Coactivation of ATM/ERK/NF-κB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes

Kazi Mokim Ahmed, Danupon Nantajit, Ming Fan, Jeffrey S. Murley, David J. Grdina, Jian-Jian Li

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1543-1550
Number of pages8
JournalFree Radical Biology and Medicine
Volume46
Issue number11
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Keywords

  • ATM
  • ERK
  • Free radicals
  • Keratinocytes
  • Low-dose radiation
  • NF-κB

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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