Glutathione Peroxidase-1 Protects from CD95-induced Apoptosis
Through the induction of apoptosis, CD95 plays a crucial role in the immune response and the elimination of cancer cells. Ligation of CD95 receptor activates a complex signaling network that appears to implicate the generation of reactive oxygen species (ROS). This study investigated the place of RO...
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Published in | The Journal of biological chemistry Vol. 277; no. 45; pp. 42867 - 42874 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
08.11.2002
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Subjects | |
Online Access | Get full text |
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Summary: | Through the induction of apoptosis, CD95 plays a crucial role in the immune response and the elimination of cancer cells.
Ligation of CD95 receptor activates a complex signaling network that appears to implicate the generation of reactive oxygen
species (ROS). This study investigated the place of ROS production in CD95-mediated apoptosis and the role of the antioxidant
enzyme glutathione peroxidase-1 (GPx1). Anti-CD95 antibodies triggered an early generation of ROS in human breast cancer T47D
cells that was blocked by overexpression of GPx1 and inhibition of initiator caspase activation. Enforced expression of GPx1
also resulted in inhibition of CD95-induced effector caspase activation, DNA fragmentation, and apoptotic cell death. Resistance
to CD95-mediated apoptosis was not due to an increased expression of anti-apoptotic molecules and could be reversed by glutathione-depleting
agents. In addition, whereas the anti-apoptotic protein Bcl-xL prevented CD95-induced apoptosis in MCF-7 cells, it did not
inhibit the early ROS production. Moreover, Bcl-xL but not GPx1 overexpression could suppress the staurosporine-induced late
generation of ROS and subsequent cell death. Altogether, these findings suggest that GPx1 functions upstream of the mitochondrial
events to inhibit the early ROS production and apoptosis induced by CD95 ligation. Finally, transgenic mice overexpressing
GPx1 were partially protected from the lethal effect of anti-CD95, underlying the importance of peroxide formation (and GPx1)
in CD95-triggered apoptosis. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M203067200 |