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J. Biol. Chem., Vol. 276, Issue 12, 8884-8891, March 23, 2001
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From the 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 down-regulates 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 Sp1 decreased. A causal relationship was
established between these observations by demonstrating that
up-regulation of Sp1 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 can 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.
Epidermal Growth Factor Sensitizes Cells to Ionizing
Radiation by Down-regulating Protein Mutated in
Ataxia-Telangiectasia*
§,
,, and
Section for Radiobiology and Molecular
Environmental Research, Röntgenweg 11, 72076 Tübingen, Germany, the ¶ Queensland Cancer Fund
Research Laboratory, The Queensland Institute of Medical Research,
P. O. Royal Brisbane Hospital, Brisbane,
Queensland 4029, Australia, the Gifu University School of
Medicine, 40 Tsukasa-Machi, Gifu 500-8076, Japan, and the
** Department of Surgery, University of Queensland, P. O. Royal
Brisbane Hospital, Brisbane, Queensland 4029, Australia
*
This work was supported in part by the Australian National
Health and Medical Research Council, the Deutsche
Forschungsgemeinschaft Grant 488/1-1, and the A-T Children's
foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: the Queensland
Cancer Fund Research Laboratory, Queensland Institute of Medical Research, P. O. Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. Tel.: 61-7-33620341; Fax: 61-7-33620106; E-mail: martinL@qimr.edu.au.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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