Co-activation of ERK, NF-κB, and GADD45β in response to ionizing radiation

NF-kappa B has been well documented to play a critical role in signaling cell stress reactions. The extracellular signal-regulated kinase (ERK) regulates cell proliferation and survival. GADD45 beta is a primary cell cycle element responsive to NF-kappa B activation in anti-apoptotic responses. The present study provides evidence demonstrating that NK-kappa B, ERK and GADD45 beta are co-activated by ionizing radiation (IR) in a pattern of mutually dependence to increase cell survival. Stress conditions generated in human breast cancer MCF-7 cells by the administration of a single exposure of 5 Gy IR resulted in the activation of ERK but not p38 or JNK, along with an enhancement of the NF-kappa B transactivation and GADD45 beta expression. Overexpression of dominant negative Erk (DN-Erk) or pre-exposure to ERK inhibitor PD98059 inhibited NF-kappa B. Transfection of dominant negative mutant I kappa B that blocks NF-kappa B nuclear translocation, inhibited ERK activity and GADD45 beta expression and increased cell radiosensitivity. Interaction of p65 and ERK was visualized in living MCF-7 cells by bimolecular fluorescence complementation analysis. Antisense inhibition of GADD45 beta strikingly blocked IR-induced NF-kappa B and ERK but not p38 and JNK. Overall, these results demonstrate a possibility that NF-kappa B, ERK, and GADD45 beta are able to coordinate in a loop-like signaling network to defend cells against the cytotoxicity induced by ionizing radiation.