title: Hepatocyte growth factor regulates cyclooxygenase-2 expression via beta-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells.
abstract: Hepatocyte growth factor (HGF) is upregulated in response to lung injury and has been implicated in tissue repair through its antiapoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play a role in cell growth. Here, we report that HGF induces gene transcription of COX-2 in human bronchial epithelial cells (HBEpC). Treatment of HBEpC with HGF resulted in phosphorylation of the HGF receptor (c-Met), activation of Akt, and upregulation of COX-2 mRNA. Adenovirus-mediated gene transfer of a dominant negative (DN) Akt mutant revealed that HGF increased COX-2 mRNA in an Akt-dependent manner. COX-2 promoter analysis in luciferase reporter constructs showed that HGF regulation required the beta-catenin-responsive T cell factor-4 binding element (TBE). The HGF activation of the COX-2 gene transcription was blocked by DN mutant of beta-catenin or by inhibitors that blocked activation of Akt. Inhibition of p42/p44 MAPK pathway blocked HGF-mediated activation of beta-catenin gene transcription but not Akt activation, suggesting that p42/p44 MAPK acts in a parallel mechanism for beta-catenin activation. We also found that inhibition of COX-2 with NS-398 blocked HGF-induced growth in HBEpC. Together, the results show that the HGF increases COX-2 gene expression via an Akt-, MAPK-, and beta-catenin-dependent pathway in HBEpC.
authors.affiliation: Department of Pharmacology, The Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
authors.forename: Young H
authors.initials: YH
authors.lastname: Lee
authors.forename: Yuichiro J
authors.initials: YJ
authors.lastname: Suzuki
authors.forename: Autumn J
authors.initials: AJ
authors.lastname: Griffin
authors.forename: Regina M
authors.initials: RM
authors.lastname: Day
mesh_terms: D000260:Adenoviruses, Human / Q000502:physiology; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics*; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051176:beta Catenin / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3