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

Oncogene volume 21, pages 7776–7785 (2002)Cite this article

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.

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Acknowledgements

M Kelleher, D Dornan and J Pamment hold studentships from Cancer Research UK, BBSRC and MRC, respectively. KL Ball is a Senior Cancer Research Fellow for Cancer Research UK. HCT116 p53−/− and AT22IJE-T derived cells were kind gifts from B Vogelstein and Y Shiloh, respectively.

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  1. Cancer Research UK Laboratories, University of Dundee Medical School, Dundee, DD1 9SY, UK

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

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  1. Jessica Pamment
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  2. Eleanor Ramsay
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Correspondence to Kathryn L Ball.

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Pamment, J., Ramsay, E., Kelleher, M. et al. Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway. Oncogene 21, 7776–7785 (2002). https://doi.org/10.1038/sj.onc.1205981

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