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Leukotriene B4 BLT Receptor Signaling Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of Ras/Raf/ERK/p42 AUF1 Pathway
Abstract
Recent studies suggest that active resolution of the inflammatory response in animal models of arthritis may involve leukotriene B(4) (LTB(4))-dependent stimulation of "intermediate" prostaglandin production, which in turn favors the synthesis of "downstream" anti-inflammatory and pro-resolving lipoxins, resolvins, and protectins. We explored a putative mechanism involving LTB(4)-dependent control of cyclooxygenase-2 (COX-2) expression, the rate-limiting step in inflammatory prostaglandin biosynthesis. Indeed, LTB(4) potently up-regulated/stabilized interleukin-1beta-induced COX-2 mRNA and protein expression under conditions of COX-2 inhibitor-dependent blockade of PGE(2) release in human synovial fibroblasts (EC(50) = 16.5 + or - 1.7 nm for mRNA; 19 + or - 2.4 nm for protein, n = 4). The latter response was pertussis toxin-sensitive, and semi-quantitative reverse transcription-PCR confirmed the quantitative predominance of the BLT2 receptor. Transfection experiments, using human COX-2 promoter plasmids and chimeric luciferase-COX-2 mRNA 3'-untranslated region (3'-UTR) reporter constructs, revealed that LTB(4) exerted its stabilizing effect at the post-transcriptional level through a 116-bp adenylate/uridylate-rich sequence in the proximal region of the COX-2 3'-UTR. Using luciferase-COX-2 mRNA 3'-UTR reporter constructs and Ras/c-Raf expression and mutant constructs, we showed that the Ras/c-Raf/MEK1/2/ERK1/2 signaling pathway mediated LTB(4)-dependent COX-2 mRNA stabilizati…
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“A recent study has linked ERK signaling pathway with the nuclear export of p42 isoform and its stabilizing activity to the 3′UTR of COX-2 mRNA in human synovial fibroblast.39”
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Cited by
Singh, A. B., Li, H., Kan, C. F. K., Dong, B., Nicolls, M. R., & Liu, J. (2014) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.112.301131 · Cited by 32
Metadata
- Authors
- Zhai, B., Yang, H., Mancini, A., He, Q., Antoniou, J., & Di Battista, J. A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 285
- Issue
- 31
- Pages
- 23568-23580
- ISSN
- 0021-9258
- Cited by
- 29
- References
- 50
- Language
- en
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- creativecommons.org/licenses/by/4.0/ (vor, 3728 d)
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- Zhai, B., Yang, H., Mancini, A., He, Q., Antoniou, J., & Di Battista, J. A. (2010). Leukotriene B4 BLT Receptor Signaling Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of Ras/Raf/ERK/p42 AUF1 Pathway. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m110.107623
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