title: The transcriptional activities and cellular localization of the human estrogen receptor alpha are affected by the synonymous Ala87 mutation.
abstract: Until recently, synonymous mutations (which do not change amino acids) have been much neglected. Some evidence suggests that this kind of mutations could affect mRNA secondary structure or stability, translation kinetics and protein structure. To explore deeper the role of synonymous mutations, we studied their consequence on the functional activity of the estrogen receptor alpha (ERα). The ERα is a ligand-inducible transcription factor that orchestrates pleiotropic cellular effects, at both genomic and non-genomic levels in response to estrogens. In this work we analyzed in transient transfection experiments, the activity of ERα carrying the synonymous mutation Ala87, a polymorphism involving about 5-10% of the population. In comparison to the wild type receptor, our results show that ERαA87 mutation reduces the transactivation efficiency of ERα on an ERE reporter gene while its expression level remains similar. This mutation enhances 4-OHT-induced transactivation of ERα on an AP1 reporter gene. Finally, the mutation affects the subcellular localization of ERα in a cell type specific manner. It enhances the cytoplasmic location of ERα without significant changes in non-genomic effects of E2. The functional alteration of the ERαA87 determined in this work highlights the relevance of synonymous mutations for biomedical and pharmacological points of view.
authors.affiliation: Biochemistry-Molecular Biology, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay; Bioinformatics Unit, Institut Pasteur Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay. Electronic address: tamfernandez@gmail.com.
authors.forename: Tamara
authors.initials: T
authors.lastname: Fernández-Calero
authors.affiliation: Cell Biology Unit, Institut Pasteur Montevideo, Montevideo, Uruguay.
authors.forename: Soledad
authors.initials: S
authors.lastname: Astrada
authors.affiliation: Cell Biology Unit, Institut Pasteur Montevideo, Montevideo, Uruguay.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alberti
authors.affiliation: Biochemistry-Molecular Biology, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Sofía
authors.initials: S
authors.lastname: Horjales
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1048, Institute of Metabolic and Cardiovascular Diseases, University of Toulouse 3, Toulouse, France.
authors.forename: Jean Francois
authors.initials: JF
authors.lastname: Arnal
authors.affiliation: Department of Oncology and CREATE Health Strategic Centre for Clinical Cancer Research, Lund University, BMC, 221 84 Lund, Sweden.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rovira
authors.affiliation: Cell Biology Unit, Institut Pasteur Montevideo, Montevideo, Uruguay.
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollati-Fogolín
authors.affiliation: University of Rennes 1, Institut de Recherche en Santé, Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.affiliation: Biochemistry-Molecular Biology, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Mónica
authors.initials: M
authors.lastname: Marin
mesh_terms: D015153:Blotting, Western; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; D018808:Transcription Factor AP-1
keywords: Ala87 polymorphism; Estrogen; Estrogen receptor alpha; Synonymous mutations