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B‐Raf/Rap1 signaling, but not c‐Raf‐1/Ras, induces the histidine decarboxylase promoter in Helicobacter pylori infection
Author(s) -
Weßler Silja,
Rapp Ulf R.,
Wiedenmann Bertram,
Meyer Thomas F.,
Schöneberg Torsten,
Höcker Michael,
Naumann Michael
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0766fje
Subject(s) - rap1 , helicobacter pylori , transactivation , histidine decarboxylase , biology , signal transduction , chemistry , cancer research , microbiology and biotechnology , enzyme , gene , gene expression , biochemistry , histidine , genetics
Histidine decarboxylase (HDC) is the key enzyme for gastric histamine synthesis, and enhanced HDC expression is critically involved in the pathogenesis of gastric disorders, including gastroduodenal ulcer disease. We characterized the pathogenicity mechanism underlying activation of the HDC promoter in H. pylori‐infected gastric epithelial cells and performed a detailed analysis of the participating signaling elements. We found that H. pylori infection of gastric epithelial cells activated the MEK1‐2/ERK1‐2 cascade through cAMP‐dependent stimulation of Rap1 and B‐Raf, but not Ras/c‐Raf‐1, leading to potent transactivation of the human HDC promoter. H. pylori‐triggered elevation of adenylate cyclase activity was directed by Gα S ‐subunits of heterotrimeric G proteins. Stimulation of this signaling cascade was triggered independent of bacterial‐cell contact by a small molecular‐ weight component(s) (~1 kDa) released by H. pylori and did not require a functional type IV secretion system. Thus, our studies demonstrate for the first time to our knowledge that the Gα S →cAMP→Rap1→B‐Raf→MEK1/2→ERK1/2 pathway is critical for H. pylori‐dependent epithelial gene regulation, which can be induced via a bioactive component(s) apart from the site of bacterial colonization. These results further elucidate the molecular mechanisms underlying interaction of H. pylori with gastric epithelial cells and help to define potential molecular targets for therapeutic interventions in the context of H. pylori ‐related gastric diseases.