title: P53 mRNA controls p53 activity by managing Mdm2 functions.
abstract: The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis. However, it is not known how this dual function of Mdm2 on p53 synthesis and degradation is achieved. Here we show that the p53 mRNA region encoding the Mdm2-binding site interacts directly with the RING domain of Mdm2. This impairs the E3 ligase activity of Mdm2 and promotes p53 mRNA translation. We also show that introduction of cancer-derived single silent point-mutations in the p53 mRNA weakens its binding to Mdm2 and results in reduced p53 activity. These data are consistent with a mechanism by which changes in silent nucleotides can affect the function of the encoded protein, and indicate that Mdm2-mediated control of p53 synthesis and degradation has evolved in the p53 mRNA sequence and its encoded amino acids.
authors.affiliation: Inserm U716, Pharmacologie Expérimentale, Institut Génétique Moléculaire, Hôpital St Louis and Université Paris 7, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Candeias
authors.forename: Laurence
authors.initials: L
authors.lastname: Malbert-Colas
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Powell
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Daskalogianni
authors.forename: Magda M
authors.initials: MM
authors.lastname: Maslon
authors.forename: Nadia
authors.initials: N
authors.lastname: Naski
authors.forename: Karima
authors.initials: K
authors.lastname: Bourougaa
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.forename: Robin
authors.initials: R
authors.lastname: Fåhraeus
mesh_terms: D001483:Base Sequence; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases