The ATM Protein Is Required for Sustained Activation of NF-kappaB Following DNA Damage

Oncogene. 1999 Apr 1;18(13):2261-71. doi: 10.1038/sj.onc.1202541.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age Factors
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / pathology
  • Ataxia Telangiectasia Mutated Proteins
  • Brain Neoplasms / pathology
  • Camptothecin / pharmacology*
  • Cell Cycle Proteins
  • Cells, Cultured
  • Child
  • Child, Preschool
  • DNA Damage*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Enzyme Inhibitors / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects*
  • Glioblastoma / pathology
  • Humans
  • I-kappa B Proteins*
  • Leupeptins / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / physiology*
  • Nuclear Proteins
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Protease Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / physiology*
  • Radiation Tolerance / genetics
  • Recombinant Fusion Proteins / physiology
  • Topoisomerase I Inhibitors
  • Transcription, Genetic
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Protein p53 / physiology
  • Tumor Suppressor Proteins

Substances

  • Antineoplastic Agents, Phytogenic
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Leupeptins
  • NF-kappa B
  • NFKBIA protein, human
  • Nuclear Proteins
  • Protease Inhibitors
  • Proteins
  • Recombinant Fusion Proteins
  • Topoisomerase I Inhibitors
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • acetylleucyl-leucyl-norleucinal
  • NF-KappaB Inhibitor alpha
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • Phosphoric Monoester Hydrolases
  • Camptothecin