Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria.

Caspase-2 is one of the earliest identified caspases, but the mechanism of caspase-2-induced apoptosis remains unknown. We show here that caspase-2 engages the mitochondria-dependent apoptotic pathway by inducing the release of cytochrome c (Cyt c) and other mitochondrial apoptogenic factors into the cell cytoplasm. In support of these observations we ...
found that Bcl-2 and Bcl-xL can block caspase-2- and CRADD (caspase and RIP adaptor with death domain)-induced cell death. Unlike caspase-8, which can process all known caspase zymogens directly, caspase-2 is completely inactive toward other caspase zymogens. However, like caspase-8, physiological levels of purified caspase-2 can cleave cytosolic Bid protein, which in turn can trigger the release of Cyt c from isolated mitochondria. Interestingly, caspase-2 can also induce directly the release of Cyt c, AIF (apoptosis-inducing factor), and Smac (second mitochondria-derived activator of caspases protein) from isolated mitochondria independent of Bid or other cytosolic factors. The caspase-2-released Cyt c is sufficient to activate the Apaf-caspase-9 apoptosome in vitro. In combination, our data suggest that caspase-2 is a direct effector of the mitochondrial apoptotic pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Apoptosis, BH3 Interacting Domain Death Agonist Protein, CRADD Signaling Adaptor Protein, Carrier Proteins, Caspase 2, Caspase 3, Caspase 8, Caspase 9, Caspases, Cytochrome c Group, Cytoplasm, Cytosol, Dose-Response Relationship, Drug, Hela Cells, Humans, Immunoblotting, Mitochondria, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins c-bcl-2, Recombinant Proteins, Time Factors, Transfection, Tumor Cells, Cultured, bcl-X Protein
J. Biol. Chem.
Date: Apr. 19, 2002
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