Abstract
The mechanism by which genotoxic stress induces IRF-1 and the signalling components upstream of this anti-oncogenic transcription factor during the response to DNA damage are not known. We demonstrate that IRF-1 and the tumour suppressor protein p53 are coordinately up-regulated during the response to DNA damage in an ATM-dependent manner. Induction of IRF-1 protein by either ionizing radiation (IR) or etoposide occurs through a concerted mechanism involving increased IRF-1 expression/synthesis and an increase in the half-life of the IRF-1 protein. A striking defect in the induction of both IRF-1 mRNA and IRF-1 protein was observed in ATM deficient cells. Although ATM deficient cells failed to increase IRF-1 in response to genotoxic stress, the induction of IRF-1 in response to viral mimetics remained intact. Re-expression of the ATM kinase in AT cells restored the DNA damage inducibility of IRF-1, whilst the PI-3 kinase inhibitor wortmannin inhibited IRF-1 induction by DNA damage in ATM-positive cells. The data highlight a role for the ATM kinase in orchestrating the coordinated induction and transcriptional cooperation of IRF-1 and p53 to regulate p21 expression. Thus, IRF-1 is controlled by two distinct signalling pathways; a JAK/STAT-signalling pathway in viral infected cells and an ATM-signalling pathway in DNA damaged cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Ataxia Telangiectasia / genetics
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Ataxia Telangiectasia / metabolism
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Ataxia Telangiectasia / pathology
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins
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Cells, Cultured / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / physiology
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Cycloheximide / pharmacology
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DNA / drug effects
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DNA / radiation effects
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DNA Damage*
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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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Etoposide / toxicity
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Fibroblasts / metabolism
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Gamma Rays / adverse effects
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Genes, Reporter
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Genes, p53
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Humans
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Interferon Regulatory Factor-1
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Melanoma / pathology
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins / biosynthesis*
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Phosphoproteins / genetics
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Phosphorylation
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Poly I-C / pharmacology
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Protein Synthesis Inhibitors / pharmacology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Signal Transduction / physiology*
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Transcription, Genetic
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / pathology
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Tumor Suppressor Protein p53 / biosynthesis*
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Tumor Suppressor Proteins
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Wortmannin
Substances
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Androstadienes
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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Enzyme Inhibitors
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IRF1 protein, human
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Interferon Regulatory Factor-1
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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Protein Synthesis Inhibitors
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RNA, Messenger
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Etoposide
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DNA
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Cycloheximide
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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Poly I-C
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Wortmannin