title: Retinoids increase alpha-1 acid glycoprotein expression at the transcriptional level through two distinct DR1 retinoic acid responsive elements.
abstract: In the present study, we analyzed the influence of retinoic acids on the expression of alpha-1 acid glycoprotein (AGP). We show that in rat primary hepatocytes, 9-cis retinoic acid and all-trans retinoic acid increase AGP gene expression at the transcriptional level. Transient transfections of rat primary hepatocytes with a reporter construct driven by the rat AGP gene promoter indicated that retinoids regulate AGP gene expression via the -763/-138 region of the AGP promoter. Furthermore, cotransfection experiments with retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha (RXRalpha) expression vectors in NIH3T3 cells demonstrated that both RXRalpha/RXRalpha homodimer and RXRalpha/RARalpha heterodimer are competent for ligand-induced transactivation of the AGP promoter. Unilateral deletion and site-directed mutagenesis identified two retinoic-acid responsive elements (RARE), RARE-I and RARE-II, which interestingly correspond to a direct repeat of two TGACCT-related hexanucleotides separated by a single bp only (DR1-type response element). Cotransfection assays showed that RXRalpha and RARalpha activate AGP gene transcription through these two elements either as a homodimer (RXRalpha/RXRalpha) or as a heterodimer (RXRalpha/RARalpha). The RXRalpha/RXRalpha homodimer acts most efficiently through the RARE-I response element to promote AGP transactivation, whereas the RXRalpha/RARalpha heterodimer mediates transactivation better via the RARE-II responsive element.
authors.affiliation: Laboratoire de Biochimie et de Biologie Cellulaire, EAD 1595, Tour D4 1(er) étage, Faculté de Pharmacie, Université Paris XI, 5, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Mouthiers
authors.forename: Najet
authors.initials: N
authors.lastname: Mejdoubi
authors.forename: Anita
authors.initials: A
authors.lastname: Baillet
authors.forename: Pires-Alves
authors.initials: PA
authors.lastname: Amélie
authors.forename: Dominique
authors.initials: D
authors.lastname: Porquet
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D019281:Dimerization; D017353:Gene Deletion; D017930:Genes, Reporter; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009961:Orosomucoid / Q000096:biosynthesis*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D008024:Ligands; D009961:Orosomucoid; C000607072:Rara protein, mouse; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; D008156:Luciferases