Gastrin regulates the TFF2 promoter through gastrin-responsive cis-acting elements and multiple signaling pathways

Area of Science:

• Gastroenterology
• Molecular Biology
• Cell Signaling

Background:

• Trefoil family factor 2 (TFF2) is crucial for gastrointestinal mucosal integrity and repair.
• Gastrin, a peptide hormone, stimulates gastric acid secretion and mucosal proliferation.
• The regulatory relationship between gastrin and TFF2 expression remains unclear.

Purpose of the Study:

• To investigate the regulatory effect of gastrin on TFF2 gene expression.
• To elucidate the molecular mechanisms underlying gastrin-mediated TFF2 regulation.

Main Methods:

• Quantitative RT-PCR and immunohistochemistry to assess TFF2 mRNA and protein levels.
• Reporter assays with TFF2 promoter constructs to evaluate promoter activity.
• Electrophoretic mobility shift assays to identify DNA-binding sites.
• Pharmacological inhibition of signaling pathways (PKC, MEK1, PI 3-kinase, EGFR).

Main Results:

• Gastrin significantly increased TFF2 mRNA and protein levels in a time- and dose-dependent manner.
• Gastrin elevated TFF2 promoter activity via specific cis-acting regions, including GC-rich enhancers.
• Gastrin-dependent TFF2 regulation involved protein kinase C (PKC), MEK1, and PI 3-kinase signaling pathways.
• The gastrin/CCK(B) receptor antagonist Y-F476 blocked gastrin-induced promoter activity.
• EGFR signaling was not involved in gastrin's regulation of TFF2.

Conclusions:

• Gastrin transcriptionally upregulates TFF2 expression through a GC-rich DNA-binding site.
• This regulation is mediated by a signaling cascade involving PKC, MEK1, and PI 3-kinase, independent of EGFR.
• Gastrin's regulation of TFF2 likely contributes to gastrointestinal mucosal maintenance and repair.