Gain of function of mutant p53 by coaggregation with multiple tumor suppressors |
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Authors: | Xu Jie Reumers Joke Couceiro José R De Smet Frederik Gallardo Rodrigo Rudyak Stanislav Cornelis Ann Rozenski Jef Zwolinska Aleksandra Marine Jean-Christophe Lambrechts Diether Suh Young-Ah Rousseau Frederic Schymkowitz Joost |
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Affiliation: | Switch Laboratory, Flanders Institute for Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium. |
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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. |
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