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

The signaling pathway through which ionizing radiation induces NF-kappa B activation is not fully understood. I kappa B-alpha, an inhibitory protein of NF-kappa B mediates the activation of NF-kappa B 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-alpha. I kappa B-alpha degradation is rapid in response to TNF-alpha 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 I kappa B-alpha. Furthermore, phosphorylation of I kappa B-alpha. 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-kappa B and a molecular basis for the sensitivity of AT patients to oxidative stresses.