Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway

Jessica Pamment, Eleanor Ramsay, Michael Kelleher, David Dornan, Kathryn L Ball

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)7776-85
Number of pages10
Issue number51
Publication statusPublished - 7 Nov 2002

Keywords / Materials (for Non-textual outputs)

  • Androstadienes
  • Ataxia Telangiectasia
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Cycloheximide
  • DNA
  • DNA Damage
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Etoposide
  • Fibroblasts
  • Gamma Rays
  • Genes, Reporter
  • Genes, p53
  • Humans
  • Interferon Regulatory Factor-1
  • Melanoma
  • Phosphatidylinositol 3-Kinases
  • Phosphoproteins
  • Phosphorylation
  • Poly I-C
  • Protein Processing, Post-Translational
  • Protein Synthesis Inhibitors
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins


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