Piret B, Schoonbroodt S, Piette J
Laboratory of Fundamental Virology and Immunology, University of Liège, CHU, Belgium.
Oncogene. 1999 Apr 1;18(13):2261-71. doi: 10.1038/sj.onc.1202541.
Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.
缺乏完整ATM基因的细胞对电离辐射高度敏感，并且在细胞周期偶联的检查点中表现出多种缺陷。DNA损伤通常通过激活p53等方式触发细胞周期停滞。另一个DNA损伤反应因子是核因子κB（NF-κB）。它可被包括氧化应激在内的各种应激情况以及拓扑异构酶毒物等DNA损伤化合物激活。我们发现，共济失调毛细血管扩张症患者的细胞在用拓扑异构酶I毒物喜树碱处理后，NF-κB激活存在缺陷。与正常细胞中观察到的情况相比，在共济失调毛细血管扩张症（AT）细胞中，这种激活会缩短或受到抑制。在AT细胞中异位表达ATM蛋白会增加对喜树碱反应时NF-κB的激活。不表达DNA-PK催化亚基的MO59J胶质母细胞瘤细胞对喜树碱反应正常。这些结果支持了以下假设：NF-κB是一种DNA损伤反应转录因子，其由DNA损伤激活的途径与导致p53激活的途径共享一些成分。
