EGF sensitizes cells to ionizing radiation by down-regulating protein mutated in ataxia-telangiectasia

Gueven, Nuri, Keatings, Katherine E., Chen, Philip, Fukao, Toshiyuki, Khanna, Kum Kum, Watters, Dianne, Rodemann, Peter H. and Lavin, Martin F. (2001) EGF sensitizes cells to ionizing radiation by down-regulating protein mutated in ataxia-telangiectasia. The Journal of Biological Chemistry, 276 12: 8884-8891. doi:10.1074/jbc.M006190200

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Author Gueven, Nuri
Keatings, Katherine E.
Chen, Philip
Fukao, Toshiyuki
Khanna, Kum Kum
Watters, Dianne
Rodemann, Peter H.
Lavin, Martin F.
Title EGF sensitizes cells to ionizing radiation by down-regulating protein mutated in ataxia-telangiectasia
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2001-03-23
Sub-type Article (original research)
DOI 10.1074/jbc.M006190200
Open Access Status File (Publisher version)
Volume 276
Issue 12
Start page 8884
End page 8891
Total pages 8
Editor Herbert Tabor
Place of publication Bethesda, MD USA
Publisher The American Society for Biochemistry and Molecular Biology .
Collection year 2001
Language eng
Subject C1
270106 Cell Development (incl. Cell Division and Apoptosis)
730108 Cancer and related disorders
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 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.
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 01:48:08 EST