kinase p38 signalling pathway in response to pro-inflammatory stimuli. A conserved ARE (AU-rich element) of the COX-2 3' untranslated region, CR1 (conserved region 1), acts as a potent instability determinant, and mediates stabilization in response to p38 activation. A detailed structural and functional analysis of this element was performed in an attempt to identify RNA-binding proteins involved in the regulation of COX-2 mRNA stability. Destabilization of a beta-globin reporter mRNA was dependent upon two distinct AREs within CR1, each containing three copies of the sequence AUUUA. CR1 was shown to bind AUF-1 [ARE/poly(U)-binding/degradation factor-1] and/or AUF-2, HuR (Hu antigen R), TTP (tristetraprolin) and FBP1 (far-upstream-sequence-element-binding protein 1), yet these factors did not appear to account for the effects of CR1 upon mRNA stability. Mutant sequences were identified that were incapable of destabilizing a reporter mRNA, yet showed unimpaired binding of FBP1 and AUF-1 and/or -2. TTP was absent from the HeLa cell line used in this analysis. Finally, RNA interference experiments argued against a prominent role for HuR in the CR1-mediated regulation of mRNA stability. We conclude that at least one critical regulator of COX-2 mRNA stability is likely to remain unidentified at present.

Type

Journal article

Journal

The Biochemical journal

Publication Date

02/2004

Volume

377

Pages

629 - 639

Addresses

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, U.K.

Keywords

Cell Line, Tumor, Hela Cells, Humans, Isoenzymes, RNA-Binding Proteins, Heterogeneous-Nuclear Ribonucleoprotein D, DNA-Binding Proteins, Immediate-Early Proteins, Membrane Proteins, Repressor Proteins, 3' Untranslated Regions, RNA, Neoplasm, Regulatory Sequences, Ribonucleic Acid, Antigens, Surface, Electrophoretic Mobility Shift Assay, DNA Mutational Analysis, Base Composition, Base Sequence, Conserved Sequence, RNA Stability, Structure-Activity Relationship, Molecular Sequence Data, Prostaglandin-Endoperoxide Synthases, Cyclooxygenase 2, Tristetraprolin