Inducible Regulation of Gastrin Gene Expression During Helicobacter PyloriInfection.

[摘要] Gastrin is a peptide hormone expressed in the adult antral stomach. Gastrin is a potent regulator of acid secretion and is a growth factor required for the maintenance of gastrointestinal physiology. The expression of gastrin is regulated by fasting, re-feeding, and gastric pH. Infection by the gut pathogen, Helicobacter pylori (H. pylori), increases the expression of gastrin.H. pylori is the most prevalent bacterial pathogen in man.In a percentage of infected subjects it generates a Th1-mediated chronic gastritis.Furthermore, H. pylori infection is a risk factor for the development of duodenal ulcers and gastric cancer. Elevated levels of gastrin have been observed in human cancers and contribute to the development of duodenal ulcers even in the absence of H. pylori. These findings implicate gastrin as a contributing factor in the progression of H. pylori–mediated disease. Therefore, the regulatory elements mediating regulation of gastrin gene by H. pylori infection were defined and characterized.In infected mice and AGS (human gastric cancer) cells, H. pylori induced a 7- to 8-fold increase in endogenous gastrin gene expression. I determined that the bacteria stimulated transcriptional initiation of gastrin by activating MAP kinase signaling.I identified GC rich promoter elements that mediated induction of the gastrin promoter by H. pylori and demonstrated that the bacteria induced binding of the transcription factors Sp1 and Sp3 to these elements.Also, the effect of the pro-inflammatory cytokine IFNγ on gastrin gene expression was studied. An increase in the numbers of G cells and plasma gastrin following IFNγ infusion was observed in mice. However, changes in gastrin gene expression were not detected.Treatment of AGS cells with IFNγ had no effect on gastrin gene expression.Therefore, I concluded that IFNγ does not regulate gastrin gene expression directly.In summary, I established that regulation of gastrin gene expression by H. pylori is mediated directly by the bacteria through GC rich elements that bind Sp1 and Sp3. These findings contribute to our knowledge of the regulatory mechanisms that activate gastrin gene expression.

[发布机构] University of Michigan

[效力级别] Transcription

[关键词] Gene Expression;Transcription;Gastrin;Helicobacter Pylori;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology