期刊
CELL RESEARCH
卷 25, 期 2, 页码 225-236出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2015.8
关键词
EGFR; ATM; tyrosine phosphorylation; DNA damage response
类别
资金
- National Institutes of Health [CA109311, CA099031, CCSG CA16672, AG045545-01]
- University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW103-TD-B-111-03]
- Program for Stem Cell and Regenerative Medicine Frontier Research [NSC102-2321-B-039-001]
- International Research-Intensive Centers of Excellence [NSC103-2911-I-002-303]
- Center for Biological Pathways
- Competitive Medical Research Fund (CMRF) of the University of Pittsburgh Medical Center
Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.
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