کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1910134 | 1046754 | 2009 | 8 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Coactivation of ATM/ERK/NF-κB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes Coactivation of ATM/ERK/NF-κB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes](/preview/png/1910134.png)
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.
Journal: Free Radical Biology and Medicine - Volume 46, Issue 11, 1 June 2009, Pages 1543–1550