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Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

Oncogene volume 30, pages 4208–4218 (2011)Cite this article

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Abstract

Mammalian Ste20-like kinase-1 (MST1) kinase mediates H2O2-induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H2O2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H2O2-induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H2O2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H2O2-induced MST1 activation. Live-cell imaging showed H2O2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H2O2-induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.

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Acknowledgements

We thank Dr Yoshiaki Kise (Flanders Institute for Biotechnology, Belgium) for technical assistance in preparing the expression constructs. This study was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) and Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Japan.

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  1. Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, Osaka, Japan

    A Morinaka, Y Funato, K Uesugi & H Miki

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  1. A Morinaka
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  2. Y Funato
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Correspondence to H Miki.

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Morinaka, A., Funato, Y., Uesugi, K. et al. Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis. Oncogene 30, 4208–4218 (2011). https://doi.org/10.1038/onc.2011.139

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