Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH-Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO-S-nitrosylation-GAPDH-Siah1 cascade may represent an important molecular mechanism of cytotoxicity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology*
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Cell Line
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cells, Cultured
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Cysteine / metabolism
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Cytoplasm / metabolism
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / physiology*
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Humans
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Microscopy, Fluorescence
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Models, Biological
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Mutation
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / genetics
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Neurons / drug effects
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Neurons / metabolism
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type II
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Binding / drug effects
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Protein Transport / drug effects
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Protein Transport / physiology
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Rats
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S-Nitrosoglutathione / pharmacology
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S-Nitrosothiols / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transfection
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Two-Hybrid System Techniques
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases
Substances
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Lipopolysaccharides
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Nerve Tissue Proteins
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Nuclear Proteins
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S-Nitrosothiols
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Ubiquitin
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Nitric Oxide
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S-Nitrosoglutathione
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N-Methylaspartate
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NOS1 protein, human
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type II
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Nos1 protein, mouse
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Nos1 protein, rat
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Nos2 protein, mouse
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Nos2 protein, rat
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
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Ubiquitin-Protein Ligases
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seven in absentia proteins
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Cysteine