| Critical role of the JNK-p53-GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons. | |
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MedLine Citation:
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PMID: 20955365 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Glutamate-induced oxidative stress plays a critical role in the induction of neuronal cell death in a number of disease states. We sought to determine the role of the c-Jun NH(2) -terminal kinase (JNK)-p53-growth arrest and DNA damage-inducible gene (GADD) 45α apoptotic cascade in mediating glutamate-induced oxidative cytotoxicity in hippocampal neuronal cells. EXPERIMENTAL APPROACH: HT22 cells, a mouse hippocampal neuronal cell line, were treated with glutamate to induce oxidative stress in vitro. Kainic acid-induced oxidative damage to the hippocampus in rats was used as an in vivo model. The signalling molecules along the JNK-p53-GADD45α cascade were probed with various means to determine their contributions to oxidative neurotoxicity. KEY RESULTS: Treatment of HT22 cells with glutamate increased the mRNA and protein levels of GADD45α, and these increases were suppressed by p53 knock-down. Knock-down of either p53 or GADD45α also prevented glutamate-induced cell death. Glutamate-induced p53 activation was preceded by accumulation of reactive oxygen species, and co-treatment with N-acetyl-cysteine prevented glutamate-induced p53 activation and GADD45α expression. Knock-down of MKK4 or JNK, or the presence of SP600125 (a JNK inhibitor), each inhibited glutamate-induced p53 activation and GADD45α expression. In addition, we also confirmed the involvement of GADD45α in mediating kainic acid-induced hippocampal oxidative neurotoxicity in vivo. CONCLUSIONS: AND IMPLICATIONS Activation of the JNK-p53-GADD45α cascade played a critical role in mediating oxidative cytotoxicity in hippocampal neurons. Pharmacological inhibition of this signalling cascade may provide an effective strategy for neuroprotection. |
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Authors:
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Hye Joung Choi; Ki Sung Kang; Masayuki Fukui; Bao Ting Zhu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: British journal of pharmacology Volume: 162 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-07 Completed Date: 2011-04-05 Revised Date: 2012-01-02 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 175-92 Citation Subset: IM |
Copyright Information:
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© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society. |
Affiliation:
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Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Blotting, Western Cell Cycle Proteins / genetics, metabolism* Cell Line Hippocampus / cytology, drug effects, enzymology, metabolism* Immunohistochemistry In Situ Nick-End Labeling Kainic Acid / pharmacology MAP Kinase Kinase 4 / metabolism* Mice Microscopy, Fluorescence Neurons / cytology, drug effects, enzymology, metabolism* Nuclear Proteins / genetics, metabolism* Oxidative Stress* Polymerase Chain Reaction RNA, Small Interfering Rats Reactive Oxygen Species / metabolism Tumor Suppressor Protein p53 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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ES015242/ES/NIEHS NIH HHS; P20RR021940/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Gadd45a protein, mouse; 0/Nuclear Proteins; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/Tumor Suppressor Protein p53; 487-79-6/Kainic Acid; EC 2.7.12.2/MAP Kinase Kinase 4 |
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