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PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

Oncogene volume 29, pages 6442–6451 (2010)Cite this article

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Abstract

The low molecular weight compound PRIMA-1 and the structural analog PRIMA-1MET, also named APR-246, reactivate mutant p53 through covalent binding to the core domain and induce apoptosis in tumor cells. Here, we asked whether PRIMA-1MET/APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. We found that PRIMA-1MET/APR-246 can restore the pro-apoptotic function to mutant TAp63γ and TAp73β in tumor cells but has less effect on TAp73α. Moreover, PRIMA-1MET/APR-246-stimulated DNA binding of mutant TAp63γ and induced expression of the p53/p63/p73 downstream targets p21 and Noxa. The reactivation of mutant p53, p63 and p73 by PRIMA-1MET/APR-246 indicates a common mechanism, presumably involving homologous structural elements in the p53 family proteins. Our findings may open avenues for therapeutic intervention in human developmental disorders with mutations in p63.

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Acknowledgements

We thank Dr Jiandong Chen, H Lee Moffitt Cancer Center, for the ts mutant p63/p73-expressing cells, and Dr Bert Vogelstein, Johns Hopkins Oncology Center, for the HCT116 cells. This work was supported by EU 6th Framework Program within the EPISTEM Integrated Project (LSHB-CT-2005-019067).

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Author notes

  1. N Rökaeus and J Shen: These authors contributed equally to this work and appear in alphabetical order.

Authors and Affiliations

  1. Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden

    N Rökaeus, J Shen, I Eckhardt, V J N Bykov & K G Wiman

  2. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden

    M T Wilhelm

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  1. N Rökaeus
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Correspondence to K G Wiman.

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Competing interests

KGW and VJNB are cofounders and shareholders of Aprea AB, a company that develops p53-based cancer therapy, and KGW is a member of its board.

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Supplementary Information accompanies the paper on the Oncogene website

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Rökaeus, N., Shen, J., Eckhardt, I. et al. PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73. Oncogene 29, 6442–6451 (2010). https://doi.org/10.1038/onc.2010.382

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