title: Amplification of the gamma-irradiation-induced cell death pathway by reactive oxygen species in human U937 cells.
abstract: Given the critical involvement of reactive oxygen species (ROS) in cell death, their hierarchical status in the cell pathway has been analyzed by many investigators. However, it has been shown that ROS can act either upstream or downstream of various death mediators depending on experimental settings. To investigate whether the contrasting relationships may exist in a single model system, human U937 cells were irradiated with lethal doses of gamma-rays. This resulted in a promotion of mitochondrial ROS production, which was found to be induced via sequential actions of c-Jun N-terminal kinase (JNK), Bax, and caspase-3. Interestingly, the induced ROS, in turn, re-activated JNK, Bax, and caspase-3 in the same model system. Consistently, the blockade of Bax action by RNA interference or Bcl-2 overexpression abolished the activation of JNK induced after, but not before, the production of ROS. Bcl-2 overexpression also blocked the translocation of Bax from the cytosol to the mitochondria only after the induction of ROS. Functional analyses revealed that the initial ROS-independent activations of JNK, Bax, and caspase-3 are not sufficient for cell death, and thus, should be re-activated by ROS in order to kill the cells. These findings suggest that ROS do not simply mediate the lethal action of gamma-irradiation, but actually amplify it by forming a feedback loop between a downstream effector caspase and the upstream initiation signals leading to the activation of JNK. This role for ROS appears to allow Bcl-2 to block the signaling events, which are initially induced upstream.
authors.affiliation: Laboratory of Radiation Tumor Physiology, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Kim
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Yang
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Jin-Nyoung
authors.initials: JN
authors.lastname: Ho
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Lee
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects*; D005720:Gamma Rays; D019254:Genes, bcl-2; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3