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Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein

Oncogene volume 20, pages 4281–4290 (2001)Cite this article

Abstract

There is evidence that ATM plays a wider role in intracellular signalling in addition to DNA damage recognition and cell cycle control. In this report we show that activation of the EGF receptor is defective in ataxia-telangiectasia (A-T) cells and that sustained stimulation of cells with EGF downregulates ATM protein in control cells but not in A-T cells expressing mutant protein. Concomitant with the downregulation of ATM, DNA-binding activity of the transcription factor Sp1 decreased in controls after EGF treatment but increased from a lower basal level in A-T cells to that in untreated control cells. Mutation in two Sp1 consensus sequences in the ATM promoter reduced markedly the capacity of the promoter to support luciferase activity in a reporter assay. Overexpression of anti-sense ATM cDNA in control cells decreased the basal level of Sp1, which in turn was increased by subsequent treatment of cells with EGF, similar to that observed in A-T cells. On the other hand full-length ATM cDNA increased the basal level of Sp1 binding in A-T cells, and in response to EGF Sp1 binding decreased, confirming that this is an ATM-dependent process. Contrary to that observed in control cells there was no radiation-induced change in ATM protein in EGF-treated A-T cells and likewise no alteration in Sp1 binding activity. The results demonstrate that EGF-induced downregulation of ATM (mutant) protein in A-T cells is defective and this appears to be due to less efficient EGFR activation and abnormal Sp1 regulation.

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Acknowledgements

We wish to thank the Australian National Health and Medical Research Council, the Queensland Cancer Fund, the Deutsche Forschungsgemeinschaft (grant number 488/1–1) and the A-T Children's Foundation for support. Thanks to Aine Farrell for technical support and Ann Knight and Tracey Laing for typing the manuscript.

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Author notes

  1. Katherine E Keating and Nuri Gueven: KE Keating and N Gueven contributed equally to the work

Authors and Affiliations

  1. The Queensland Cancer Fund Research Laboratory, The Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Qld. 4029, Australia

    Katherine E Keating & Martin F Lavin

  2. Section for Radiobiology and Molecular Environmental Research, Röntgenweg 11, 72076, Tübingen, Germany

    Nuri Gueven & H Peter Rodemann

  3. The Department of Surgery, University of Queensland, PO Royal Brisbane Hospital, Brisbane, Qld. 4029, Australia

    Dianne Watters & Martin F Lavin

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Keating, K., Gueven, N., Watters, D. et al. Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein. Oncogene 20, 4281–4290 (2001). https://doi.org/10.1038/sj.onc.1204527

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