Transcriptional regulation of the human trefoil factor, TFF1, by gastrin.
OBJECTIVE
This study aimed to identify gastrin-sensitive genes that may mediate the effects of this hormone on gastric epithelial architecture.


METHODS
Gastrin-sensitive genes were identified by messenger RNA (mRNA) differential display of the gastric fundus from gastrin-deficient (GAS-KO) or wild-type mice. Gastrin-stimulated expression of the trefoil peptide TFF1 in mouse fundus and in the gastric cancer cell line AGS-G(R) was determined by Northern blot and real-time polymerase chain reaction. Transcriptional regulation of TFF1 in AGS-G(R) cells was studied using promoter-reporter assays and electrophoretic mobility shift assay. Expression of TFF1 and the cholecystokinin(B) receptor in response to gastric mucosal injury was determined by immunohistochemistry.


RESULTS
mRNA differential display identified TFF1 as a gastrin-regulated gene. TFF1 mRNA was reversibly reduced in GAS-KO mice and increased in a hypergastrinemic transgenic strain versus respective background strains. TFF1 mRNA expression was rapidly and potently induced by gastrin in a gastric cancer cell line that expresses the gastrin/cholecystokinin(B) receptor. Gastrin responsiveness of the human TFF1 promoter mapped to a G-C rich region 300 base pairs upstream of the transcriptional start site. This region bound the transcription factors SP3 and MAZ. Gastrin activated transcription through a Raf-, Mek- and Erk-dependent but Ras-independent pathway. TFF1 expression was induced both directly and by transactivation between neighboring cells. Neither direct nor indirect gastrin-induced TFF1 expression required activation of the epidermal growth factor receptor.


CONCLUSIONS
Gastrin exerts tonic control of TFF1 expression but also has the potential for rapid up-regulation of this trefoil factor. TFF1 is a potential candidate to counterbalance the proliferative effects of gastrin.
Khan
Zara E
ZE
Physiological Laboratory, University of Liverpool, Liverpool, England UK.
Wang
Timothy C
TC
Cui
Guanglin
G
Chi
Alfred L
AL
Dimaline
Rod
R
D000818:Animals; D002118:Calcium / Q000502:physiology; D005755:Gastrins / Q000502:physiology*; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010455:Peptides / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000502:physiology; D011506:Proteins; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000502:physiology; D020218:Response Elements; D014158:Transcription, Genetic; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins
D005755:Gastrins; D006133:Growth Substances; D010455:Peptides; D011506:Proteins; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium