Regulation of flavin-containing monooxygenase 1 expression by ying yang 1 and hepatic nuclear factors 1 and 4.
The flavin-containing monooxygenases (FMOs) are important for the oxidation of a variety of environmental toxicants, natural products, and therapeutics. Consisting of six family members (FMO1-5), these enzymes exhibit distinct but broad and overlapping substrate specificity and are expressed in a highly tissue- and species-selective manner. Corresponding to previously identified regulatory domains, a YY1 binding site was identified at the major rabbit FMO1 promoter, position -8 to -2, two overlapping HNF1alpha sites, position -132 to -105, and two HNF4alpha sites, position -467 to -454 and -195 to -182. Cotransfection studies with HNF1alpha and HNF4alpha expression vectors demonstrated a major role for each of these factors in enhancing FMO1 promoter activity. In contrast, YY1 was shown by site-directed mutagenesis to be dispensable for basal promoter activity but suppressed the ability of the upstream domains to enhance transcription. Finally, comparisons between rabbit and human FMO1 demonstrated conservation of each of these regulatory elements. With the exception of the most distal HNF4alpha site, each of the orthologous human sequences also was able to compete with rabbit FMO1 cis-elements for specific protein binding. These data are consistent with these same elements being important for regulating human FMO1 developmental- and tissue-specific expression.
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Departments of Pediatrics and Pharmacology and Toxicology, Birth Defects Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-4801, USA.
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D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050981:Erythroid-Specific DNA-Binding Factors; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010105:Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011817:Rabbits; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)