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J. Cell Biol., Volume 144, Number 5, March 8, 1999 915-926

Activation of Membrane-associated Procaspase-3 Is Regulated by Bcl-2

Joseph F. Krebs,* Robert C. Armstrong,* Anu Srinivasan,* Teresa Aja,* Angela M. Wong,* Aileen Aboy,* Rob Sayers,* Bryan Pham,* Tam Vu,* Kim Hoang,* Donald S. Karanewsky,* Christian Leist,Dagger Albert Schmitz,Dagger Joe C. Wu,* Kevin J. Tomaselli,* and Lawrence C. Fritz*

* IDUN Pharmaceuticals, La Jolla, California 92037; and Dagger  Novartis Pharma AG, CH-4002 Basel, Switzerland

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.

Key words: apoptosis;  Bcl-2;  caspase;  cytochrome c;  programmed cell death


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