title: Proteomic analysis of phosphorylated nuclear proteins underscores novel roles for rapid actions of retinoic acid in the regulation of mRNA splicing and translation.
abstract: Retinoic acid (RA) signaling is mediated by the retinoic acid receptor (RAR), belonging to the nuclear hormone receptor superfamily. In addition to its classical transcriptional actions, RAR also mediates rapid transcription-independent (nongenomic) actions, consisting in the activation of signal transduction pathways, as the phosphatidyl-inositol-3-kinase or the ERK MAPK-signaling pathways. RA-induced rapid transcription-independent actions play a role in different physiological contexts. As an effort toward understanding the functions of those rapid actions on signaling elicited by RA, we have identified nuclear proteins the phosphorylation state of which is rapidly modified by RA treatment in neuroblastoma cells, using a proteomic approach. Our results show that RA treatment led to changes in the phosphorylation patterns in two families of proteins: 1) those related to chromatin dynamics in relation to transcriptional activation, and 2) those related to mRNA processing and, in particular, mRNA splicing. We show that treatment of neuroblastoma cells with RA leads to alteration of the regulation of pre-mRNA splicing and mRNA translation. Thus, our results underscore novel functions for the rapid signaling elicited by RAR in the regulation of mRNA processing. We conclude that RA activation of signaling pathways can indeed regulate mRNA processing as part of a cellular response orchestrated by the nuclear receptor RAR.
authors.affiliation: Biology of Hormone Action Unit, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, [corrected] E-46010 Valencia, Spain.
authors.forename: Emilio J
authors.initials: EJ
authors.lastname: Laserna
authors.forename: M Luz
authors.initials: ML
authors.lastname: Valero
authors.forename: Libia
authors.initials: L
authors.lastname: Sanz
authors.forename: Manuel M Sánchez
authors.initials: MM
authors.lastname: del Pino
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Calvete
authors.forename: Domingo
authors.initials: D
authors.lastname: Barettino
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000737:chemistry; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D040901:Proteomics / Q000379:methods*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases