The MDM2-p53 Pathway is Involved in Preconditioning-induced Neuronal Tolerance to Ischemia

Overview

Journal Sci Rep

Specialty Science

Date 2018 Jan 27

PMID 29371613

Citations 18

Authors

Rebeca Vecino

Maria C Burguete

Teresa Jover-Mengual

Jesus Agulla

Veronica Bobo-Jimenez

Juan B Salom

Angeles Almeida

Maria Delgado-Esteban

Affiliations

Soon will be listed here.

Abstract

Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome. Here, we study the role of MDM2-p53 pathway on PC-induced neuroprotection both in cultured neurons (in vitro) and rat brain (in vivo). Our results show that PC increased neuronal MDM2 protein levels, which prevented ischemia-induced p53 stabilization and neuronal death. Indeed, PC attenuated ischemia-induced activation of the p53/PUMA/caspase-3 signaling pathway. Pharmacological inhibition of MDM2-p53 interaction in neurons abrogated PC-induced neuroprotection against ischemia. Finally, the relevance of the MDM2-p53 pathway was confirmed in rat brain using a PC model in vivo. These findings demonstrate the key role of the MDM2-p53 pathway in PC-induced neuroprotection against a subsequent ischemic insult and poses MDM2 as an essential target in ischemic tolerance.

Citing Articles

Pluripotential GluN1 (NMDA NR1): Functional Significance in Cellular Nuclei in Pain/Nociception.

McNearney T, Westlund K Int J Mol Sci. 2023; 24(17).

PMID: 37686003 PMC: 10488196. DOI: 10.3390/ijms241713196.

Involvement of Proteasomal and Endoplasmic Reticulum Stress in Neurodegeneration After Global Brain Ischemia.

Ziakova K, Kovalska M, Pilchova I, Dibdiakova K, Brodnanova M, Pokusa M Mol Neurobiol. 2023; 60(11):6316-6329.

PMID: 37452223 PMC: 10533597. DOI: 10.1007/s12035-023-03479-5.

MDMX elevation by a novel Mdmx-p53 interaction inhibitor mitigates neuronal damage after ischemic stroke.

Yan H, Sasaki T, Kanki H, Hirata Y, Nishiyama K, Hisada S Sci Rep. 2022; 12(1):21110.

PMID: 36473920 PMC: 9726886. DOI: 10.1038/s41598-022-25427-4.

Dose-Dependent Effects of Astaxanthin on Ischemia/Reperfusion Induced Brain Injury in MCAO Model Rat.

Taheri F, Sattari E, Hormozi M, Ahmadvand H, Bigdeli M, Kordestani-Moghadam P Neurochem Res. 2022; 47(6):1736-1750.

PMID: 35286515 DOI: 10.1007/s11064-022-03565-5.

Targeting PI3K/Akt signal transduction for cancer therapy.

He Y, Sun M, Zhang G, Yang J, Chen K, Xu W Signal Transduct Target Ther. 2021; 6(1):425.

PMID: 34916492 PMC: 8677728. DOI: 10.1038/s41392-021-00828-5.

References

Oliner J, Kinzler K, Meltzer P, GEORGE D, Vogelstein B . Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992; 358(6381):80-3. DOI: 10.1038/358080a0. View

Mocanu M, Yellon D . p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning. FEBS Lett. 2003; 555(2):302-6. DOI: 10.1016/s0014-5793(03)01260-2. View

Crumrine R, Thomas A, Morgan P . Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab. 1994; 14(6):887-91. DOI: 10.1038/jcbfm.1994.119. View

Zhao Y, Aguilar A, Bernard D, Wang S . Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J Med Chem. 2014; 58(3):1038-52. PMC: 4329994. DOI: 10.1021/jm501092z. View

Delgado-Esteban M, Garcia-Higuera I, Maestre C, Moreno S, Almeida A . APC/C-Cdh1 coordinates neurogenesis and cortical size during development. Nat Commun. 2013; 4:2879. DOI: 10.1038/ncomms3879. View

Longa E, Weinstein P, Carlson S, Cummins R . Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20(1):84-91. DOI: 10.1161/01.str.20.1.84. View

Manfredi J . The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev. 2010; 24(15):1580-9. PMC: 2912554. DOI: 10.1101/gad.1941710. View

Delgado-Esteban M, Almeida A, Medina J . Tetrahydrobiopterin deficiency increases neuronal vulnerability to hypoxia. J Neurochem. 2002; 82(5):1148-59. DOI: 10.1046/j.1471-4159.2002.01055.x. View

Nakano K, Vousden K . PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001; 7(3):683-94. DOI: 10.1016/s1097-2765(01)00214-3. View

10.

Severino P, Muller G, Vandresen-Filho S, Tasca C . Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid. Life Sci. 2011; 89(15-16):570-6. DOI: 10.1016/j.lfs.2011.05.014. View

11.

Bobo-Jimenez V, Delgado-Esteban M, Angibaud J, Sanchez-Moran I, de la Fuente A, Yajeya J . APC/C-Rock2 pathway controls dendritic integrity and memory. Proc Natl Acad Sci U S A. 2017; 114(17):4513-4518. PMC: 5410848. DOI: 10.1073/pnas.1616024114. View

12.

Stenzel-Poore M, Stevens S, King J, Simon R . Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke. 2007; 38(2 Suppl):680-5. DOI: 10.1161/01.STR.0000251444.56487.4c. View

13.

Li J, Chen G, Gao X, Shen C, Zhou P, Wu X . p53 participates in the protective effects of ischemic post-conditioning against OGD-reperfusion injury in primary cultured spinal cord neurons. Neurosci Lett. 2016; 638:129-134. DOI: 10.1016/j.neulet.2016.12.037. View

14.

Bederson J, Pitts L, Germano S, Nishimura M, Davis R, Bartkowski H . Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke. 1986; 17(6):1304-8. DOI: 10.1161/01.str.17.6.1304. View

15.

Clemens J, Stephenson D, Smalstig E, Dixon E, Little S . Global ischemia activates nuclear factor-kappa B in forebrain neurons of rats. Stroke. 1997; 28(5):1073-80; discussion 1080-1. DOI: 10.1161/01.str.28.5.1073. View

16.

Gomez-Sanchez J, Delgado-Esteban M, Rodriguez-Hernandez I, Sobrino T, Perez de la Ossa N, Reverte S . The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke. J Exp Med. 2011; 208(3):429-37. PMC: 3058581. DOI: 10.1084/jem.20101523. View

17.

Schuler M, Green D . Mechanisms of p53-dependent apoptosis. Biochem Soc Trans. 2001; 29(Pt 6):684-8. DOI: 10.1042/0300-5127:0290684. View

18.

Barreto G, White R, Ouyang Y, Xu L, Giffard R . Astrocytes: targets for neuroprotection in stroke. Cent Nerv Syst Agents Med Chem. 2011; 11(2):164-73. PMC: 3167939. DOI: 10.2174/187152411796011303. View

19.

Morrison R, Kinoshita Y . The role of p53 in neuronal cell death. Cell Death Differ. 2001; 7(10):868-79. DOI: 10.1038/sj.cdd.4400741. View

20.

Lobner D . Comparison of the LDH and MTT assays for quantifying cell death: validity for neuronal apoptosis?. J Neurosci Methods. 2000; 96(2):147-52. DOI: 10.1016/s0165-0270(99)00193-4. View