Article
- The EMBO Journal (2006) 25, 1883 - 1894
- doi:10.1038/sj.emboj.7601077
Published online: 6 April 2006
Subject Categories:
Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2
Ekaterina Gresko1,a, Ana Roscic1, Stefanie Ritterhoff1, Anton Vichalkovski2, Giannino del Sal3,4 and M Lienhard Schmitz5
- Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy
- Dipartimento di Biochimica Biofisica Chimica delle Macromolecole, Trieste, Italy
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany
Correspondence to:
M Lienhard Schmitz, Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany. Tel.: +49 641 994 7570; Fax: +49 641 994 7589; E-mail: lienhard.schmitz@biochemie.med.uni-giessen.de
aPresent address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4002 Basel, Switzerland
Received 9 August 2005; Accepted 9 March 2006
Abstract
The serine/threonine kinase HIPK2 phosphorylates the p53 protein at Ser 46, thus promoting p53-dependent gene expression and subsequent apoptosis. Here, we show that DNA damaging chemotherapeutic drugs cause degradation of endogenous HIPK2 dependent on the presence of a functional p53 protein. Early induced p53 allows caspase-mediated cleavage of HIPK2 following aspartic acids 916 and 977. The resulting C-terminally truncated HIPK2 forms show an enhanced induction of the p53 response and cell death, thus allowing the rapid amplification of the p53-dependent apoptotic program during the initiation phase of apoptosis by a regulatory feed-forward loop. The active HIPK2 fragments are further degraded during the execution and termination phase of apoptosis, thus ensuring the occurrence of HIPK2 signaling only during the early phases of apoptosis induction.
Keywords:
- apoptosis,
- caspases,
- HIPK2,
- p53
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