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  • Title: Structural and functional characterization of liver cell-specific activity of the human sodium/taurocholate cotransporter.
    Author: Shiao T, Iwahashi M, Fortune J, Quattrochi L, Bowman S, Wick M, Qadri I, Simon FR.
    Journal: Genomics; 2000 Oct 15; 69(2):203-13. PubMed ID: 11031103.
    Abstract:
    Bile salts are rapidly removed from the circulation by the liver-specific sodium/taurocholate cotransporter (SLC10A1). To understand factors controlling its liver-specific expression, we isolated human SLC10A1 from a YAC chromosomal clone. SLC10A1 spans approximately 23 kb distributed over five exons. The major transcription start site is at 299 bp, and a minor start site is at 395 bp from the translational start site. A 1.2-kb portion of the 5' flanking region was sequenced and shown to contain a number of liver-enriched elements, but no TATA box. Using secreted alkaline phosphatase reporter constructs liver-specific expression was examined. Transient transfection demonstrated that SLC10A1 promoter expression was selectively expressed eightfold in FAO and rat hepatocytes, while deletion mutants demonstrated liver-specific expression in a region extending from -5 to +198 bp, which contained putative sites for C/EBP and HNF3. Mutations of the C/EBP site resulted in loss of 77% of transcriptional activity. Cotransfection of C/EBP, but not other putative liver-enriched binding factors, increased SLC10A1 promoter activity. Electrophoretic mobility shift assays demonstrated specific protein-DNA interactions that involved C/EBPalpha and beta. These studies demonstrate that the TATA-less human SLC10A1 promoter exhibits liver-specific activity and its regulatory elements contain binding sites for C/EBP, which contributes specifically to its transcriptional regulation.
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