Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-{gamma}.
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(-) (HCO(3)(-)) exchange process in the human intestine. We have previously shown the inhibitory effects of IFN-gamma (30 ng/ml, 24 h) on both SLC26A3 and A6 expression and promoter activity. We also demonstrated that the effects of IFN-gamma 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-gamma 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-gamma on DRA promoter (p--1183/+114) activity. Deletion analysis indicated that the IFN-gamma response element is located within the -1183 to -790 region, and sequence analysis of this region revealed the presence of potential gamma-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-gamma. These studies provide evidence for the involvement of STAT1 in the inhibition of SLC26A3 gene expression by IFN-gamma in the human intestine.
Saksena
Seema
S
Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. saksena@uic.edu
Singla
Amika
A
Goyal
Sonia
S
Katyal
Shivani
S
Bansal
Nikhil
N
Gill
Ravinder K
RK
Alrefai
Waddah A
WA
Ramaswamy
Krishnamurthy
K
Dudeja
Pradeep K
PK
D000236:Adenoma / Q000235:genetics / Q000503:physiopathology*; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism; D018938:Caco-2 Cells; D027963:Chloride-Bicarbonate Antiporters; D003092:Colitis / Q000235:genetics / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000503:physiopathology*; D003967:Diarrhea / Q000235:genetics / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D007408:Intestinal Absorption / Q000502:physiology; D007422:Intestines / Q000166:cytology / Q000502:physiology*; D053612:Janus Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012965:Sodium Chloride / Q000378:metabolism; D000076988:Sulfate Transporters; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; C081011:SLC26A3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000076988:Sulfate Transporters; D012965:Sodium Chloride; D007371:Interferon-gamma; D053612:Janus Kinases