title: Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis.
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.
authors.affiliation: Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Morinaka
authors.forename: Y
authors.initials: Y
authors.lastname: Funato
authors.forename: K
authors.initials: K
authors.lastname: Uesugi
authors.forename: H
authors.initials: H
authors.lastname: Miki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001704:Biopolymers; D002945:Cisplatin / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D054464:Peroxiredoxins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D000970:Antineoplastic Agents; D001704:Biopolymers; D002945:Cisplatin; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D054464:Peroxiredoxins; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C515940:PRDX1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases