Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2–p53 Pathway

International Journal of Molecular Sciences

Rebeca Vecino¹  Cristina Rodríguez¹  Emilia Barrio¹  Irene Sánchez-Morán¹  Alberto Suárez-Pindado¹  Angeles Almeida¹  Maria Delgado-Esteban¹  Juan P. Bolaños¹ 

[1] Institute of Functional Biology and Genomics, University of Salamanca, CSIC, 37007 Salamanca, Spain;

关键词: AKT;    MDM2;    p53;    PI3K;    ischemic tolerance;    preconditioning;   

DOI  :  10.3390/ijms22147275

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown