PMID:16172118
| Citation |
Gao, Z, Shao, Y and Jiang, X (2005) Essential roles of the Bcl-2 family of proteins in caspase-2-induced apoptosis. J. Biol. Chem. 280:38271-5 |
|---|---|
| Abstract |
Caspase-2 is an initiating caspase required for stress-induced apoptosis in various human cancer cells. Recent studies suggest that it can mediate the death function of tumor suppressor p53 and is activated by a multimeric protein complex, PIDDosome. However, it is not clear how caspase-2 exerts its apoptotic function in cells and whether its enzymatic activity is required for the apoptotic function. In this study, we used both in vitro mitochondrial cytochrome c release assays and cell culture apoptosis analyses to investigate the mechanism by which caspase-2 induces apoptosis. We show that active caspase-2, but neither a catalytically mutated caspase-2 nor active caspase-2 with its inhibitor, can cause cytochrome c release. Caspase-2 failed to induce cytochrome c release from mitochondria with Bid(-/-) background, and the release could be restored by addition of the wild-type Bid protein, but not by Bid with the caspase-2 cleavage site mutated. Caspase-2 was not able to induce cytochrome c release from Bax(-/-)Bak(-/-) mitochondria either. In cultured cells, gene deletion of Bax/Bak or Bid abrogated apoptosis induced by overexpression of caspase-2. Collectively, these results indicate that proteolytic activation of Bid and the subsequent induction of the mitochondrial apoptotic pathway through Bax/Bak is essential for apoptosis triggered by caspase-2. |
| Links |
PubMed Online version:10.1074/jbc.M506488200 |
| Keywords |
Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein/metabolism; Caspase 2; Caspases/biosynthesis; Caspases/metabolism; Catalysis; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cytochromes/metabolism; Cytochromes c/metabolism; DNA, Complementary/metabolism; Enzyme Activation; Escherichia coli/metabolism; HeLa Cells; Humans; Mice; Mice, Transgenic; Mitochondria/metabolism; Mutagenesis, Site-Directed; Plasmids/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; RNA Interference; Tumor Suppressor Protein p53/metabolism; bcl-2 Homologous Antagonist-Killer Protein/metabolism; bcl-2-Associated X Protein/metabolism |
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