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PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage

Oncogene volume 28, pages 698–708 (2009)Cite this article

Abstract

The promyelocytic leukemia (PML) tumor suppressor protein, a central regulator of cell proliferation and apoptosis, is frequently fused to the retinoic acid receptor-α (RARα) in acute PML. Here we show the interaction of PML with another tumor suppressor protein, the serine/threonine kinase homeodomain-interacting protein kinase (HIPK2). In response to DNA damage, HIPK2 phosphorylates PML at serines 8 and 38. Although HIPK2-mediated phosphorylation of PML occurs early during the DNA damage response, the oncogenic PML-RARα fusion protein is phosphorylated with significantly delayed kinetics. DNA damage or HIPK2 expression leads to the stabilization of PML and PML-RARα proteins. The N-terminal phosphorylation sites contribute to the DNA damage-induced PML SUMOylation and are required for the ability of PML to cooperate with HIPK2 for the induction of cell death.

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Acknowledgements

We are grateful to Drs Giannino Del Sal (Trieste, Italy) and Myung K Kim (NIH, USA) for generously providing expression vectors. The study from our laboratory was supported by grants from the Deutsche Forschungsgemeinschaft projects SCHM 1417/4-1, SCHM 1417/5-1, SFB 547 and the ECCPS—Excellence Cluster Cardio-Pulmonary System. FMI is a part of Novartis Research Foundation and EG was supported by the Swiss Cancer League Grant OCS 01667-02-2005.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland

    E Gresko

  2. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    E Gresko, A Vichalkovski, D Hess & B A Hemmings

  3. Institute of Biochemistry, Justus-Liebig-University, Giessen, Germany

    S Ritterhoff, J Sevilla-Perez, A Roscic, K Fröbius & M L Schmitz

  4. Novartis Pharma AG WKL-125.7.04, Basel, Switzerland

    A Roscic

  5. Institute for Biomedical Engineering, University and ETH Z,

    I Kotevic

  6. ü,

    I Kotevic

  7. rich, Z, ü, rich, Switzerland

    I Kotevic

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  1. E Gresko
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Gresko, E., Ritterhoff, S., Sevilla-Perez, J. et al. PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage. Oncogene 28, 698–708 (2009). https://doi.org/10.1038/onc.2008.420

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  • DOI: https://doi.org/10.1038/onc.2008.420

Keywords

  • HIPK2
  • PML
  • phosphorylation
  • cell death

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