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

Oncogene. 2002 Nov 7;21(51):7776-85. doi: 10.1038/sj.onc.1205981.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / metabolism
  • Ataxia Telangiectasia / pathology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cells, Cultured / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / physiology
  • Cycloheximide / pharmacology
  • DNA / drug effects
  • DNA / radiation effects
  • DNA Damage*
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Enzyme Inhibitors / pharmacology
  • Etoposide / toxicity
  • Fibroblasts / metabolism
  • Gamma Rays / adverse effects
  • Genes, Reporter
  • Genes, p53
  • Humans
  • Interferon Regulatory Factor-1
  • Melanoma / pathology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / biosynthesis*
  • Phosphoproteins / genetics
  • Phosphorylation
  • Poly I-C / pharmacology
  • Protein Processing, Post-Translational
  • Protein Synthesis Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Signal Transduction / physiology*
  • Transcription, Genetic
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology
  • Tumor Suppressor Protein p53 / biosynthesis*
  • Tumor Suppressor Proteins
  • Wortmannin

Substances

  • Androstadienes
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Etoposide
  • DNA
  • Cycloheximide
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Poly I-C
  • Wortmannin