Proteinase-activated receptor-2 induces cyclooxygenase-2 expression through β-catenin and cyclic AMP-response element-binding protein

Hongying Wang, Shoubin Wen, Nigel W. Bunnett, Richard Leduc, Morley D. Hollenberg, Wallace K. MacNaughton

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)809-815
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number2
DOIs
StatePublished - Jan 11 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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