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

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...

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Bibliographic Details
Authors: Lang, Valérie, Pallara, Chiara, Zabala, Amaia, Lobato-Gil, Sofia, Lopitz-Otsoa, Fernando, Farrás, Rosa, Hjerpe, Roland, Torres-Ramos, Mónica, Zabaleta, Lorea, Blattner, Christine, Hay, Ronald T., Barrio, Rosa, Carracedo, Arkaitz, Fernández-Recio, Juan, Rodríguez, Manuel S., Aillet, Fabienne
Format: article
Status:Versión aceptada para publicación
Publication Date:2014
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/378263
Online Access:http://hdl.handle.net/10261/378263
Access Level:Open access
Keyword:Oligomerization
Proteasome
Transcription
Ubiquitylation
p53
Description
Summary: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.

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