Activation of membrane-associated procaspase-3 is regulated by Bcl-2 |
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Authors: | Krebs J F Armstrong R C Srinivasan A Aja T Wong A M Aboy A Sayers R Pham B Vu T Hoang K Karanewsky D S Leist C Schmitz A Wu J C Tomaselli K J Fritz L C |
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Institution: | IDUN Pharmaceuticals, La Jolla, California 92037, USA. |
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Abstract: | The mechanism by which membrane-bound Bcl-2 inhibits the activation of cytoplasmic procaspases is unknown. Here we characterize an intracellular, membrane-associated form of procaspase-3 whose activation is controlled by Bcl-2. Heavy membranes isolated from control cells contained a spontaneously activatable caspase-3 zymogen. In contrast, in Bcl-2 overexpressing cells, although the caspase-3 zymogen was still associated with heavy membranes, its spontaneous activation was blocked. However, Bcl-2 expression had little effect on the levels of cytoplasmic caspase activity in unstimulated cells. Furthermore, the membrane-associated caspase-3 differed from cytosolic caspase-3 in its responsiveness to activation by exogenous cytochrome c. Our results demonstrate that intracellular membranes can generate active caspase-3 by a Bcl-2-inhibitable mechanism, and that control of caspase activation in membranes is distinct from that observed in the cytoplasm. These data suggest that Bcl-2 may control cytoplasmic events in part by blocking the activation of membrane-associated procaspases. |
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Keywords: | apoptosis Bcl-2 caspase cytochrome c programmed cell death |
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