Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10738360 | Free Radical Biology and Medicine | 2011 | 10 Pages |
Abstract
The redox-sensitive transcription factor NF-κB mediates the expression of genes involved in inflammation and cell survival. Thioredoxin reductase-1 (TR1) and its substrate thioredoxin-1 act together to reduce oxidized cysteine residues within the DNA-binding domain of NF-κB and promote maximal DNA-binding activity in vitro. It is not clear, however, if NF-κB is regulated via this mechanism within living cells. The purpose of this study was to determine the mechanism of NF-κB modulation by TR1 in cells stimulated with the inflammatory cytokine tumor necrosis factor-α (TNF). In both control cells and cells depleted of TR1 activity through chemical inhibition or siRNA knockdown, TNF stimulation resulted in degradation of the cytoplasmic NF-κB inhibitor IκB-α and translocation of NF-κB to the nucleus. Similarly, the DNA-binding activity and redox state of NF-κB were unaffected by TR1 depletion. In contrast, NF-κB-mediated gene expression was markedly inhibited in cells lacking TR1 activity, suggesting that the transactivation potential of NF-κB is sensitive to changes in TR1 activity. Consistent with this concept, phosphorylation of the transactivation domain of NF-κB was inhibited in the presence of curcumin. Surprisingly, another TR1 inhibitor, 1-chloro-2,4-dinitrobenzene, had no effect, and siRNA knockdown of TR1 actually increased phosphorylation at this site. These results demonstrate that TR1 activity controls the transactivation potential of NF-κB and that more than one mechanism may mediate this effect.
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Ageing
Authors
Jacqueline M. Heilman, Tom J. Burke, Craig J. McClain, Walter H. Watson,