B-Raf/Rap1 signaling, but not c-Raf-1/Ras, induces the histidine decarboxylase promoter in Helicobacter pylori infection.
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 GalphaS-subunits of heterotrimeric G proteins. Stimulation of this signaling cascade was triggered independent of bacterial-cell contact by a small molecular- weight component(s) (approximately 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 GalphaS-->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.
Wessler
Silja
S
Max-Planck-Institut für Infektionsbiologie, Abt. Molekulare Biologie, Berlin, Germany.
Rapp
Ulf R
UR
Wiedenmann
Bertram
B
Meyer
Thomas F
TF
Schöneberg
Torsten
T
Höcker
Michael
M
Naumann
Michael
M
D000818:Animals; D001685:Biological Factors / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D005753:Gastric Mucosa / Q000201:enzymology*; D005767:Gastrointestinal Diseases / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D016481:Helicobacter Infections / Q000201:enzymology / Q000235:genetics; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006640:Histidine Decarboxylase / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015533:Transcriptional Activation; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D001685:Biological Factors; D000242:Cyclic AMP; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D020827:rap1 GTP-Binding Proteins; D006640:Histidine Decarboxylase