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Preconditioning-induced early Akt activation controls MDM2/p53 interaction and promotes neuronal ischemic tolerance

AuthorsVecino, Rebeca; Barrio, Emilia; Sánchez Morán, Irene; Suarez-Pindado, Alberto; Bolaños, Juan P. ; Almeida, Angeles ; Delgado-Esteban, María
Issue Date2019
Citation42ⁿᵈ Congress of the Spanish Society of Biochemistry and Molecular Biology (2019)
AbstractAttenuation of cell apoptosis has been involved in endogenous neuroprotection induced during brain tolerance related to ischemic preconditioning (IPC). The PI3K/Akt pathway regulates cell development, growth, and survival. Several studies have reported that activated Akt, a serine-threonine specific protein kinase B enhances MDM2-mediated p53 destabilization triggering survival in cancer cells. Recently, we demonstrated that IPC prevents the activation of p53/PUMA/Caspase-3 apoptotic pathway by increasing MDM2/p53 interaction in cortical neurons. Here, we aimed to clarify the role of Akt in the IPC-induced neuronal tolerance against lethal ischemia. To do that, primary cortical neurons were exposed to a validated in vitro model of IPC (oxygen glucose deprivation; OGD; 20 min) prior to prolonged ischemia (OGD, 90min). Akt levels were modulated by specific siRNA and PI3K/Akt activity was inhibited by wortmannin. Protein levels were determined by Western blotting. Neuronal apoptosis (Annexin-V-staining and caspase-3 activation) was analyzed by flow cytometry and fluorimetry. For ectopic human MDM2 expression, a plasmid construction expressing YFP-tagged Mdm2 was used. Our results show that IPC promoted early phosphorylation of Akt, followed by an increase in Akt-MDM2 interaction. Indeed, Akt activation promoted stabilization of phosphorylated MDM2, which enhanced IPC-promoted nuclear MDM2-p53 complex at 4 hours of reoxygenation after ischemia. Furthermore, PI3K/Akt specific inhibition by wortmannin and siRNA against Akt, completely induced a cytosolic MDM2 translocation, leading to the prevention of IPC-mediated neuroprotection. In conclusion, the PI3K/Akt signaling pathway is involved in ischemic tolerance, through controlling the MDM2/p53 interaction.
DescriptionResumen del trabajo presentado al Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019.
Appears in Collections:(IBFG) Comunicaciones congresos
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