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 (FMO1â5), these enzymes exhibit distinct but broad and overlapping substrate specificity and are expressed in a...
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Veröffentlicht in: | Molecular pharmacology 2001-12, Vol.60 (6), p.1421-1430 |
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Sprache: | eng |
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Zusammenfassung: | 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 (FMO1â5), 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 â8 to â2, two overlapping HNF1α sites, position â132 to â105, and two HNF4α sites, position â467 to â454
and â195 to â182. Cotransfection studies with HNF1α and HNF4α 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 HNF4α 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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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.60.6.1421 |