The ATM protein is required for sustained activation of NF-kappaB following DNA damage.
Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.
D000293:Adolescent; D000367:Age Factors; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D001932:Brain Neoplasms / Q000473:pathology; D002166:Camptothecin / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins; D007976:Leupeptins / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D009687:Nuclear Proteins; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011836:Radiation Tolerance / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D059004:Topoisomerase I Inhibitors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins