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  • EGF sensitises cells to ionising radiation by downregulating ATM

    Author(s)
    Gueven, Nuri
    Keating, Katherine E
    Chen, Phillip
    Fukao, Toshiyuki
    Khanna, Kum Kum
    Watters, Dianne Josephine
    Rodemann, Peter H
    Lavin, Martin F.
    Griffith University Author(s)
    Watters, Dianne J.
    Year published
    2001
    Metadata
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    Abstract
    Epidermal growth factor (EGF) has been reported to either sensitize or protect cells against ionizing radiation. We report here that EGF increases radiosensitivity in both human fibroblasts and lymphoblasts and downregulates both ATM (mutated in ataxia-telangiectasia (A-T)) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). No further radiosensitization was observed in A-T cells after pretreatment with EGF. The down-regulation of ATM occurs at the transcriptional level. Concomitant with the down-regulation of ATM, the DNA binding activity of the transcription factor Spl decreased. A causal relationship was ...
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    Epidermal growth factor (EGF) has been reported to either sensitize or protect cells against ionizing radiation. We report here that EGF increases radiosensitivity in both human fibroblasts and lymphoblasts and downregulates both ATM (mutated in ataxia-telangiectasia (A-T)) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). No further radiosensitization was observed in A-T cells after pretreatment with EGF. The down-regulation of ATM occurs at the transcriptional level. Concomitant with the down-regulation of ATM, the DNA binding activity of the transcription factor Spl decreased. A causal relationship was established between these:observations by demonstrating that upregulation of Spl DNA binding activity by granulocyte/ macrophage colony-stimulating factor rapidly reversed the EGF-induced decrease in ATM protein and restored radiosensitivity to normal levels. Failure to radiosensitize EGF-treated cells to the same extent as observed for A-T cells ban be explained by induction of ATM protein and kinase activity with time post-irradiation, Although ionizing radiation damage to DNA rapidly activates ATM kinase and cell cycle checkpoints, we have provided evidence for the first time that alteration in the amount of ATM protein occurs in response to both EGF and radiation exposure. Taken together these data support complex control of ATM function that has important repercussions for targeting ATM to improve radiotherapeutic benefit.
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    Journal Title
    Journal of Biological Chemistry
    Volume
    276
    Publisher URI
    http://www.jbc.org/content/276/12.toc
    Subject
    Chemical Sciences
    Biological Sciences
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/54913
    Collection
    • Journal articles

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