Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death
| Autor: | Vera Greiner, Thomas G. Hofmann, Carolina Glas, Elisa Conrad, Francesca Peri, Kathrin Schultheiss, Christoph Herbel, Dirk Sombroek, Nadja Bitomsky, Christian Moritz, Fiamma Mantovani, Tilman Polonio-Vallon, Giannino Del Sal |
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| Přispěvatelé: | University of Zurich, Hofmann, T G, N., Bitomsky, E., Conrad, C., Moritz, T., Polonio Vallon, D., Sombroek, K., Schulthei, C., Gla, V., Greiner, C., Herbel, Mantovani, Fiamma, DEL SAL, Giannino, F., Peri, T. G., Hofmann |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Programmed cell death
DNA damage Genetic Vectors Apoptosis Protein Serine-Threonine Kinases medicine.disease_cause Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ubiquitin medicine Humans Phosphorylation RNA Small Interfering 030304 developmental biology 0303 health sciences Mutation 1000 Multidisciplinary Multidisciplinary biology Autophosphorylation Post-Translational Peptidylprolyl Isomerase Protein-Serine-Threonine Kinases apoptosi Post-Translational Protein-Serine-Threonine Kinase 10124 Institute of Molecular Life Sciences Cell biology Enzyme Activation NIMA-Interacting Peptidylprolyl Isomerase apoptosis Post-Translational Protein-Serine-Threonine Kinases chemistry Biochemistry Microscopy Fluorescence PNAS Plus 030220 oncology & carcinogenesis biology.protein PIN1 570 Life sciences RNA Interference Carrier Proteins DNA DNA Damage |
| Zdroj: | Proceedings of the National Academy of Sciences |
| Popis: | Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. Moreover, HIPK2 autophosphorylation is conserved between human and zebrafish and is important for DNA damage-induced apoptosis in vivo. Mechanistically, autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1. Pin1 links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1–HIPK2 interaction. Concordantly, Pin1 is required for DNA damage-induced HIPK2 stabilization and p53 Ser46 phosphorylation and is essential for induction of apotosis both in cellulo and in zebrafish. Our results identify an evolutionary conserved mechanism regulating DNA damage-induced apoptosis. |
| Databáze: | OpenAIRE |
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