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DNA repair, 2008-10, Vol.7 (10), p.1746-1756
2008
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Details
- Autor(en) / Beteiligte
- Titel
- PI3K-Akt signaling regulates basal, but MAP-kinase signaling regulates radiation-induced XRCC1 expression in human tumor cells in vitro
- Ist Teil von
- DNA repair, 2008-10, Vol.7 (10), p.1746-1756
- Ort / Verlag
- Amsterdam: Elsevier B.V
- Erscheinungsjahr
- 2008
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- As demonstrated recently, ionizing radiation (IR) can mediate phosphorylation of DNA-PKcs in human tumor cells through stimulation of the PI3K/Akt pathway. It is also known that DNA-PKcs directly interacts the X-ray repair cross-complementing group 1 protein (XRCC1) involved in base excision repair (BER). Therefore, in the present study we investigated the role of PI3K/Akt activity and DNA-PKcs on XRCC1 expression/stabilization. In contrast to the DNA-PKcs-deficient glioblastoma cell line MO59J, the DNA-PKcs-proficient counterpart MO59K as well as human lung adenocarcinoma A549 cells presented a high basal level of XRCC1 expression. Radiation doses of 3–12 Gy did not stimulate a further enhanced expression of XRCC1 in DNA-PKcs-proficient cells (MO59K and A549) within 180 min post-irradiation. However, a marked induction of XRCC1 expression was apparent in DNA-PKcs-deficient MO59J cells. Targeting of DNA-PKcs as well as PI3K/Akt pathway by specific kinase inhibitors and/or siRNA reduced basal XRCC1 expression in un-irradiated DNA-PKcs-proficient cells to the level observed in DNA-PKcs-deficient cells. Reduction of basal expression of XRCC1 by XRCC1-siRNA, AKT-siRNA as well as DNA-PKcs inhibitor facilitated IR-induced XRCC1 expression. XRCC1 expression induced by irradiation, however, was independent of PI3K/Akt signaling, but dependent of MAPK-ERK1/2. By immuno-precipitation experiments and confocal microscopy a complex formation of XRCC1 and DNA-PKcs was shown. Applying γ-H2AX foci analysis it was shown that basal expression of XRCC1 is important for the repair of IR-induced DNA-double strand breaks (DNA-DSBs). These data indicate that IR-induced XRCC1 expression is dependent on the expression level of DNA-PKcs and basal activity status of PI3K/Akt signaling. Likewise, potential of IR-induced XRCC1 expression depends on its basal expression level.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1568-7864eISSN: 1568-7856DOI: 10.1016/j.dnarep.2008.06.017Titel-ID: cdi_proquest_miscellaneous_69576686
- Format
- –
- Schlagworte
- Bacteriology, Biological and medical sciences, Cell Line, Tumor, DNA Breaks, Double-Stranded - drug effects, DNA Breaks, Double-Stranded - radiation effects, DNA Repair - drug effects, DNA Repair - radiation effects, DNA-Activated Protein Kinase - deficiency, DNA-Activated Protein Kinase - metabolism, DNA-Binding Proteins - metabolism, DNA-PKcs, Extracellular Signal-Regulated MAP Kinases - metabolism, Fundamental and applied biological sciences. Psychology, Growth, nutrition, cell differenciation, Humans, Ionizing radiation, MAP Kinase Signaling System - drug effects, MAP Kinase Signaling System - radiation effects, Microbiology, Mitogen-Activated Protein Kinases - metabolism, Molecular and cellular biology, Molecular genetics, Mutagenesis. Repair, Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Phosphatidylinositol 3-Kinases - metabolism, PI3K/Akt, Protein Binding - drug effects, Protein Binding - radiation effects, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins c-akt - antagonists & inhibitors, Proto-Oncogene Proteins c-akt - metabolism, Radiation, Ionizing, Receptor, Epidermal Growth Factor - metabolism, Recombinant Fusion Proteins - metabolism, Recombination, Genetic - drug effects, Recombination, Genetic - radiation effects, X-ray Repair Cross Complementing Protein 1, XRCC1