Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts.
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.
Sagan
Daniel
D
Institute of Radiobiology, GSF-National Research Center for Environment and Health, 85758 Neuherberg, Germany. daniel.sagan@gsf.de
Mörtl
Simone
S
Müller
Irene
I
Eckardt-Schupp
Friederike
F
Eichholtz-Wirth
Hedda
H
D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D053181:Caspase 8 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005720:Gamma Rays; D006801:Humans; D008214:Lymphocytes / Q000502:physiology / Q000528:radiation effects; D049932:Nijmegen Breakage Syndrome; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053181:Caspase 8