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. 2011 May;7(5):285-95.
doi: 10.1038/nchembio.546. Epub 2011 Mar 27.

Gain of function of mutant p53 by coaggregation with multiple tumor suppressors

Jie Xu  1 , Joke Reumers, José R Couceiro, Frederik De Smet, Rodrigo Gallardo, Stanislav Rudyak, Ann Cornelis, Jef Rozenski, Aleksandra Zwolinska, Jean-Christophe Marine, Diether Lambrechts, Young-Ah Suh, Frederic Rousseau, Joost Schymkowitz
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V体育2025版 - Gain of function of mutant p53 by coaggregation with multiple tumor suppressors

Jie Xu et al. Nat Chem Biol. 2011 May.

"V体育平台登录" 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 VSports手机版. 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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