Abstract
Glutaredoxin 2 (Grx2) from Escherichia coli protects cerebellar neurons from dopamine-induced apoptosis via nuclear factor kappa B (NF-kappaB) activation, which is mediated by the expression of redox factor-1 (Ref-1). An analysis of the mechanisms underlying Grx2 protective activity revealed dual activation of signal transduction pathways. Grx2 significantly activated the Ras/phosphoinositide 3-kinase/Akt/NF-kappaB cascade in parallel to the Jun N-terminal kinase (JNK)/AP1 cascade. Dopamine, in comparison, down-regulated both pathways. Treatment of neurons with Ref-1 antisense oligonucleotide reduced the ability of Grx2 to activate Akt and AP-1 but had no effect on the phosphorylation of JNK1/2, suggesting that Akt/NF-kappaB and AP-1 are regulated by Ref-1. Exposure of the neurons to JNK1/2 antisense oligonucleotide in the presence of Grx2 significantly reduced AP-1 and NF-kappaB DNA binding activities and abolished Grx2 protection. These results demonstrate that dual activation of Ras/phosphoinositide 3-kinase and AP-1 cascades, which are mediated by Ref-1, is an essential component of the Grx2 mechanism of action.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Apoptosis / drug effects*
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Bacterial Proteins / pharmacology
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Cells, Cultured
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Cerebellum / cytology*
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Cerebellum / physiology
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Dopamine / pharmacology*
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Escherichia coli
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Farnesol / analogs & derivatives*
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Farnesol / pharmacology
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Glutaredoxins
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinases / metabolism*
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Models, Neurological
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NF-kappa B / metabolism
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Neurons / cytology
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Neurons / drug effects*
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Neurons / physiology
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Oxidoreductases*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proteins / pharmacology*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Salicylates / pharmacology
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ras Proteins / metabolism
Substances
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Bacterial Proteins
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Enzyme Inhibitors
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Glrx2 protein, mouse
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Glutaredoxins
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NF-kappa B
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Proteins
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Proto-Oncogene Proteins
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Salicylates
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farnesylthiosalicylic acid
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Farnesol
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Oxidoreductases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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ras Proteins
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Dopamine