Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway.
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.
Pamment
Jessica
J
Cancer Research UK Laboratories, University of Dundee Medical School, Dundee DD1 9SY, UK.
Ramsay
Eleanor
E
Kelleher
Michael
M
Dornan
David
D
Ball
Kathryn L
KL
D000730:Androstadienes / Q000494:pharmacology; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000633:toxicity; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays / Q000009:adverse effects; D017930:Genes, Reporter; D016158:Genes, p53; D006801:Humans; D050856:Interferon Regulatory Factor-1; D008545:Melanoma / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin
D000730:Androstadienes; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003513:Cycloheximide; D004247:DNA; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005047:Etoposide; D050856:Interferon Regulatory Factor-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011070:Poly I-C; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin; C493956:CDKN1A protein, human; C494257:IRF1 protein, human; C576324:ATM protein, human