TY - JOUR
T1 - Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-γ
AU - Saksena, Seema
AU - Singla, Amika
AU - Goyal, Sonia
AU - Katyal, Shivani
AU - Bansal, Nikhil
AU - Gill, Ravinder K.
AU - Alrefai, Waddah A.
AU - Ramaswamy, Krishnamurthy
AU - Dudeja, Pradeep K.
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Chloride absorption
KW - DRA (downregulated in adenoma) promoter
KW - JAK (Janus kinases)
KW - STAT1 (signal transducer and activator of transcription 1)
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U2 - 10.1152/ajpgi.00374.2009
DO - 10.1152/ajpgi.00374.2009
M3 - Article
C2 - 19940027
AN - SCOPUS:76749167144
SN - 0193-1857
VL - 298
SP - G159-G166
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 2
ER -