Loss of PIDD limits NF-κB activation and cytokine production but not cell survival or transformation after DNA damage
Loss of PIDD limits NF-κB activation and cytokine production but not cell survival or transformation after DNA damage
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DOI：
10.1038/cdd.2012.152
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发表时间：
2013-04-01
影响因子：
12.4
通讯作者：
Villunger, A.
中科院分区：
文献类型：
--
作者：
Bock, F. J.;Krumschnabel, G.;Villunger, A.
DNA损伤时NF-kappa B （B细胞中kappa轻链基因增强子的核因子）的激活被认为有助于基因损伤的修复，增加细胞存活和细胞因子的释放。调控这一细胞质事件的分子机制涉及核DNA损伤反应机制的核心成分，包括atm -激酶（共济失调毛细血管扩张突变激酶）和PARP-1（聚（adp -核糖）聚合酶1）。然而，在这种情况下，nf - κ B活化缺陷的生理后果仍未得到充分研究。在这里，我们报道了“带有死亡结构域的p53诱导蛋白”PIDD的作用，PIDD和PARP-1在这一过程中出现速率限制。尽管NF-kappa B激活受损，DNA损伤不会增加细胞死亡或降低各种缺乏PIDD的细胞类型的克隆存活，如小鼠胚胎成纤维细胞或造血系统的干细胞和祖细胞。此外，c-照射（IR）诱导的淋巴瘤发生不受PIDD或PARP-1缺乏的影响，这表明DNA损伤触发的nf - κ B信号的丢失不会影响IR驱动的肿瘤发生。然而，在急性IR损伤后，这两种基因的缺失都会影响细胞因子的释放。因此，我们认为原代细胞DNA损伤后NF-kappa B最显著的功能与细胞因子的释放有关，从而导致无菌炎症。细胞死亡与分化（2013）20,546-557；doi: 10.1038 / cdd.2012.152;2012年12月14日在线发布
Activation of NF-kappa B (nuclear factor of kappa light chain gene enhancer in B cells) in response to DNA damage is considered to contribute to repair of genetic lesions, increased cell survival and cytokine release. The molecular mechanisms orchestrating this cytoplasmic event involve core components of the nuclear DNA damage response machinery, including ATM-kinase (ataxia telangiectasia mutated kinase) and PARP-1 (poly (ADP-ribose) polymerase 1). The physiological consequences of defective NF-kappa B activation in this context, however, remain poorly investigated. Here we report on the role of the 'p53-induced protein with a death domain', PIDD, which appears rate limiting in this process, as is PARP-1. Despite impaired NF-kappa B activation, DNA damage did not increase cell death or reduce clonal survival of various cell types lacking PIDD, such as mouse embryonic fibroblasts or stem and progenitor cells of the hematopoietic system. Furthermore, lymphomagenesis induced by c-irradiation (IR) was unaffected by deficiency for PIDD or PARP-1, indicating that loss of DNA damage-triggered NF-kappa B signalling does not affect IR-driven tumorigenesis. However, loss of either gene compromised cytokine release after acute IR injury. Hence, we propose that NF-kappa B's most notable function after DNA damage in primary cells is related to the release of cytokines, thereby contributing to sterile inflammation. Cell Death and Differentiation (2013) 20, 546-557; doi:10.1038/cdd.2012.152; published online 14 December 2012