A NOVEL IONIZING RADIATION-INDUCED SIGNALING PATHWAY THAT ACTIVATES THE TRANSCRIPTION FACTOR NF-KAPPA-B

The signaling pathway through which ionizing radiation induces NF-kapp a 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 respon se to various stimuli, including cytokines, mitogens, oxidants and oth er stresses. We have now identified an ionizing radiation-induced sign aling pathway that is independent of TNF-alpha. I kappa B-alpha degrad ation is rapid in response to TNF-alpha induction, but it is absent in response to ionizing radiation exposure in cells from individuals wit h ataxia-telangiectasia (AT). Overexpression of wild-type ATM, the pro duct of the gene defective in AT patients, restores radiation-induced degradation of I kappa B-alpha. Furthermore, phosphorylation of I kapp a B-alpha. by immunoprecipitated ATM kinase is increased in control fi broblasts and transfected AT cells following ionizing radiation exposu re. These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-kappa B and a molecular basis f or the sensitivity of AT patients to oxidative stresses.