HIPK2 phosphorylates Δnp63α and promotes its degradation in response to DNA damage

C. Lazzari, A. Prodosmo, F. Siepi, C. Rinaldo, F. Galli, M. Gentileschi, A. Bartolazzi, A. Costanzo, A. Sacchi, L. Guerrini, S. Soddu

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4802-4813
Number of pages12
JournalOncogene
Volume30
Issue number48
DOIs
Publication statusPublished - Dec 1 2011

Fingerprint

Homeodomain Proteins
Protein Kinases
DNA Damage
Doxorubicin
Apoptosis
Pharmaceutical Preparations
Phosphorylation
Drug Therapy
Null Lymphocytes
Post Translational Protein Processing
RNA Interference
Cell Cycle Checkpoints
Ionizing Radiation
Cisplatin

Keywords

  • Chemotherapy
  • Degradation
  • DNp63
  • HIPK2
  • Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lazzari, C., Prodosmo, A., Siepi, F., Rinaldo, C., Galli, F., Gentileschi, M., ... Soddu, S. (2011). HIPK2 phosphorylates Δnp63α and promotes its degradation in response to DNA damage. Oncogene, 30(48), 4802-4813. https://doi.org/10.1038/onc.2011.182

HIPK2 phosphorylates Δnp63α and promotes its degradation in response to DNA damage. / Lazzari, C.; Prodosmo, A.; Siepi, F.; Rinaldo, C.; Galli, F.; Gentileschi, M.; Bartolazzi, A.; Costanzo, A.; Sacchi, A.; Guerrini, L.; Soddu, S.

In: Oncogene, Vol. 30, No. 48, 01.12.2011, p. 4802-4813.

Research output: Contribution to journalArticle

Lazzari, C, Prodosmo, A, Siepi, F, Rinaldo, C, Galli, F, Gentileschi, M, Bartolazzi, A, Costanzo, A, Sacchi, A, Guerrini, L & Soddu, S 2011, 'HIPK2 phosphorylates Δnp63α and promotes its degradation in response to DNA damage', Oncogene, vol. 30, no. 48, pp. 4802-4813. https://doi.org/10.1038/onc.2011.182
Lazzari C, Prodosmo A, Siepi F, Rinaldo C, Galli F, Gentileschi M et al. HIPK2 phosphorylates Δnp63α and promotes its degradation in response to DNA damage. Oncogene. 2011 Dec 1;30(48):4802-4813. https://doi.org/10.1038/onc.2011.182
Lazzari, C. ; Prodosmo, A. ; Siepi, F. ; Rinaldo, C. ; Galli, F. ; Gentileschi, M. ; Bartolazzi, A. ; Costanzo, A. ; Sacchi, A. ; Guerrini, L. ; Soddu, S. / HIPK2 phosphorylates Δnp63α and promotes its degradation in response to DNA damage. In: Oncogene. 2011 ; Vol. 30, No. 48. pp. 4802-4813.
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