Helicobacter and gastrin stimulate Reg1 expression in gastric epithelial cells through distinct promoter elements.
The gastric pathogen Helicobacter pylori accelerates the progression to gastric cancer but the precise mechanisms that mediate carcinogenesis remain unidentified. We now describe how Helicobacter and gastrin stimulate the expression of a putative growth factor, Reg1, in primary gastric epithelial cells. RT-PCR and Western immunoblotting of human gastric corpus and antrum showed significantly increased Reg1alpha in H. pylori-infected patients. Similarly, Reg1 was increased in the stomachs of H. felis-infected INS-GAS mice. To study transcriptional regulation of the Reg1 gene, we transfected primary mouse gastric glands with -2111 bp and -104 bp Reg1 promoter-luciferase reporter constructs. Expression of both constructs was detected in pepsinogen- and VMAT-2-expressing cells, which corresponds to the normal pattern of expression of human and mouse endogenous Reg1. The expression of both constructs was increased in response to gastrin and H. pylori, and there were potentiating interactions between them; in contrast, only the -2111 bp construct responded to H. felis. Mutation of a C-rich putative regulatory element within the -104 bp sequence abolished the response to gastrin but not to H. pylori whereas mutation of the proximal -98 to -93 region of the promoter reduced the response to H. pylori but not to gastrin. Stimulation of Reg1 by H. pylori required the virulence factor CagA. These data indicate that expression of the putative growth factor Reg1 is controlled through separate promoter elements by gastrin and Helicobacter.
Steele
Islay A
IA
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, UK.
Dimaline
Rod
R
Pritchard
D Mark
DM
Peek
Richard M
RM
Wang
Timothy C
TC
Dockray
Graham J
GJ
Varro
Andrea
A
D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D005755:Gastrins / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D051847:Lithostathine / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011706:Pyloric Antrum / Q000378:metabolism; D051381:Rats
D005755:Gastrins; D051847:Lithostathine; C497615:Reg1 protein, mouse