title: PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after ischemic stress.
abstract: Angiogenesis is induced by various conditions, including hypoxia. Although cap-dependent translation is globally inhibited during ischemia, the mRNAs encoding two important proangiogenic growth factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2), are translated at early time points in ischemic muscle. The translation of these mRNAs can occur through internal ribosome entry sites (IRESs), rather than through cap-dependent translation. Hypoxic conditions also induce the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, leading us to assess the interplay between hypoxia, ER stress, and IRES-mediated translation of FGF-2 and VEGF We found that unlike cap-dependent translation, translation through FGF-2 and VEGF IRESs was efficient in cells and transgenic mice subjected to ER stress-inducing stimuli. We identified PERK, a kinase that is activated by ER stress, as the driver of VEGF and FGF-2 IRES-mediated translation in cells and in mice expressing IRES-driven reporter genes and exposed to hypoxic stress. These results demonstrate the role of IRES-dependent translation in the induction of the proangiogenic factors VEGF and FGF-2 in response to acute hypoxic stress. Furthermore, the PERK pathway could be a viable pharmacological target to improve physiological responses to ischemic situations.
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Philippe
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Quelen
authors.affiliation: INSERM US006, CREFRE (Centre régional d'exploration fonctionnelle et de ressources expérimentales), F-31000 Toulouse, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Desquesnes
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France. Vectorology Platform, CRCT Technological Pole, F-31037 Toulouse, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Van Den Berghe
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France. Vectorology Platform, CRCT Technological Pole, F-31037 Toulouse, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Ségura
authors.affiliation: Clinical Trial Office, Department of Statistics, IUCT (Institut Universitaire du Cancer de Toulouse)-Oncopole, F-31100 Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France. Laboratoire d'Excellence Toulouse Cancer (TOUCAN), F-31037 Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Prats
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France. Laboratoire d'Excellence Toulouse Cancer (TOUCAN), F-31037 Toulouse, France. Department of Pathology, IUCT-Oncopole, F-31100 Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Brousset
authors.affiliation: INSERM, UMR 1037, CRCT (Cancer Research Center of Toulouse), F-31037 Toulouse, France. Université Toulouse III Paul Sabatier, F-31000 Toulouse, France. christian.touriol@inserm.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Touriol
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000067556:Internal Ribosome Entry Sites; D007511:Ischemia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D016222:Fibroblast Growth Factor 2; D036341:Intercellular Signaling Peptides and Proteins; D000067556:Internal Ribosome Entry Sites; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D019892:eIF-2 Kinase; C460640:EIF2AK3 protein, human