Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c

Caspases are cysteine proteases that mediate apoptosis by proteolysis of specific substrates, Although many caspase substrates have been identified, for most substrates the physiologic caspase(s) required for cleavage is unknown. The Bcl-2 protein, which inhibits apoptosis, is cleaved at Asp-34 by caspases during apoptosis and by recombinant caspase-3 in vitro. In the present study, we show that endogenous caspase-3 is a physiologic caspase for Bcl-2, Apoptotic extracts from 293 cells cleave Bcl-2 but not Bax, even though Bax is cleaved to an 18-kDa fragment in SK-NSH cells treated with ionizing radiation. In contrast to Bcl-2, cleavage of Bax was only partially blocked by caspase inhibitors. Inhibitor profiles indicate that Bax may be cleaved by more than one type of noncaspase protease, Immunodepletion of caspase-3 from 293 extracts abolished cleavage of Bcl-2 and caspase-7, whereas immunodepletion of caspase-7 had no effect on Bcl-2 cleavage. Furthermore, MCF-7 cells, which lack caspase-3 expression, do not cleave Bcl-2 following staurosporine-induced cell death. However, transient transfection of caspase-3 into MCF-7 cells restores Bcl-2 cleavage after staurosporine treatment. These results demonstrate that in these models of apoptosis, specific cleavage of Bcl-2 requires activation of caspase-3, When the pro-apoptotic caspase cleavage fragment of Bcl-2 is transfected into baby hamster kidney cells, it localizes to mitochondria and causes the release of cytochrome c into the cytosol. Therefore, caspase-3-dependent cleavage of Bcl-2 appears to promote further caspase activation as part of a positive feedback loop for executing the cell.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
1999-07
Language
ENG
Keywords

DRUG-INDUCED APOPTOSIS; CELL-DEATH; MORPHOLOGICAL-CHANGES; DNA FRAGMENTATION; CASPASE FAMILY; PROTEIN; BAX; ACTIVATION; PATHWAY; MITOCHONDRIA

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.274, no.30, pp.21155 - 21161

ISSN
0021-9258
DOI
10.1074/jbc.274.30.21155
URI
http://hdl.handle.net/10203/74857
Appears in Collection
BS-Journal Papers(저널논문)
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