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Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2

Nature Cell Biology volume 4, pages 1–10 (2002)Cite this article

Abstract

Transcriptional activity of p53, a central regulatory switch in a network controlling cell proliferation and apoptosis, is modulated by protein stability and post-translational modifications including phosphorylation and acetylation. Here we demonstrate that the human serine/threonine kinase homeodomain-interacting protein kinase-2 (HIPK2) colocalizes and interacts with p53 and CREB-binding protein (CBP) within promyelocytic leukaemia (PML) nuclear bodies. HIPK2 is activated by ultraviolet (UV) radiation and selectively phosphorylates p53 at Ser 46, thus facilitating the CBP-mediated acetylation of p53 at Lys 382, and promoting p53-dependent gene expression. Accordingly, the kinase function of HIPK2 mediates the increased expression of p53 target genes, which results in growth arrest and the enhancement of UV-induced apoptosis. Interference with HIPK2 expression by antisense oligonucleotides impairs UV-induced apoptosis. Our results imply that HIPK2 is a novel regulator of p53 effector functions involved in cell growth, proliferation and apoptosis.

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Figure 1: PML3 recruits HIPK2 to PML-NBs.
Figure 2: Colocalization of HIPK2 with p53, CBP and PML in PML-NBs.
Figure 3: HIPK2 interacts with p53 in vitro and in vivo.
Figure 4: HIPK2 activates p53-dependent promoters.
Figure 5: HIPK2 is activated by UV irradiation and phosphorylates Ser 46 of p53.
Figure 6: Physical and functional interactions between HIPK2 and CBP.
Figure 7: Kinase-dependent cell proliferation block by HIPK2 expression.
Figure 8: HIPK2 participates in UV-mediated apoptosis.

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Acknowledgements

We are grateful to S. Soddu for sharing results before publication, E. Appella and L. Florin for helpful comments on the manuscript, T. Hamid and N. Stephan for excellent technical assistance, P. Gutwein for help with microscopy, and all colleagues who generously provided plasmids and reagents: W. Gu, G. Haegeman, M. Oren, B. Vogelstein, G. del Sal, G. Blandino and A. J. Fornace Jr. Our laboratories are supported by grants from the EU (QLK3-CT-2000-00463), Deutsche Krebshilfe, Deutsche Forschungsgemeinschaft (Schm 1417/3-1), Universität Heidelberg and Fonds der chemischen Industrie. The HPI is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit. Correspondence and requests for materials should be addressed to M.L.S.

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  1. M. Lienhard Schmitz

    Present address: Department for Chemistry and Biochemistry, Freiestrasse 3, CH-3012, Bern, Switzerland

Authors and Affiliations

  1. Division of Immunochemistry (G0200) German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Thomas G. Hofmann, Andreas Möller, Wulf Dröge & M. Lienhard Schmitz

  2. Department of General Virology, Heinrich-Pette-Institut für experimentelle Virologie und Immunologie, Martinistrasse 52, 20251, Hamburg, Germany

    Thomas G. Hofmann, Hüseyin Sirma & Hans Will

  3. Division of Applied Tumour Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Hanswalter Zentgraf

  4. Radiobiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, 104-0045, Tokyo, Japan

    Yoichi Taya

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Figure S1 HIPK2-mediated phosphorylation of p53. (PDF 175 kb)

Figure S2 UV-radiation does not alter endogenous HIPK2 levels.

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Hofmann, T., Möller, A., Sirma, H. et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 4, 1–10 (2002). https://doi.org/10.1038/ncb715

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