The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation
The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation
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DOI：
10.1101/gad.1062403
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发表时间：
2003-04-01
影响因子：
10.5
通讯作者：
Liu, ZG
中科院分区：
文献类型：
--
作者：
Hur, GM;Lewis, J;Liu, ZG
当细胞暴露于基因毒性应激时，转录因子NF-kappaB被激活。有人认为，DNA损伤会触发细胞质信号传导，导致IKK和NF-kappaB的激活，但IKK上游的信号传导成分尚未确定。在这里，我们报道了受体相互作用蛋白RIP是IKK上游组分，对于DNA损伤激活NF-kappaB至关重要。此外，我们的研究结果表明，DNA损伤引起的NF-kappaB激活不是由自分泌或TNF-R1信号通路介导的。在野生型成纤维细胞中，阿霉素、喜树碱和电离辐射等药物诱导的DNA损伤可诱导NF-kappaB活化。然而，我们发现DNA损伤不能激活RIP-/-成纤维细胞中的NF-kappaB。DNA损伤诱导IkappaBalpha降解在TNF-R1-/-、TRAF2-/-、TRAF5-/-和FADD-/-成纤维细胞中或在新生蛋白合成被阻断时是正常的。更重要的是，RIP-/-细胞中RIP表达的重建恢复了DNA损伤诱导的NF-kappaB激活。我们还发现RIP在DNA损伤时与IKK形成复合物。因此，我们的研究提供了一个可能的机制，启动细胞质信号，激活NF-kappaB，以响应DNA损伤。
The transcription factor NF-kappaB is activated when cells are exposed to genotoxic stress. It has been suggested that DNA damage will trigger a cytoplasmic signaling that leads to the activation of IKK and NF-kappaB, but the signaling components upstream of IKK have not yet been identified. Here we report that the receptor interacting protein, RIP, is the IKK upstream component, essential for the activation of NF-kappaB by DNA damage. Also, our findings suggest that this NF-kappaB activation by DNA damage is not mediated by autocrine or TNF-R1 signaling pathway. In wild-type fibroblasts, DNA damage induced by agents such as adriamycin, campthothecin, and ionizing radiation induces NF-kappaB activation. We found, however, that DNA damage failed to activate NF-kappaB in RIP-/- fibroblasts. The induction Of IkappaBalpha degradation by DNA damage was normal in TNF-R1-/-, TRAF2-/-, TRAF5-/- and FADD-/- fibroblasts or when de novo protein synthesis was blocked. More importantly, the reconstitution of RIP expression in RIP-/- cells restores DNA damage-induced NF-kappaB activation. We also found that RIP forms a complex with IKK in response to DNA damage. Therefore, our study provides a possible mechanism for the initiation of the cytoplasmic signaling to activate NF-kappaB in response to DNA damage.