The human medium chain Acyl-CoA dehydrogenase gene promoter consists of a complex arrangement of nuclear receptor response elements and Sp1 binding sites.
Expression of the gene encoding the mitochondrial fatty acid. beta-oxidation enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), is regulated among tissues during development and in response to alterations in substrate availability. To identify and characterize cis-acting MCAD gene promoter regulatory elements and corresponding transcription factors, DNA-protein binding studies and mammalian cell transfection analyses were performed with hjman MCAD gene promoter fragments. DNA:protein binding studies with nuclear protein extracts prepared from hepatoma G2 cells, 3T3 fibroblasts, or Y-1 adrenal tumor cells identified three sequences (nuclear receptor response element 1 or NRRE-1, NRRE-2, and NRRE-3) that bind orphan members of the steroid/thyroid nuclear receptor superfamily including chicken ovalbumin upstream promoter transcription factor and steroidogenic factor 1. Sp1 binding sites (A-C) were identified in close proximity to each of the NRREs. NRRE-3 conferred cell line-specific transcriptional repression by interacting with chicken ovalbumin upstream promoter transcription factor or activation via steroidogenic factor 1. In contrast, the Sp1 binding site A behaved as a transcriptional activator in all cell lines examined. We propose that multiple nuclear receptor transcription factors interact with MCAD gene promoter elements to differentially regulate transcription among a variety of cell types.
Leone
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TC
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cresci
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Carter
M E
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Zhang
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Lala
D S
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Strauss
A W
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Kelly
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DP
D016475:3T3 Cells; D042964:Acyl-CoA Dehydrogenase; D044944:Acyl-CoA Dehydrogenases / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002645:Chickens; D004274:DNA, Recombinant / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D054339:Steroidogenic Factor 1; D014158:Transcription, Genetic; D014162:Transfection
D004274:DNA, Recombinant; C515057:NR5A1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D016329:Sp1 Transcription Factor; D054339:Steroidogenic Factor 1; C515058:steroidogenic factor 1, mouse; D010047:Ovalbumin; D044944:Acyl-CoA Dehydrogenases; D042964:Acyl-CoA Dehydrogenase