title: Programmed translational readthrough generates antiangiogenic VEGF-Ax.
abstract: Translational readthrough, observed primarily in less complex organisms from viruses to Drosophila, expands the proteome by translating select transcripts beyond the canonical stop codon. Here, we show that vascular endothelial growth factor A (VEGFA) mRNA in mammalian endothelial cells undergoes programmed translational readthrough (PTR) generating VEGF-Ax, an isoform containing a unique 22-amino-acid C terminus extension. A cis-acting element in the VEGFA 3' UTR serves a dual function, not only encoding the appended peptide but also directing the PTR by decoding the UGA stop codon as serine. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 binds this element and promotes readthrough. Remarkably, VEGF-Ax exhibits antiangiogenic activity in contrast to the proangiogenic activity of VEGF-A. Pathophysiological significance of VEGF-Ax is indicated by robust expression in multiple human tissues but depletion in colon adenocarcinoma. Furthermore, genome-wide analysis revealed AGO1 and MTCH2 as authentic readthrough targets. Overall, our studies reveal a novel protein-regulated PTR event in a vertebrate system.
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Sandeepa M
authors.initials: SM
authors.lastname: Eswarappa
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Alka A
authors.initials: AA
authors.lastname: Potdar
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Kommireddy
authors.initials: K
authors.lastname: Vasu
authors.affiliation: Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindner
authors.affiliation: Mass Spectrometry Laboratory for Protein Sequencing, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Biomedical Engineering, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Graham
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: DiCorleto
authors.affiliation: Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: foxp@ccf.org.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
mesh_terms: D020413:3' Untranslated Regions; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D018388:Codon, Terminator; D042783:Endothelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics; D016415:Sequence Alignment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D018388:Codon, Terminator; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D020033:Protein Isoforms; C000613307:VEGF-Ax protein, human; D042461:Vascular Endothelial Growth Factor A