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

Nature Chemical Biology volume 7, pages 285–295 (2011)Cite this article

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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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Figure 1: Structure of p53 protein and the effects of mutations on protein cellular localization.
Figure 2: Immunostain of p53 aggregates in tumor cell lines and tissues.
Figure 3: Mutant p53 induced coaggregation of wild-type p53 and caused dominant-negative activity.
Figure 4: Sequestration of p63 and p73 by mutant p53 aggregates.
Figure 5: Mutant p53 interacted and interfered with p73 through coaggregation.
Figure 6: Aggregation of mutant p53 is linked to lower rate of loss of heterogeneity and patient survival.
Figure 7: Schematic graph showing the proposed model for coaggregation of p53, p63 and p73.

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Acknowledgements

The VIB Switch Laboratory was supported by the Research Foundation Flanders and the Agency for Innovation by Science and Technology Flanders. J.X. and A.Z. were supported by Linking Sino-European Universities through Mobility and National Natural Science Foundation of China (81000861) and the Research Foundation Flanders, respectively. D.L. was supported by the Research Council Katholieke Universiteit Leuven, Center of Excellence (KUL PFV/10/016 SymBioSys) and the Stichting Tegen Kanker. We thank G. Peuteman, D. Smeets and T. Van Brussel for technical assistance. We thank G. Lozano for access to tumor tissues from transgenic mice and G. Melino for plasmids.

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Author notes

  1. Frederic Rousseau & Joost Schymkowitz

    Present address: Current address: Switch Laboratory, Flanders Institute for Biotechnology, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven, Belgium (F.R., J.S.).,

Authors and Affiliations

  1. Switch Laboratory, Flanders Institute for Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium

    Jie Xu, Joke Reumers, José R Couceiro, Frederik De Smet, Rodrigo Gallardo, Stanislav Rudyak, Frederic Rousseau & Joost Schymkowitz

  2. Department of Pathology, Regionaal ziekenhuis Heilig Hart, Tienen, Belgium

    Ann Cornelis

  3. Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium

    Jef Rozenski

  4. Department of Molecular and Developmental Genetics, Laboratory for Molecular Cancer Biology, Flanders Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium

    Aleksandra Zwolinska & Jean-Christophe Marine

  5. Vesalius Research Center, Flanders Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium

    Diether Lambrechts

  6. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas

    Young-Ah Suh

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Contributions

J.X. performed BN-PAGE, immunofluorescence, immunoprecipitation, qPCR and analyzed clinical data; J. Reumers analyzed stability of p53 mutants by FoldX; J.R.C. studied peptide aggregation and analyzed tumor tissues with J.X.; R.G. purified p53 and performed electron microscopy and FTIR; J. Rozenski performed ESI-MS study; A.C. provided clinical tissue samples; F.D.S., S.R., A.Z. and J.-C.M. did cellular experiments; D.L. sequenced TP53 in tumors; Y.-A.S. prepared tissue sections from mice; J.X., F.R., J.S. and F.D.S. wrote the manuscript; F.R. and J.S. formulated the project.

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Correspondence to Frederic Rousseau or Joost Schymkowitz.

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Xu, J., Reumers, J., Couceiro, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat Chem Biol 7, 285–295 (2011). https://doi.org/10.1038/nchembio.546

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