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HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function

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Abstract

The p53 oncosuppressor protein is subject to negative regulation by MDM2, which efficiently inhibits its activity through an autoregulatory loop. In response to stress, however, p53 undergoes post-translational modifications that allow the protein to escape MDM2 control, accumulate, and become active. Recent studies have shown that, following DNA damage, the HIPK2 serine/threonine kinase binds and phosphorylates p53, inducing p53 transcriptional activity and apoptotic function. Here, we investigated the role of HIPK2 in the activation of p53 in the presence of MDM2. We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition, and that restoration of this p53 function induces apoptosis. Recovery of p53-dependent apoptosis is achieved by preventing p53 nuclear export and ubiquitination mediated by MDM2 in vitro and in vivo following genotoxic stress. These results shed new light on the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis.

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Acknowledgements

This work was supported by grants from Associazione Italiana Ricerca sul Cancro (AIRC), Ministero Sanità, FIRB, MIUR-CNR, and MIUR Fondi Ateneo. We gratefully acknowledge constructive criticisms and helpful discussion by Dr F Moretti, Dr S Bacchetti, and Dr A Porrello.

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Authors and Affiliations

  1. Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome, 00158, Italy

    Valeria Di Stefano, Giovanni Blandino, Ada Sacchi, Silvia Soddu & Gabriella D'Orazi

  2. Department of Oncology and Neurosciences, University ‘G D'Annunzio’, Chieti, 66013, Italy

    Gabriella D'Orazi

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  1. Valeria Di Stefano
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  2. Giovanni Blandino
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  3. Ada Sacchi
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  4. Silvia Soddu
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  5. Gabriella D'Orazi
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Correspondence to Gabriella D'Orazi.

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Stefano, V., Blandino, G., Sacchi, A. et al. HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Oncogene 23, 5185–5192 (2004). https://doi.org/10.1038/sj.onc.1207656

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