title: Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors.
abstract: Cyclooxygenase-2 (COX-2) represents the inducible key enzyme of arachidonic acid metabolism and contributes to the pathogenesis of gastroduodenal ulcers and gastric cancer. Helicobacter pylori infection is associated with elevated gastric COX-2 levels, but the mechanisms underlying H. pylori-dependent cox-2 gene expression are unclear. H. pylori stimulated cox-2 mRNA and protein abundance in gastric epithelial cells in vitro and in vivo, and functional analysis of the cox-2 gene promoter mapped its H. pylori-responsive region to a proximal CRE/Ebox element at -56 to -48. Moreover, USF1/-2 and CREB transcription factors binding to this site were identified to transmit H. pylori-dependent cox-2 transcription. Activation of MEK/ERK1/-2 signalling by bacterial virulence factors located outside the H. pylori cag pathogenicity island (cagPAI) was found to mediate bacterial effects on the cox-2 promoter. Our study provides a detailed description of the molecular pathways underlying H. pylori-dependent cox-2 gene expression in gastric epithelial cells, and may thus contribute to a better understanding of mechanisms underlying H. pylori pathogenicity.
authors.affiliation: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité- Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jüttner
authors.forename: Thorsten
authors.initials: T
authors.lastname: Cramer
authors.forename: Silja
authors.initials: S
authors.lastname: Wessler
authors.forename: Anna
authors.initials: A
authors.lastname: Walduck
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitz
authors.forename: Christian
authors.initials: C
authors.lastname: Wunder
authors.forename: Matthias
authors.initials: M
authors.lastname: Weber
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Schmidt
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
authors.forename: Michael
authors.initials: M
authors.lastname: Höcker
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000382:microbiology*; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051720:Upstream Stimulatory Factors; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D037521:Virulence Factors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases