Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity

Valerie Lang, Chiara Pallara, Amaia Zabala, Sofia Lobato-Gil, Fernando Lopitz-Otsoa, Rosa Farrás, Roland Hjerpe, Monica Torres-Ramos, Lorea Zabaleta, Christine Blattner, Ronald T. Hay, Rosa Barrio, Arkaitz Carracedo, Juan Fernandez-Recio, Manuel S. Rodríguez (Lead / Corresponding author), Fabienne Aillet

    Research output: Contribution to journalArticlepeer-review

    12 Citations (Scopus)

    Abstract

    The tumor suppressor p53 regulates the expression of genes involved in cell cycle progression, senescence and apoptosis. Here, we investigated the effect of single point mutations in the oligomerization domain (OD) on tetramerization, transcription, ubiquitylation and stability of p53. As predicted by docking and molecular dynamics simulations, p53 OD mutants show functional defects on transcription, Mdm2-dependent ubiquitylation and 26S proteasome-mediated degradation. However, mutants unable to form tetramers are well degraded by the 20S proteasome. Unexpectedly, despite the lower structural stability compared to WT p53, p53 OD mutants form heterotetramers with WT p53 when expressed transiently or stably in cells wild type or null for p53. In consequence, p53 OD mutants interfere with the capacity of WT p53 tetramers to be properly ubiquitylated and result in changes of p53-dependent protein expression patterns, including the pro-apoptotic proteins Bax and PUMA under basal and adriamycin-induced conditions. Importantly, the patient derived p53 OD mutant L330R (OD1) showed the more severe changes in p53-dependent gene expression. Thus, in addition to the well-known effects on p53 stability, ubiquitylation defects promote changes in p53-dependent gene expression with implications on some of its functions.
    Original languageEnglish
    Pages (from-to)1026-1042
    Number of pages17
    JournalMolecular Oncology
    Volume8
    Issue number5
    DOIs
    Publication statusPublished - 2014

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