Transcriptional regulation of the human trefoil factor, TFF1, by gastrin.

Abstract

BACKGROUND & AIMS:

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.

• Authors: Zara E Khan, Timothy C Wang, Guanglin Cui, Alfred L Chi, Rod Dimaline
• Journal: Gastroenterology (Gastroenterology) Vol. 125 Issue 2 Pg. 510-21 (Aug 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12891554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Gastrins
• Growth Substances
• Peptides
• Proteins
• Receptor, Cholecystokinin B
• Receptors, Cholecystokinin
• TFF1 protein, human
• Trefoil Factor-1
• Tumor Suppressor Proteins
• Protein Kinase C
• Mitogen-Activated Protein Kinases
• Calcium

Topics

• Animals
• Calcium (physiology)
• Gastrins (physiology)
• Gene Expression Regulation
• Growth Substances (genetics)
• Humans
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinases (physiology)
• Peptides (genetics)
• Promoter Regions, Genetic
• Protein Kinase C (physiology)
• Proteins
• Receptor, Cholecystokinin B
• Receptors, Cholecystokinin (physiology)
• Response Elements
• Transcription, Genetic
• Trefoil Factor-1
• Tumor Suppressor Proteins