Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors.
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.
Jüttner
Stefan
S
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité- Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
Cramer
Thorsten
T
Wessler
Silja
S
Walduck
Anna
A
Gao
Feng
F
Schmitz
Frank
F
Wunder
Christian
C
Weber
Matthias
M
Fischer
Susan M
SM
Schmidt
Wolfgang E
WE
Wiedenmann
Bertram
B
Meyer
Thomas F
TF
Naumann
Michael
M
Höcker
Michael
M
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
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