Transactivation of gene expression by NF-κB is dependent on thioredoxin reductase activity.
Transactivation of gene expression by NF-κB is dependent on thioredoxin reductase activity.
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DOI：
10.1016/j.freeradbiomed.2011.06.028
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发表时间：
2011-10-15
影响因子：
7.4
通讯作者：
Watson, Walter H.
中科院分区：
文献类型：
--
作者：
Heilman, Jacqueline M.;Burke, Tom J.;McClain, Craig J.;Watson, Walter H.
氧化还原敏感性转录因子NFκB介导参与炎症和细胞存活的基因的表达。硫氧还蛋白还原酶-1（TR 1）及其底物硫氧还蛋白-1（Trx 1）共同作用，以减少NFκB DNA结合结构域内的氧化半胱氨酸残基，并促进体外最大DNA结合活性。然而，在活细胞中NFκB是否通过这种机制调节尚不清楚。本研究的目的是确定炎症细胞因子肿瘤坏死因子-α（TNF）刺激细胞中TR 1调节NFκB的机制。在对照细胞和通过化学抑制或siRNA敲低去除TR 1活性的细胞中，TNF刺激导致细胞质NFκB抑制剂IκB-α降解和NFκB易位至细胞核。同样，DNA结合活性和NFκB的氧化还原状态不受TR 1耗竭的影响。相反，NFκ B介导的基因表达在缺乏TR 1活性的细胞中被显著抑制，表明NFκB的反式激活潜力对TR 1活性的变化敏感。与此一致的是，在姜黄素存在下，NFκB的反式激活结构域的磷酸化被抑制。令人惊讶的是，另一种TR 1抑制剂，1-氯-2，4-二硝基苯，没有效果，siRNA敲低TR 1实际上增加了该位点的磷酸化。这些结果表明，TR 1活性控制NFκB的反式激活潜力，并且不止一种机制可能介导这种效应。
The redox-sensitive transcription factor NFκB mediates the expression of genes involved in inflammation and cell survival. Thioredoxin reductase-1 (TR1) and its substrate thioredoxin-1 (Trx1) act together to reduce oxidized cysteine residues within the DNA binding domain of NFκB and promote maximal DNA binding activity in vitro. It is not clear, however, if NFκB is regulated via this mechanism within living cells. The purpose of the present study was to determine the mechanism of NFκB modulation by TR1 in cells stimulated with the inflammatory cytokine tumor necrosis factor-α (TNF). In both control cells and in cells depleted of TR1 activity through chemical inhibition or siRNA knock down, TNF stimulation resulted in degradation of the cytoplasmic NFκB inhibitor IκB-α and translocation of NFκB to the nucleus. Similarly, the DNA binding activity and redox state of NFκB were unaffected by TR1 depletion. In contrast, NFκB-mediated gene expression was markedly inhibited in cells lacking TR1 activity, suggesting that the transactivation potential of NFκB is sensitive to changes in TR1 activity. Consistent with this concept, phosphorylation of the transactivation domain of NFκB was inhibited in the presence of curcumin. Surprisingly, another TR1 inhibitor, 1-chloro-2,4-dinitrobenzene, had no effect, and siRNA knock down of TR1 actually increased phosphorylation at this site. These results demonstrate that TR1 activity controls the transactivation potential of NFκB, and that more than one mechanism may mediate this effect.
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DOI：
10.1152/ajpgi.90232.2008
发表时间：
2008-10-01
影响因子：
4.5
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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