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

2021 ◽  
Vol 22 (14) ◽  
pp. 7275
Author(s):  
Emilia Barrio ◽  
Rebeca Vecino ◽  
Irene Sánchez-Morán ◽  
Cristina Rodríguez ◽  
Alberto Suárez-Pindado ◽  
...  

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.

2019 ◽  
Vol 56 (12) ◽  
pp. 8203-8219 ◽  
Author(s):  
Takeshi Okada ◽  
Budbazar Enkhjargal ◽  
Zachary D. Travis ◽  
Umut Ocak ◽  
Jiping Tang ◽  
...  

1999 ◽  
Vol 19 (9) ◽  
pp. 6195-6206 ◽  
Author(s):  
Ju-Ming Wang ◽  
Jyh-Rong Chao ◽  
Wannhsin Chen ◽  
Min-Liang Kuo ◽  
Jeffrey J.-Y. Yen ◽  
...  

ABSTRACT mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) signaling pathways and plays an important role in the viability response of these cytokines. In this study, we demonstrated that cytokine stimulation of mcl-1 mRNA and protein expression were attenuated by pretreatment of cells with phosphatidylinositol 3-kinase (PI3-K) inhibitors. Reporter gene assays further showed that the PI3-K/Akt signaling pathway was involved in IL-3 activation of mcl-1 gene transcription. Analysis of the mcl-1 promoter revealed that both promoter elements, SIE at position −87 and CRE-2 at −70, contribute to IL-3 stimulation of mcl-1 gene expression. Although either the SIE site or the CRE-2 site alone was sufficient to confer IL-3 inducibility on a heterologous promoter, only IL-3 activation of the CRE-2 reporter was mediated via the PI3-K/Akt pathway. The SIE binding activity was constitutively high in cells deprived of or stimulated by IL-3. In contrast, the CRE-2 binding activity was low in cytokine-starved cells and was strongly induced within 1 h following cytokine treatment of cells. In addition, cytokine induction of the CRE-2 but not of the SIE binding activity was dependent on activation of the PI3-K/Akt signaling pathway. Lastly, we showed that CREB was one component of the CRE-2 binding complex and played a role in IL-3 activation of themcl-1 reporter gene. Taken together, our results suggest that both PI3-K/Akt-dependent and -independent pathways contribute to the IL-3 activation of mcl-1 gene expression. Activation ofmcl-1 by the PI3-K/Akt-dependent pathway is through a transcription factor complex containing CREB.


2020 ◽  
Vol 326 ◽  
pp. 113179
Author(s):  
Ling-Yun Wu ◽  
Budbazar Enkhjargal ◽  
Zhi-Yi Xie ◽  
Zachary D. Travis ◽  
Cheng-Mei Sun ◽  
...  

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