title: Coactivation of ATM/ERK/NF-kappaB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes.
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-kappaB upon exposure to ionizing radiation. This study provides evidence of the cooperative functions of ATM, ERK, and NF-kappaB 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-kappaB luciferase activity at 24 h post-LDR. However, NF-kappaB reporter gene transactivation without a significant enhancement of p65 or p50 protein level suggests that NF-kappaB is activated as a rapid protein response via ATM without involving the transcriptional activation of NF-kappaB subunit genes. A direct interaction between ATM and NF-kappaB 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-kappaB 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-kappaB pathways in LDR-treated human skin keratinocytes, which is absent from mutant IkappaB cells (HK18/mIkappaB), which fail to express NF-kappaB activity.
authors.affiliation: Graduate Program of Radiation and Cancer Biology, Purdue University School of Health Sciences, West Lafayette, IN 47907,USA.
authors.forename: Kazi Mokim
authors.initials: KM
authors.lastname: Ahmed
authors.forename: Danupon
authors.initials: D
authors.lastname: Nantajit
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li