Abstract
Stimulation of cells with tumor necrosis factor-alpha (TNF-alpha) results in the increase in generation of H(2)O(2) in mitochondria that leads to apoptosis. The effect of H(2)O(2) produced by TNF-alpha on the redox status of selenocysteine (SeCys) residue essential for mitochondrial thioredoxin reductase (TrxR2) was investigated in HeLa cells. TNF-alpha caused accumulation of oxidized TrxR2 with a thioselenide bond. The conditional induction of SeCys-deficient TrxR2 resulted in the increased production of H(2)O(2) and apoptosis. These results suggest that the SeCys residue of TrxR2 plays a critical role in cell survival by serving as an electron donor for Trx-II and subsequent peroxiredoxin-III, which is a primary line of defense against H(2)O(2) in mitochondria.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Cysteine / chemistry
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Cysteine / metabolism
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Cytoplasm / metabolism
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DNA Fragmentation
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Disulfides / chemistry
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Genes, Dominant
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HeLa Cells
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Humans
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Hydrogen Peroxide / chemistry
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Hydrogen Peroxide / metabolism
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Mitochondria, Liver / enzymology
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Mutation
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NADP / chemistry
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Oxidation-Reduction
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Rats
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Selenocysteine / chemistry
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Selenocysteine / metabolism
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Thioredoxin Reductase 1
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Thioredoxin Reductase 2
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Thioredoxin-Disulfide Reductase / chemistry*
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Thioredoxin-Disulfide Reductase / genetics
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Thioredoxin-Disulfide Reductase / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Disulfides
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Selenocysteine
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NADP
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Hydrogen Peroxide
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TXNRD1 protein, human
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TXNRD2 protein, human
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Thioredoxin Reductase 1
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Thioredoxin Reductase 2
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Thioredoxin-Disulfide Reductase
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Txnrd1 protein, rat
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Txnrd2 protein, rat
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Cysteine