Title: Gain of function of mutant p53 by coaggregation with multiple tumor suppressors
Authors: Xu, Jie
Reumers, Joke
Couceiro, Jose R
De Smet, Frederik
Gallardo, Rodrigo
Rudyak, Stanislav
Cornelis, Ann
Rozenski, Jef
Zwolinska, Aleksandra
Marine, Chris
Lambrechts, Diether
Suh, Young-Ah
Rousseau, Frederic
Schymkowitz, Joost # ×
Issue Date: May-2011
Publisher: Nature Pub. Group
Series Title: Nature Chemical Biology vol:7 issue:5 pages:285-295
Abstract: Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.
ISSN: 1552-4450
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry (Rega Institute)
Vesalius Research Centre (-)
Switch Laboratory (VIB-KU Leuven Center for Brain & Disease Research)
Laboratory for Molecular Cancer Biology (VIB-KU Leuven Centre for Cancer Biology)
Department of Human Genetics - miscellaneous
Laboratory of Translational Genetics (VIB-KU Leuven Center for Cancer Biology)
× corresponding author
# (joint) last author

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