Feedback inhibition of the retinaldehyde dehydrogenase gene ALDH1 by retinoic acid through retinoic acid receptor alpha and CCAAT/enhancer-binding protein beta.
Aldehyde dehydrogenase 1 (ALDH1) plays a major role in the biosynthesis of retinoic acid (RA), a hormone required for several essential life processes. Recent evidence, using the aryl hydrocarbon receptor-null mouse, suggests that elevated hepatic RA down-regulates ALDH1 in a unique feedback pathway to control RA biosynthesis. To determine the mechanism of suppression of the ALDH1 gene by RA, transactivation studies were carried out in Hepa-1 mouse hepatoma cells. RA decreased expression of an ALDH1-CAT construct containing -2536 base pairs of DNA upstream of the transcription start site. Retinoic acid receptor alpha (RARalpha) transactivates the ALDH1 gene promoter through a complex with an RA response-like element (RARE) located at -91/-75 bp, which bound to the RARalpha/retinoid X receptor beta heterodimer. CCAAT/enhancer-binding protein (C/EBPbeta) also transactivates the ALDH1 gene promoter through a CCAAT box located 3' and directly adjacent to the RARE, and the ALDH1 gene is down-regulated in C/EBPbeta-null mouse liver. Exposure of Hepa-1 cells to RA results in a decrease in C/EBPbeta mRNA levels; however, there was no difference in mRNA and protein levels between wild-type and AHR-null mouse liver. These data support a model in which the RARalpha and C/EBPbeta activate the ALDH1 gene promoter through the RARE and C/EBP response elements, and in Hepa-1 cells, high levels of RA inhibit this activation by decreasing cellular levels of C/EBPbeta.
Elizondo
G
G
Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Corchero
J
J
Sterneck
E
E
Gonzalez
F J
FJ
D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D015152:Blotting, Northern; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020218:Response Elements; D050697:Retinal Dehydrogenase; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D022782:CCAAT-Enhancer-Binding Protein-beta; D007527:Isoenzymes; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D015500:Chloramphenicol O-Acetyltransferase