Rapid radiation-induction of atm protein levels in situ

Ataxia-telangiectasia (A-T) is characterised by hypersensitivity to ionisin g radiation (IR), immunodeficiency, neurodegeneration and predisposition to malignancy. Mutations in the A-T gene (ATM) often result in reduced levels of ATM protein and/or compromise ATM function. IR induced DNA damage is kn own to rapidly upregulate ATM kinase activity/phosphorylation events in the control of cell cycle progression and other processes. Variable expression of ATM levels in different tissues and its upregulation during cellular pr oliferation indicate that the level of ATM is also regulated by mechanisms other than gene mutation. Here, we report on the IR induction of ATM protei n levels within a number of different cell types and tissues. Induction had begun within 5 min and peaked within 2 h of exposure to 2 Gy of IR, sugges ting a rapid post-translational mechanism. Low basal levels of ATM protein were more responsive to IR induction compared to high ATM levels in the sam e cell type. Irradiation of fresh skin biopsies led to an average three-fol d increase in ATM levels while immunohistochemical analyses indicated "low expressing" cells within the basal layer with ten-fold increases in ATM lev els following IR. ATM "high expressing" lymphoblastoid cell lines (LCLs) wh ich were initially resistant to the radiation-induction of ATM levels also became responsive to IR after ATM antisense expression was used to reduce t he basal levels of the protein. These results demonstrate that ATM is prese nt in variable amounts in different tissue/cell types and where basal level s are low ATM levels can be rapidly induced by IR to saturable levels speci fic for different cell types. ATM radiation-induction is a sensitive and ra pid radioprotective response that complements the IR mediated activation of ATM.