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Vol. 56, Issue 3, 526-536, September 1999

Activation of the Mouse TATA-less and Human TATA-Containing UDP-Glucuronosyltransferase 1A1 Promoters by Hepatocyte Nuclear Factor 11

Pascal Bernard, Hervé Goudonnet, Yves Artur, Béatrice Desvergne, and Walter Wahli

Institut de Biologie Animale, Bâtiment de Biologie, Université de Lausanne, Lausanne, Switzerland (P.B., B.D., W.W.); and Laboratoire de Biochimie Pharmacologique, Unité de Formation et de Recherche Pharmacie, Université de Bourgogne, Dijon, France (P.B., H.G., Y.A.)

UDP-glucuronosyltransferase (UGT) 1A1 (UGT1A1) catalyzes the glucuronidation of bilirubin in liver. Among all UGT isoforms identified to date, it is the only relevant bilirubin-glucuronidating enzyme in human. Because glucuronoconjugation is the major route of bilirubin elimination, any genetic alteration that affects bilirubin glucuronosyltransferase activity may result in a more or less severe hyperbilirubinemia. In this study, we report the cloning and characterization of the transcriptional regulation of the mouse UGT1A1 gene. Primary-structure analysis of the mouse Thymidine Adevice promoter revealed marked differences with its human homolog. First, the mouse promoter lacks the highly polymorphic thymidine/adenine repeat occurring in the human promoter, which has been associated with some forms of hyperbilirubinemia. Second, an L1 transposon element, which is absent in the human promoter, is found 480 bp upstream of the transcription start site in mouse. Using the electromobility shift and DNase I footprinting experiments, we have identified a hepatocyte nuclear factor 1-binding site in the mouse UGT1A1 promoter that confers responsiveness to both factors HNF1alpha and HNF1beta in HEK293 cells. Furthermore, we show that this element, which is conserved in the human promoter, also confers strong HNF1 responsiveness to the human UGT1A1 gene. Together, these results provide evidence for a major regulatory function of this liver-enriched transcription factor in UGT1A1 activity in both rodents and human.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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