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J. Biol. Chem., Vol. 283, Issue 2, 809-815, January 11, 2008

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Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through β-Catenin and Cyclic AMP-response Element-binding Protein^*

Hongying Wang¹, Shoubin Wen, Nigel W. Bunnett, Richard Leduc^¶, Morley D. Hollenberg^||, and Wallace K. MacNaughton^**2

From the Inflammation Research Network and the Departments of ^**Physiology and Biophysics and ^||Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta T2N 4N1, Canada, the Department of Surgery and Physiology, University of California, San Francisco, California 94143-0104, and the ^¶University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada

Chronic inflammation of mucosae is associated with an increased cancer risk. Tumorigenesis in these tissues is associated with the activity of some proteinases, cyclooxygenase-2 (COX-2), and β-catenin. Serine proteinases participate in both inflammation and tumorigenesis through the activation of proteinase-activated receptor-2 (PAR₂), which up-regulates COX-2 by an unknown mechanism. We sought to determine whether β-catenin participated in PAR₂-induced COX-2 expression and through what cellular mechanism. In A549 epithelial cells, we showed that PAR₂ activation increased COX-2 expression through the β-catenin/T cell factor transcription pathway. This effect was dependent upon ERK1/2 MAPK, which inhibited the β-catenin-regulating protein, glycogen synthase kinase-3β, and induced the activity of the cAMP-response element-binding protein (CREB). Knockdown of CREB by small interfering RNA revealed that PAR₂-induced β-catenin transcriptional activity and COX-2 expression were CREB-dependent. A co-immunoprecipitation assay revealed a physical interaction between CREB and β-catenin. Thus, PAR₂ up-regulated COX-2 expression via an ERK1/2-mediated activation of the β-catenin/Tcf-4 and CREB pathways. These findings reveal new cellular mechanisms by which serine proteinases may participate in tumor development and are particularly relevant to cancers associated with chronic mucosal inflammation, where serine proteinases are abundant and COX-2 overexpression is a common feature.

Received for publication, April 10, 2007 , and in revised form, October 5, 2007.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (to W. K. M. and M. D. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a post-doctoral award from the Canadian Institutes of Health Research, the Canadian Association of Gastroenterology, and Axcan Pharma.

² Senior Scholar of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-5882; Fax: 403-283-3840; E-mail: wmacnaug{at}ucalgary.ca.

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