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© The Rockefeller University Press, 0021-9525/1999//915 $5.00
The Journal of Cell Biology, Volume 144, Number 5, , 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, Albert Schmitz, Joe C. Wu^*, Kevin J. Tomaselli^*, and Lawrence C. Fritz^*

^* IDUN Pharmaceuticals, La Jolla, California 92037; and 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

Abbreviations used in this paper: 697-neo cells, 697 cells stably infected with a retrovirus expressing the neomycin resistance gene; 697-Bcl-2 cells, 697 cells stably infected with a retrovirus expressing human bcl-2 cDNA; acDEVD-amc, acetyl-Asp-Glu-Val-Asp-aminomethylcoumarin; acYVAD-ald, acetyl-Tyr-Val-Ala-Asp-aldehyde; Bcl-2-membranes, heavy membranes prepared from 697-Bcl-2 cells; neo-membranes, heavy membranes prepared from 697-neo cells; PARP, poly(ADP-ribose) polymerase.

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