Induction of apoptosis by adenovirus-mediated manganese superoxide dismutase overexpression in SV-40-transformed human fibroblasts.
Although mitochondrial reactive oxygen species (ROS) have been implicated both as an initiator and as an effector of apoptosis, the exact role of mitochondrial ROS has been difficult to establish due to the lack of an appropriate experimental system where ROS could be specifically generated from mitochondria and subsequent effects on cells analyzed. In this study, a manganese superoxide dismutase (MnSOD) activity-mediated apoptosis model was established and characterized. It was shown that despite early increases in the steady-state levels of ROS upon MnSOD overexpression, cellular oxidative damage was decreased significantly at later time points. Alterations in levels of peroxiredoxin (Prxn1) protein preceded the onset of apoptosis after MnSOD overexpression. A time course study demonstrated that increases in MnSOD activity prior to the onset of apoptosis correlated with alterations in the levels of nitration of tyrosine residue(s) of MnSOD protein. A direct correlation between MnSOD activity and the degree of apoptosis was demonstrated using a mutant MnSOD with decreased activity. The current study supports a causative role of mitochondrial ROS leading to the onset of apoptosis. The MnSOD activity-mediated apoptosis model described here could be further utilized to study mitochondrial apoptotic pathways.
Kim
Aekyong
A
Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
Oberley
Larry W
LW
Oberley
Terry D
TD
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D015536:Down-Regulation; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation; D018384:Oxidative Stress; D010544:Peroxidases / Q000378:metabolism; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism*; D013539:Simian virus 40 / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D014443:Tyrosine; D010544:Peroxidases; D054464:Peroxiredoxins; D013482:Superoxide Dismutase