Identification and characterization of functional hepatocyte nuclear factor 1-binding sites in UDP-glucuronosyltransferase genes.
The hepatocyte nuclear factor 1 (HNF1) transcription factor family is composed of two closely related homeodomain proteins with similar but distinct expression profiles. Homodimers and heterodimers of these transcription factors, HNF1alpha and HNF1beta, increase transcription from target genes through direct physical interaction with one or more elements of sufficient similarity to a 13 nucleotide-inverted dyad consensus-binding sequence. Potential HNF1-binding sites have been found in the proximal upstream regulatory regions of most known human UDP-glucuronosyltransferase (UGT) genes. As the liver and gastrointestinal tract are both important sites of glucuronidation and express significant levels of one or both HNF1 proteins, it is thought that these homeoproteins may play a role in transcriptional regulation of UGTs. This chapter explores the current evidence that HNF1 transcription factors are explicitly involved in the transcription of mammalian UGT genes. Most data supporting this hypothesis come from in vitro reporter assays, site-directed mutagenesis, and electrophoretic mobility-shift assays, for which methods are detailed. However, as in vitro functionality of transcription factors does not necessarily imply significance in vivo, some of the limitations of these techniques are also examined. In addition, available in vivo data are discussed, with particular attention given to contributions made by HNF1alpha knockout mouse models and microarray studies of human tissue. Finally, possible scenarios in which HNF1-mediated regulation of UGT expression may be clinically relevant are suggested.
Gardner-Stephen
Dione A
DA
Department of Clinical Oncology, Flinders University School of Medicine, Flinders-Medical Center, Adelaide, Australia.
Gregory
Philip A
PA
Mackenzie
Peter I
PI
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology; D016415:Sequence Alignment; D014158:Transcription, Genetic
D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D014453:Glucuronosyltransferase