Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bcl-2 cleavage and cytochrome c release.
It is now known that caspase-3-like protease activation can promote Bcl-2 cleavage and mitochondrial cytochrome c release and that these events can lead to further downstream caspase activation. NO has been proposed as a potent, endogenous inhibitor of caspase-3-like protease activity. Experiments were carried out to determine whether NO could interrupt Bcl-2 cleavage or cytochrome c release by the inhibition of caspase activity linking these events. NO inhibited the capacity of purified caspase-3 to cleave recombinant Bcl-2. Both Bcl-2 cleavage and cytochrome c release were inhibited in tumor necrosis factor alpha- and actinomycin D-treated MCF-7 cells exposed to NO donors. The NO-mediated inhibition of Bcl-2 cleavage and cytochrome c release occurred in association with an inhibition of apoptosis and caspase-3-like activation. Thus, NO suppresses a key step in the positive feedback amplification of apoptotic signaling by preventing Bcl-2 cleavage and cytochrome c release.
Kim
Y M
YM
Department of Surgery, University of Pittsburgh, Pittsburgh Pennsylvania 15261, USA.
Kim
T H
TH
Seol
D W
DW
Talanian
R V
RV
Billiar
T R
TR
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D003574:Cytochrome c Group / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D008099:Liver / Q000166:cytology / Q000201:enzymology; D009569:Nitric Oxide / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; C110881:S-nitro-N-acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D009569:Nitric Oxide; D053148:Caspase 3; D010396:Penicillamine