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An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response

Nature Cell Biology volume 11, pages 85–91 (2009)Cite this article

Abstract

Oxygen deprivation (hypoxia) results in reprogrammed gene expression patterns that induce multifaceted cellular responses. Here we identify a regulated interaction between the serine/threonine kinase HIPK2 and the ubiquitin E3 ligase Siah2 as a mechanism controlling the hypoxic response. Under normoxic conditions, several mechanisms ensure HIPK2 stability: only a fraction of HIPK2 is found in association with Siah2, whereas HIPK2-mediated phosphorylation of this E3 ligase at positions 26, 28 and 68 weakens mutual binding and destabilizes its phosphorylated interaction partner. Hypoxic conditions allow a markedly increased HIPK2/Siah2 interaction and result in efficient polyubiquitylation and proteasomal degradation of the kinase. Accordingly, hypoxia-induced HIPK2 elimination is markedly reduced in Siah2-deficient cells. As HIPK2 has an important role as a negative regulator of gene expression, its elimination from promoter-associated repressor complexes allows the induction of a substantial fraction of hypoxia-induced genes.

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Figure 1: Analysis of Siah2 effects on HIPK2.
Figure 2: HIPK2-mediated Siah2 phosphorylation.
Figure 3: Degradation of HIPK2 under hypoxic conditions.
Figure 4: Hypoxia-triggered association between HIPK2 and Siah2.
Figure 5: Physiological consequences of hypoxia-mediated HIPK2 decay.

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Acknowledgements

We are grateful to Stephanie Wack for excellent technical assistance, Michael Kracht for inspiring discussions and Elena Puccetti (Frankfurt) for help with microarrays. Our work is 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. M.A.C has been partially co-funded by the ISCIII-RETIC RD06/006 (RIS).

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Authors and Affiliations

  1. Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, Giessen, D-35392, Germany

    Marco A. Calzado, Laureano de la Vega & M. Lienhard Schmitz

  2. Department of Research, Peter MacCallum Cancer Centre, Cancer Genomics and Biochemistry Laboratory, St. Andrews Place, East Melbourne, 3002, Victoria, Australia

    Andreas Möller & David D. L. Bowtell

  3. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Andreas Möller & David D. L. Bowtell

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  1. Marco A. Calzado
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  2. Laureano de la Vega
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  3. Andreas Möller
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  5. M. Lienhard Schmitz
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Contributions

M.A.C. designed and performed the experiments; L.d.l.V. and A.M. performed experiments; D.D.B. contributed conceptual input; M.L.S. supervised the whole project.

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Correspondence to M. Lienhard Schmitz.

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Calzado, M., de la Vega, L., Möller, A. et al. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol 11, 85–91 (2009). https://doi.org/10.1038/ncb1816

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