1. Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts
- Author
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Hedda Eichholtz-Wirth, Daniel Sagan, Friederike Eckardt-Schupp, Irene Müller, and Simone Mörtl
- Subjects
Cancer Research ,DNA damage ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,Cell Cycle Proteins ,Biology ,Caspase 8 ,Cell Line ,Phosphatidylinositol 3-Kinases ,medicine ,Humans ,Lymphocytes ,fas Receptor ,Radiosensitivity ,Nijmegen Breakage Syndrome ,Protein kinase B ,Pharmacology ,Lymphoblast ,Biochemistry (medical) ,Nuclear Proteins ,Cell Biology ,Fas receptor ,medicine.disease ,Cell biology ,Gamma Rays ,Tumor Suppressor Protein p53 ,Proto-Oncogene Proteins c-akt ,Nijmegen breakage syndrome - Abstract
The molecular causes for enhanced radiosensitivity of Nijmegen Breakage Syndrome cells are unclear, especially as repair of DNA damage is hardly impeded in these cells. We clearly demonstrate that radiation hypersensitivity is accompanied by enhanced gamma-radiation-induced apoptosis in NBS1 deficient lymphoblastoid cell lines. Differences in the apoptotic behavior of NBS1 (-/-) and NBS1 (+/-) cells are not due to an altered p53 stabilization or phosphorylation in NBS1 (-/-) cells. gamma-radiation-induced caspase-8 activity is increased and visualization of CD95 clustering by laser scanning microscopy shows a significant higher activation of the death receptor in NBS1 (-/-) cells. Further investigation of the molecular mechanisms reveals a role for reactive oxygen species-triggered activation of CD95. These results demonstrate that NBS1 suppresses the CD95 death receptor-dependent apoptotic pathway after gamma-irradiation and evidence is given that this is achieved by regulation of the PI3-K/AKT survival pathway.
- Published
- 2007
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