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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / physiology*
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Active Transport, Cell Nucleus / radiation effects*
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Animals
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Antibodies, Monoclonal / metabolism
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Cell Fractionation
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Cell Line, Tumor
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Cell Nucleus / chemistry
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Cell Nucleus / metabolism
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Cell Survival
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DNA Repair
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DNA-Activated Protein Kinase
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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ErbB Receptors / metabolism*
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Humans
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Macromolecular Substances
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Mice
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Nuclear Proteins
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Radiation, Ionizing
Substances
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Antibodies, Monoclonal
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DNA-Binding Proteins
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Macromolecular Substances
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Nuclear Proteins
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ErbB Receptors
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases