title: The alternative translated MDMX(p60) isoform regulates MDM2 activity.
abstract: Isoforms derived from alternative splicing, mRNA translation initiation or promoter usage extend the functional repertoire of the p53, p63 and p73 genes family and of their regulators MDM2 and MDMX. Here we show cap-independent translation of an N-terminal truncated isoform of hMDMX, hMDMX(p60), which is initiated at the 7th AUG codon downstream of the initiation site for full length hMDMX(FL) at position +384. hMDMX(p60) lacks the p53 binding motif but retains the RING domain and interacts with hMDM2 and hMDMX(FL). hMDMX(p60) shows higher affinity for hMDM2, as compared to hMDMX(FL). In vitro data reveal a positive cooperative interaction between hMDMX(p60) and hMDM2 and in cellulo data show that low levels of hMDMX(p60) promote degradation of hMDM2 whereas higher levels stabilize hMDM2 and prevent hMDM2-mediated degradation of hMDMX(FL). These results describe a novel alternatively translated hMDMX isoform that exhibits unique regulatory activity toward hMDM2 autoubiquitination. The data illustrate how the N-terminus of hMDMX regulates its C-terminal RING domain and the hMDM2 activity.
authors: a Cibles Thérapeutiques, Equipe Labellisée la Ligue Contre le Cancer, Institut National de la Santé et de la Recherche Médicale UMR1162; Institut de Génétique Moléculaire , Université Paris 7 ; Hôpital St. Louis; Paris , France.
authors: Anne-Sophie
authors: AS
authors: Tournillon
authors: Ignacio
authors: I
authors: López
authors: Laurence
authors: L
authors: Malbert-Colas
authors: Nadia
authors: N
authors: Naski
authors: Vanesa
authors: V
authors: Olivares-Illana
authors: Robin
authors: R
authors: Fåhraeus
mesh_terms: D017398:Alternative Splicing; D018797:Cell Cycle Proteins; D002460:Cell Line; D003062:Codon / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012315:RNA Caps / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D003062:Codon; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012315:RNA Caps; D012333:RNA, Messenger; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; MDMX; alternative translation; isoforms; protein stability