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Transcriptional repression of TFF1 in gastric epithelial cells by CCAAT/enhancer binding protein-beta

Narendra V Sankpal1, Marty W Mayo, Steven M Powell

  • 1Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA.

Biochimica Et Biophysica Acta
|March 22, 2005
PubMed

Insights

The Trefoil Factor 1 (TFF1) gene is often downregulated in gastric cancers. Researchers identified a repressor region and the transcription factor C/EBPbeta, which binds to it, downregulating TFF1 expression in gastric cells.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Cancer Research

Background:

  • Trefoil Factor 1 (TFF1) is a gastrointestinal peptide crucial for gastric tissue integrity.
  • Loss of TFF1 expression is a hallmark of many human gastric cancers, impacting biological functions.
  • While gene mutations are rare, the molecular mechanisms causing TFF1 downregulation remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the repression of human TFF1 gene expression.
  • To identify specific regulatory regions and transcription factors involved in TFF1 gene silencing.

Main Methods:

  • Characterization of the 5'-flanking region of the human TFF1 gene.
  • Electrophoretic Mobility Shift Assay (EMSA) to identify transcription factor binding.
  • Site-directed mutagenesis to assess the role of identified binding sites.
  • Reporter gene assays to quantify promoter activity.

Main Results:

  • A repressor region (-241 to -84) within the TFF1 5'-flanking region was identified and found active in gastric cancer cells.
  • A consensus binding site for C/EBPbeta was identified, with EMSA confirming specific CEBPbeta binding.
  • Mutation of the C/EBPbeta binding site significantly increased TFF1 transactivation (50-145%).
  • Co-transfection with C/EBPbeta isoforms decreased TFF1 promoter activity, confirming its repressive role.

Conclusions:

  • The transcription factor C/EBPbeta plays a significant role in down-regulating TFF1 gene expression.
  • C/EBPbeta-mediated repression likely contributes to the loss of TFF1 expression observed in human and mouse gastric epithelial cells during transformation.

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