title: Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage.
abstract: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is conventionally considered a critical enzyme that involves in glycolysis for energy production. Recent previous studies have suggested that GAPDH is important in glutamate-induced neuronal excitotoxicity, while accumulated evidence also demonstrated that GAPDH nuclear translocation plays a critical role in cell death. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we showed that GAPDH translocates to the nucleus in a Siah1-dependent manner upon glutamate stimulation. The nuclear GAPDH forms a protein complex with p53 and enhances p53 expression and phosphorylation. Disruption of the GAPDH-p53 interaction with an interfering peptide blocks glutamate-induced cell death and GAPDH-mediated up-regulation of p53 expression and phosphorylation. Furthermore, administration of the interfering peptide in vivo protects against ischemia-induced cell death in rats subjected to tMCAo. Our data suggest that the nuclear p53-GAPDH complex is important in regulating glutamate-mediated neuronal death and could serve as a potential therapeutic target for ischemic stroke treatment.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Zhai
authors.forename: Kyle
authors.initials: K
authors.lastname: Chin
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, Ontario M5T 1R8, Canada. f.liu.a@utoronto.ca.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D018698:Glutamic Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007608:Kainic Acid; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C104722:glutamate receptor ionotropic, AMPA 2