Mammalian cells exposed with low dose ionizing radiation (LDIR; ≤10 cGy) show a significant advantage in surviving subsequent radiation insults. The mechanism governing the LDIR-induced adaptive radioresistance remains elusive. The present study reveals that LDIR-treated human keratinocytes HK18 increase cell survival with the activation of DNA-damage sensor ATM and transcription factor NF-κB. Inhibition of either ATM or NF-κB eliminates the adaptive radioresistance and LDIR-induced expression of chaperon protein 14-3-3ζ and cyclin D1. 14-3-3ζ and cyclin D1 form a complex in unstressed cells and high dose irradiation (5-Gy γ-ray) maintains the 14-3-3ζ/cyclin D1 complex formation that causes nuclear translocation of cyclin D1. In contrast, LDIR unexpectedly reduces the 14-3-3ζ/cyclin D1 complex with increased cytoplasmic cyclin D1 and no cyclin D1 nuclear translocation, indicating a different regulation of 14-3-3ζ/cyclin D1 complex in high versus low dose irradiation. Cyclin D1 interacts with both mitochondrial anti-apoptotic Bcl-2 and pro-apoptotic Bax. However, LDIR enhances cyclin D1/Bax complex formation and mitochondrial membrane potential (Δψm). SiRNA-mediated cyclin D1 inhibition blocks cyclin D1/Bax complex and reduces Δψm. Taken together, our data provide the evidence that 14-3-3ζ/cyclin D1 up-regulated by ATM/NF-κB pathway interacts and inhibits Bax activity to enhance Δψm in LDIR-induced adaptive radioresistance.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA