P53 mRNA controls p53 activity by managing Mdm2 functions.
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.
Candeias
Marco M
MM
Inserm U716, Pharmacologie Expérimentale, Institut Génétique Moléculaire, Hôpital St Louis and Université Paris 7, 27 rue Juliette Dodu, 75010 Paris, France.
Malbert-Colas
Laurence
L
Powell
Darren J
DJ
Daskalogianni
Chrysoula
C
Maslon
Magda M
MM
Naski
Nadia
N
Bourougaa
Karima
K
Calvo
Fabien
F
Fåhraeus
Robin
R
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
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases