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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Age Factors
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Antineoplastic Agents, Phytogenic / pharmacology*
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Ataxia Telangiectasia / genetics*
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Ataxia Telangiectasia / pathology
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Ataxia Telangiectasia Mutated Proteins
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Brain Neoplasms / pathology
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Camptothecin / pharmacology*
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Cell Cycle Proteins
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Cells, Cultured
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Child
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Child, Preschool
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DNA Damage*
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DNA-Activated Protein Kinase
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Enzyme Inhibitors / pharmacology*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Regulation / drug effects*
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Glioblastoma / pathology
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Humans
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I-kappa B Proteins*
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Leupeptins / pharmacology
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NF-KappaB Inhibitor alpha
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NF-kappa B / physiology*
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Nuclear Proteins
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Protease Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / physiology*
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Radiation Tolerance / genetics
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Recombinant Fusion Proteins / physiology
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Topoisomerase I Inhibitors
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Transcription, Genetic
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Suppressor Protein p53 / physiology
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Tumor Suppressor Proteins
Substances
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Antineoplastic Agents, Phytogenic
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Cell Cycle Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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I-kappa B Proteins
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Leupeptins
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NF-kappa B
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NFKBIA protein, human
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Nuclear Proteins
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Protease Inhibitors
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Proteins
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Recombinant Fusion Proteins
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Topoisomerase I Inhibitors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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acetylleucyl-leucyl-norleucinal
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NF-KappaB Inhibitor alpha
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases
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Phosphoric Monoester Hydrolases
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Camptothecin