Functional dichotomy of A20 in apoptotic and necrotic cell death.
Functional dichotomy of A20 in apoptotic and necrotic cell death.
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A20 在细胞凋亡和坏死细胞死亡中的功能二分法。
DOI：
10.1042/bj20041443
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Toker,Alex
中科院分区：
文献类型：
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作者：
Storz,Peter;Döppler,Heike;Ferran,Christiane;Grey,ShaneT;Toker,Alex
ROS（活性氧）在许多人类病理的进展中发挥着重要作用。 ROS促进细胞死亡，但也可以诱导基因转录。转录因子 NF-κB（核因子 κB）在氧化应激反应中发挥着关键作用。 NF-κB 调节的蛋白质之一是锌指蛋白 A20。在 TNF（肿瘤坏死因子）-α 信号传导中，A20 的 NF-κB 诱导可导致细胞存活率增加。在本文中，我们表明，在应对氧化应激时，A20 实际上通过坏死而非细胞凋亡来增强细胞死亡。细胞暴露于 ROS 会导致 A20 上调，A20 通过负反馈回路发挥作用，阻止 NF-κB 激活和细胞存活。通过 RNAi（RNA 干扰）沉默 A20 会增加 NF-κB 的诱导以及随后暴露于高剂量氧化应激的细胞的存活率，在未经处理的细胞中，氧化应激会促进坏死死亡。与 A20 表达较低的细胞相比，表达高基础水平 A20 的细胞较少受到氧化应激诱导的细胞死亡的保护。我们还表明，A20 通过阻止 IκB（抑制性蛋白 κB）α 的降解来调节 NF-κB。这些数据强调了 A20 在氧化应激反应中的新作用，它可以终止 NF-κB 依赖性生存信号传导，从而使细胞对坏死敏感。
ROS (reactive oxygen species) play important roles in the progression of a number of human pathologies. ROS promote cell death, but can also induce gene transcription. The transcription factor NF-κB (nuclear factor κB) plays a critical role in oxidative stress responses. One of the proteins regulated by NF-κB is the zinc-finger protein A20. In TNF (tumour necrosis factor)-α signalling, NF-κB induction of A20 leads to increased cell survival. In the present paper, we show that in response to oxidative stress, A20 actually enhances cell death by necrosis, but not by apoptosis. Exposure of cells to ROS leads to the up-regulation of A20 which acts via a negative-feedback loop to block NF-κB activation and cellular survival. Silencing of A20 by RNAi (RNA interference) increases both the induction of NF-κB and the subsequent survival of cells exposed to high doses of oxidative stress, which, in untreated cells, promotes death by necrosis. Cells which express high basal levels of A20 are less protected from oxidative-stress-induced cell death when compared with cells with lower A20 expression. We also show that A20 regulates NF-κB by blocking the degradation of IκB (inhibitory protein κB) α. These data highlight a novel role for A20 in oxidative stress responses by terminating NF-κB-dependent survival signalling and thus sensitizing cells to death by necrosis.