title: CFTR mRNA expression is regulated by an upstream open reading frame and RNA secondary structure in its 5' untranslated region.
abstract: Post-transcriptional regulation of gene expression through 5' untranslated region (5'UTR)-encoded cis-acting elements is an important mechanism for the control of protein expression levels. Through controlling specific aspects of translation initiation, expression can be tightly regulated while remaining responsive to cellular requirements. With respect to cystic fibrosis (CF), the overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking mutants, such as delta-F508, is of great biological and clinical interest. By understanding the post-transcriptional mechanisms that regulate CFTR expression, new procedures can be developed to enhance CFTR expression in homozygous delta-F508 CF patients. We have identified the key elements of a complex negative regulatory mechanism that is encoded within the human CFTR 5'UTR and show how these elements act in combination to restrict CFTR gene expression to a consistently low level in a transcript-specific manner. This study shows, for the first time, that endogenous human CFTR expression is post-transcriptionally regulated through a 5'UTR-mediated mechanism. We show that the very low levels of endogenous CFTR expression, compared with other low expression genes, are maintained through the co-operative inhibitory effects of an upstream open reading frame and a thermodynamically stable RNA secondary structure.
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Equine Genetics Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia samuel.lukowski@unige.ch.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Lukowski
authors.affiliation: School of Chemistry and Molecular Biosciences and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Rothnagel
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Equine Genetics Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Ann E O
authors.initials: AE
authors.lastname: Trezise
mesh_terms: D020121:5' Untranslated Regions; D000595:Amino Acid Sequence; D001482:Base Composition; D001483:Base Sequence; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D009154:Mutation; D009690:Nucleic Acid Conformation; D016366:Open Reading Frames; D010442:Peptide Chain Initiation, Translational; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*; D020038:RNA, Spliced Leader; D013816:Thermodynamics
chemical_list: D020121:5' Untranslated Regions; D012333:RNA, Messenger; D020038:RNA, Spliced Leader; D019005:Cystic Fibrosis Transmembrane Conductance Regulator