Abstract
Previous evidence supports the notion of a redox regulation of protein phosphatase calcineurin that might be relevant for neurodegenerative processes where an imbalance between generation and removal of reactive oxygen species occurs. We have recently observed that calcineurin activity is depressed in human neuroblastoma cells expressing Cu,Zn superoxide dismutase (SOD1) mutant G93A and in brain areas from G93A transgenic mice, and that mutant G93A-SOD1 oxidatively inactivates calcineurin in vitro. We have studied the possibility that, by interfering directly with calcineurin activity, mutant SOD1 can modulate pathways of signal transduction mediated by redox-sensitive transcription factors. In this paper, we report a calcineurin-dependent activation of nuclear factor-kappaB (NF-kappaB) induced by the expression of familial amyotrophic lateral sclerosis (fALS)-SOD1s in human neuroblastoma cell lines. Alteration of the phosphorylation state of IkappaBalpha (the inhibitor of NF-kappaB translocation into the nucleus) and induction of cyclooxygenase 2 are consistent with the up-regulation of this transcription factor in this system. All of these modifications might be relevant to signaling pathways involved in the pathogenesis of fALS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Amyotrophic Lateral Sclerosis / enzymology*
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Amyotrophic Lateral Sclerosis / genetics
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Blotting, Western
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Calcineurin / metabolism
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Calcineurin Inhibitors
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Cyclooxygenase 2
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Cysteine Endopeptidases / metabolism
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Electrophoretic Mobility Shift Assay
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Enzyme Activators / pharmacology
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Enzyme Induction / drug effects
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Enzyme Induction / physiology
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Enzyme Inhibitors / pharmacology
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Humans
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I-kappa B Proteins / metabolism
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Isoenzymes / metabolism
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Membrane Proteins
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Multienzyme Complexes / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Neuroblastoma / chemistry
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Neuroblastoma / metabolism*
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Oxidation-Reduction
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Phosphorylation / drug effects
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Prostaglandin-Endoperoxide Synthases / metabolism
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Proteasome Endopeptidase Complex
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism*
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Superoxide Dismutase-1
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Calcineurin Inhibitors
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Enzyme Activators
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Enzyme Inhibitors
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I-kappa B Proteins
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Isoenzymes
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Membrane Proteins
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Multienzyme Complexes
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Reactive Oxygen Species
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SOD1 protein, human
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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SOD1 G93A protein
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Calcineurin
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex