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Vol. 57, Issue 5, 940-947, May 2000

Octamer Transcription Factor-1 Enhances Hepatic Nuclear Factor-1alpha -Mediated Activation of the Human UDP Glucuronosyltransferase 2B7 Promoter1

Yuji Ishii,2 Antony J. Hansen, and Peter I. Mackenzie

Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park, South Australia, Australia

The human UDP glucuronosyltransferase, UGT2B7, is expressed in the liver and gastrointestinal tract, where it catalyzes the glucuronidation of steroids and bile acids. In this study, the UGT2B7 gene was isolated and its proximal promoter was analyzed. The UGT2B7 gene consists of 6 exons and extends over 16 kilobases (kb). It does not contain a canonical TATA box but has a region (-2 to -40) adjacent to the transcription start site that binds nuclear proteins. This region contains a consensus hepatic nuclear factor-1alpha (HNF1alpha )-binding site and an overlapping AT-rich segment. Varying lengths of the UGT2B7 gene promoter, with and without these sites, were fused to the firefly luciferase reporter gene and transfected into HepG2 cells. UGT2B7 promoter activity with the HNF1/AT-rich element was stimulated by cotransfection with HNF1alpha . Additional activation was observed when HNF1alpha and octamer transcription factor-1 (Oct-1) were cotransfected simultaneously. However, Oct-1 alone did not stimulate promoter activity and did not bind to the promoter in the absence of HNF1alpha . Deletion of the HNF1/AT-rich region, or mutations in this region, abolished UGT2B7 gene promoter activity and prevented HNF1alpha -mediated increases in promoter activity. The presence of HNF1alpha and octamer transcription factor-1 (Oct-1) in the protein complex that bound to the HNF1/AT-rich region was demonstrated by gel shift analyses with antibodies specific to HNF1alpha and Oct-1 protein. These results strongly suggest that the liver-enriched factor HNF1alpha binds to, and activates, the UGT2B7 gene promoter and that the ubiquitous transcription factor, Oct-1, enhances this activation by directly interacting with HNF1alpha . This interaction between HNF1alpha and Oct-1 may fine-tune UGT2B7 expression.

1 This work was supported by the National Health and Medical Research Council of Australia and grants from the Flinders Medical Centre and Anti-Cancer Foundations of South Australia. Part of this work was presented at the IXth International Workshop on Glucuronidation and the UDP Glucuronosyltransferases (Brisbane, Australia, Oct 21-23, 1998). P.I.M. is a National Health and Medical Council Principal Research Fellow. Y.I. is a recipient of an Overseas Fellowship from the Japan Research Foundation for Clinical Pharmacology and the Bilateral Scientist Exchange Program of the Japan Society for the Promotion of Science with the Australian Academy of Science.

2 Present address: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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