C-JUN AND EGR-1 PARTICIPATE IN DNA-SYNTHESIS AND CELL-SURVIVAL IN RESPONSE TO IONIZING-RADIATION EXPOSURE

Exposure of mammalian cells to ionizing radiation results in the induc tion of the immediate early genes, c-jun and Egr-1, which encode trans cription factors implicated in cell growth as well as the cellular res ponse to oxidative stress, We studied the role of these immediate earl y genes in cell cycle kinetics and cell survival following x-irradiati on of clones containing inducible dominant negatives to c-jun and Egr- 1, The dominant negative constructs to c-jun (Delta 9) and Egr-1 (WT/E gr) prevented x-ray induction of transcription through the AP-1 and Eg r binding sites, respectively. Twenty percent of confluent, serum-depr ived SQ20B human tumor cells, normal fibroblasts, and fibroblasts from patients with ataxia telangiectasia entered S phase within 5 h of irr adiation, Clones containing inducible Delta 9 and WT/Egr dominant nega tive constructs demonstrated attenuation of the percentage of cells ex iting G(1) phase and reduced survival following irradiation, These dat a indicate that the dominant negatives to the stress-inducible immedia te early genes Egr-1 and c-jun prevent the onset of S phase and reduce the survival of human cells exposed to ionizing radiation.