Coactivation of ATM/ERK/NF-kappaB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes.
Coactivation of ATM/ERK/NF-kappaB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes.
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DOI：
10.1016/j.freeradbiomed.2009.03.012
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发表时间：
2009-06-01
影响因子：
7.4
通讯作者：
Li JJ
中科院分区：
文献类型：
--
作者：
Ahmed KM;Nantajit D;Fan M;Murley JS;Grdina DJ;Li JJ
阐明低剂量辐射（LDR）介导的放射适应性反应的分子机制对于发明潜在的治疗方法以改善放射治疗中的正常组织保护至关重要。ATM是一种DNA损伤传感器，已知在电离辐射暴露时激活应激敏感性转录因子NF-κB。本研究提供了ATM、ERK和NF-κB在LDR治疗（10 cGy X射线）后通过放射适应性反应诱导生存优势中的协同作用的证据。通过使用p53抑制的人皮肤角质形成细胞，我们发现ATM，MEK和ERK（但不是JNK或p38）的磷酸化增强沿着NF-κB荧光素酶活性在LDR后24小时增加两倍。然而，NF-κB报告基因的反式激活没有显著增强p65或p50蛋白水平，表明NF-κB作为快速蛋白应答通过ATM被激活，而不涉及NF-κB亚基基因的转录激活。在静息细胞中检测到ATM和NF-κB p65之间的直接相互作用，并且这种相互作用随着LDR处理而显著增加。用咖啡因、KU-55933或siRNA抑制ATM或抑制MEK/ERK通路可阻断LDR诱导的NF-κB活化并消除LDR诱导的存活优势。总之，这些结果表明，在LDR处理的人皮肤角质形成细胞中，存在一个涉及ATM、MEK/ERK和NF-κB通路共激活的p53非依赖性促生存网络，而突变型IκB细胞（HK 18/mIκB）中不存在这种网络，突变型IκB细胞不能表达NF-κB活性。
Elucidating the molecular mechanism of the low-dose radiation (LDR)-mediated radioadaptive response is crucial for inventing potential therapeutic approaches to improving normal tissue protection in radiation therapy. ATM, a DNA-damage sensor, is known to activate the stress-sensitive transcription factor NF-κB upon exposure to ionizing radiation. This study provides evidence of the cooperative functions of ATM, ERK, and NF-κB in inducing a survival advantage through a radioadaptive response as a result of LDR treatment (10 cGy X-rays). By using p53-inhibited human skin keratinocytes, we show that phosphorylation of ATM, MEK, and ERK (but not JNK or p38) is enhanced along with a twofold increase in NF-κB luciferase activity at 24 h post-LDR. However, NF-κB reporter gene transactivation without a significant enhancement of p65 or p50 protein level suggests that NF-κB is activated as a rapid protein response via ATM without involving the transcriptional activation of NF-κB subunit genes. A direct interaction between ATM and NF-κB p65 is detected in the resting cells and this interaction is significantly increased with LDR treatment. Inhibition of ATM with caffeine, KU-55933, or siRNA or inhibition of the MEK/ERK pathway can block the LDR-induced NF-κB activation and eliminate the LDR-induced survival advantage. Altogether, these results suggest a p53-independent prosurvival network involving the coactivation of the ATM, MEK/ERK, and NF-κB pathways in LDR-treated human skin keratinocytes, which is absent from mutant IκB cells (HK18/mIκB), which fail to express NF-κB activity.
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