Preconditioning-activated AKT controls neuronal tolerance to ischemia through the MDM2-p53 pathway
EN][One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation...
| Autores: | , , , , , , , |
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| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2021 |
| País: | España |
| Recursos: | Universidad de Salamanca (USAL) |
| Repositório: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/155253 |
| Acesso em linha: | http://hdl.handle.net/10366/155253 |
| Access Level: | Acceso aberto |
| Palavra-chave: | AKT MDM2 p53 PI3K Ischemic tolerance Preconditioning Proto-Oncogene Proteins c-mdm2 Ischemic Preconditioning HEK293 Cells Humans Ischemia Neurons Apoptosis Phosphorylation Animals Proto-Oncogene Proteins c-akt Tumor Suppressor Protein p53 Signal Transduction Phosphatidylinositol 3-Kinases Mice transducción de señales apoptosis humanos ratones neuronas fosfatidil inositol 3 cinasas proteína supresora de tumor p53 animales proteínas protooncogénicas c-mdm2 isquemia células HEK293 preacondicionamiento isquémico fosforilación proteínas protooncogénicas c-akt |
| Resumo: | EN][One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT is known to increase the expression of murine double minute-2 (MDM2), an E3-ubiquitin ligase that destabilizes p53 to promote the survival of cancer cells. In neurons, we recently showed that the MDM2-p53 interaction is potentiated by pharmacological preconditioning, based on subtoxic stimulation of NMDA glutamate receptor, which prevents ischemia-induced neuronal apoptosis. However, whether this mechanism contributes to the neuronal tolerance during ischemic preconditioning (IPC) is unknown. Here, we show that IPC induced PI3K-mediated phosphorylation of AKT at Ser473, which in turn phosphorylated MDM2 at Ser166. This phosphorylation triggered the nuclear stabilization of MDM2, leading to p53 destabilization, thus preventing neuronal apoptosis upon an ischemic insult. Inhibition of the PI3K/AKT pathway with wortmannin or by AKT silencing induced the accumulation of cytosolic MDM2, abrogating IPC-induced neuroprotection. Thus, IPC enhances the activation of PI3K/AKT signaling pathway and promotes neuronal tolerance by controlling the MDM2-p53 interaction. Our findings provide a new mechanistic pathway involved in IPC-induced neuroprotection via modulation of AKT signaling, suggesting that AKT is a potential therapeutic target against ischemic injury. |
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