A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB

Abstract

The signaling pathway through which ionizing radiation induces NF-κB activation is not fully understood. IκB-α, an inhibitory protein of NF-κB mediates the activation of NF-κB in response to various stimuli, including cytokines, mitogens, oxidants and other stresses. We have now identified an ionizing radiation-induced signaling pathway that is independent of TNF-α. IκB-α degradation is rapid in response to TNF-α induction, but it is absent in response to ionizing radiation exposure in cells from individuals with ataxia-telangiectasia (AT). Overexpression of wild-type ATM, the product of the gene defective in AT patients, restores radiation-induced degradation of IκB-α. Furthermore, phosphorylation of IκB-α by immunoprecipitated ATM kinase is increased in control fibroblasts and transfected AT cells following ionizing radiation exposure. These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-κB and a molecular basis for the sensitivity of AT patients to oxidative stresses.