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HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

Oncogene volume 30, pages 4802–4813 (2011)Cite this article

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Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-β treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called ‘p53-independent apoptosis and drug response’ in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of ΔNp63α, a prosurvival ΔN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of ΔNp63α. In DOX-treated cells, we show that HIPK2 depletion interferes with ΔNp63α degradation, and expression of a HIPK2-resistant ΔNp63α-Δ390 mutant induces chemoresistance. We identify T397 as the ΔNp63α residue phosphorylated by HIPK2, and show that the non-phosphorylatable ΔNp63α-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate ΔNp63α as a novel target of HIPK2 in response to genotoxic drugs.

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Abbreviations

CDDP:

cisplatin

Ctr:

control

DDR:

DNA damage response

DOX:

doxorubicin

eGST:

eukaryotic-Glutathione S Transferase

HIPK2:

homeodomain-interacting protein kinase 2

TCE:

total cell extract

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Acknowledgements

We are grateful to all people cited in the text for their kind gifts of cells and reagents and to Dr F Socciarelli for technical support. This work was supported by Ministero della Salute and ‘New Idea Award’ form the Scientific Direction of the Regina Elena Cancer Institute to SS. FS was a recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro.

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Authors and Affiliations

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

    C Lazzari, A Prodosmo, F Siepi, C Rinaldo, M Gentileschi, A Sacchi & S Soddu

  2. Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan, Italy

    F Galli & L Guerrini

  3. Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden

    A Bartolazzi

  4. Department of Pathology, Sant’Andrea University Hospital, Rome, Italy

    A Bartolazzi

  5. Department of Dermatology, University of ‘Tor Vergata’, Rome, Italy

    A Costanzo

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  1. C Lazzari
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Correspondence to S Soddu.

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Lazzari, C., Prodosmo, A., Siepi, F. et al. HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage. Oncogene 30, 4802–4813 (2011). https://doi.org/10.1038/onc.2011.182

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