Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase.
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.
Dittmann
Klaus
K
Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, Germany. dittmann@uni-tuebingen.de
Mayer
Claus
C
Fehrenbacher
Birgit
B
Schaller
Martin
M
Raju
Uma
U
Milas
Luka
L
Chen
David J
DJ
Kehlbach
Rainer
R
Rodemann
H Peter
HP
D021581:Active Transport, Cell Nucleus / Q000502:physiology* / Q000528:radiation effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D009687:Nuclear Proteins; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D066246:ErbB Receptors; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases