Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-γ

Seema Saksena, Amika Singla, Sonia Goyal, Shivani Katyal, Nikhil Bansal, Ravinder K. Gill, Waddah A. Alrefai, Krishnamurthy Ramaswamy, Pradeep K. Dudeja

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Two members of the SLC26 gene family, SLC26A3 or DRA (downregulated in adenoma) and SLC26A6 (putative anion transporter 1, PAT1), are known to play a major role in apical Cl-/OH- (HCO3-) exchange process in the human intestine. We have previously shown the inhibitory effects of IFN-γ (30 ng/ml, 24 h) on both SLC26A3 and A6 expression and promoter activity. We also demonstrated that the effects of IFN-γ on SLC26A6 gene expression were mediated via IRF-1 transcription factor. However, the molecular mechanisms underlying the transcriptional modulation of SLC26A3 gene expression by IFN-γ in the intestine are not known. The present studies were, therefore, designed to elucidate the signaling mechanisms and transcription factor(s) involved in mediating the inhibitory effects of IFN-γ on DRA promoter (p--1183/+114) activity. Deletion analysis indicated that the IFN-γ response element is located within the -1183 to -790 region, and sequence analysis of this region revealed the presence of potential γ-activated site (GAS), a binding site (-933/-925 bp) for signal transducer and activator of transcription factor 1 (STAT1). Mutations in the potential GAS element abrogated the inhibitory effects of IFN-γ. These studies provide evidence for the involvement of STAT1 in the inhibition of SLC26A3 gene expression by IFN-γ in the human intestine.

Original languageEnglish (US)
Pages (from-to)G159-G166
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume298
Issue number2
DOIs
StatePublished - Feb 2010

Keywords

  • Chloride absorption
  • DRA (downregulated in adenoma) promoter
  • JAK (Janus kinases)
  • STAT1 (signal transducer and activator of transcription 1)

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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