title: HDMX folds the nascent p53 mRNA following activation by the ATM kinase.
abstract: Regulated protein synthesis via changes in mRNA structures forms an important part of how prokaryotic cells adapt protein expression in response to changes in the environment. Little is known regarding how this concept has adapted to regulate mRNA translation via signaling pathways in mammalian cells. Here, we show that following phosphorylation by the ataxia telangiectasia mutated (ATM) kinase at serine 403, the C-terminal RING domain of HDMX binds the nascent p53 mRNA to promote a conformation that supports the p53 mRNA-HDM2 interaction and the induction of p53 synthesis. HDMX and its homolog HDM2 bind the same p53 internal ribosome entry sequences (IRES) structure but with different specificity and function. The results show how HDMX and HDM2 act as nonredundant IRES trans-acting factors (ITAFs) to bring a positive synergistic effect on p53 expression during genotoxic stress by first altering the structure of the newly synthesized p53 mRNA followed by stimulation of translation.
authors.affiliation: Cibles Thérapeutiques, Equipe Labellisée Ligue Contre le Cancer, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Malbert-Colas
authors.affiliation: Cibles Thérapeutiques, Equipe Labellisée Ligue Contre le Cancer, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, 75010 Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
authors.forename: Anand
authors.initials: A
authors.lastname: Ponnuswamy
authors.affiliation: Instituto de Fisica, Universidad Autonoma de San Luis Potosí, 78290 San Luis Potosí, Mexico.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Olivares-Illana
authors.affiliation: Cibles Thérapeutiques, Equipe Labellisée Ligue Contre le Cancer, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Tournillon
authors.affiliation: Cibles Thérapeutiques, Equipe Labellisée Ligue Contre le Cancer, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Naski
authors.affiliation: Cibles Thérapeutiques, Equipe Labellisée Ligue Contre le Cancer, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, 75010 Paris, France. Electronic address: robin.fahraeus@inserm.fr.
authors.forename: Robin
authors.initials: R
authors.lastname: Fåhraeus
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001483:Base Sequence; D018797:Cell Cycle Proteins; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D055029:Inverted Repeat Sequences; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D059370:RNA Folding; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins