Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase |
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Authors: | Dittmann Klaus Mayer Claus Fehrenbacher Birgit Schaller Martin Raju Uma Milas Luka Chen David J Kehlbach Rainer Rodemann H Peter |
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Institution: | Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, Germany. dittmann@uni-tuebingen.de |
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Abstract: | Ionizing radiation, but not stimulation with epidermal growth factor (EGF), triggers EGF receptor (EGFR) import into the nucleus in a probably karyopherin alpha-linked manner. An increase in nuclear EGFR is also observed after treatment with H2O2, heat, or cisplatin. During, this process, the proteins Ku70/80 and the protein phosphatase 1 are transported into the nucleus. As a consequence, an increase in the nuclear kinase activity of DNA-dependent kinase (DNA-PK) and increased formation of the DNA end-binding protein complexes containing DNA-PK, essential for repair of DNA-strand breaks, occurred. Blockade of EGFR import by the anti-EGFR monoclonal antibody C225 abolished EGFR import into the nucleus and radiation-induced activation of DNA-PK, inhibited DNA repair, and increased radiosensitivity of treated cells. Our data implicate a novel function of the EGFR during DNA repair processes. |
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