title: Selective 14-3-3γ induction quenches p-β-catenin Ser37/Bax-enhanced cell death in cerebral cortical neurons during ischemia.
abstract: Ischemia-induced cell death is a major cause of disability or death after stroke. Identifying the key intrinsic protective mechanisms induced by ischemia is critical for the development of effective stroke treatment. Here, we reported that 14-3-3γ was a selective ischemia-inducible survival factor in cerebral cortical neurons reducing cell death by downregulating Bax depend direct 14-3-3γ/p-β-catenin Ser37 interactions in the nucleus. 14-3-3γ, but not other 14-3-3 isoforms, was upregulated in primary cerebral cortical neurons upon oxygen-glucose deprivation (OGD) as measured by quantitative PCR, western blot and fluorescent immunostaining. The selective induction of 14-3-3γ in cortical neurons by OGD was verified by the in vivo ischemic stroke model. Knocking down 14-3-3γ alone or inhibiting 14-3-3/client interactions was sufficient to induce cell death in normal cultured neurons and exacerbate OGD-induced neuronal death. Ectopic overexpression of 14-3-3γ significantly reduced OGD-induced cell death in cultured neurons. Co-immunoprecipitation and fluorescence resonance energy transfer demonstrated that endogenous 14-3-3γ bound directly to more p-β-catenin Ser37 but not p-Bad, p-Ask-1, p-p53 and Bax. During OGD, p-β-catenin Ser37 but not p-β-catenin Ser45 was increased prominently, which correlated with Bax elevation in cortical neurons. OGD promoted the entry of 14-3-3γ into the nuclei, in correlation with the increase of nuclear p-β-catenin Ser37 in neurons. Overexpression of 14-3-3γ significantly reduced Bax expression, whereas knockdown of 14-3-3γ increased Bax in cortical neurons. Abolishing β-catenin phosphorylation at Ser37 (S37A) significantly reduced Bax and cell death in neurons upon OGD. Finally, 14-3-3γ overexpression completely suppressed β-catenin-enhanced Bax and cell death in neurons upon OGD. Based on these data, we propose that the 14-3-3γ/p-β-catenin Ser37/Bax axis determines cell survival or death of neurons during ischemia, providing novel therapeutic targets for ischemic stroke as well as other related neurological diseases.
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Lai
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Ye
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Q R
authors.initials: QR
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: S B
authors.initials: SB
authors.lastname: Yu
authors.affiliation: Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, The Key Laboratory of Neuroscience, The Ministry of Education and Ministry of Health (PKU), Peking University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.affiliation: Translational Medical Center for Development and Disease, Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, The Key Laboratory of Neuroscience, The Ministry of Education and Ministry of Health (PKU), Peking University, Beijing, China.
authors.forename: A C H
authors.initials: AC
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: X Q
authors.initials: XQ
authors.lastname: Chen
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D019610:Cytoprotection; D015536:Down-Regulation; D005947:Glucose / Q000172:deficiency; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D020033:Protein Isoforms; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; D010768:Phosphoserine; D005947:Glucose; D010100:Oxygen
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