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
IDUN Pharmaceuticals, La Jolla, California 92037, USA.
J Cell Biol. 1999 Mar 8;144(5):915-26. doi: 10.1083/jcb.144.5.915.
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.
膜结合型Bcl-2抑制细胞质中procaspases激活的机制尚不清楚。在此，我们鉴定了一种细胞内、与膜相关的procaspase-3形式，其激活受Bcl-2控制。从对照细胞中分离出的重膜含有一种可自发激活的caspase-3酶原。相比之下，在过表达Bcl-2的细胞中，尽管caspase-3酶原仍与重膜相关，但其自发激活被阻断。然而，Bcl-2表达对未刺激细胞中细胞质caspase活性水平影响很小。此外，膜相关的caspase-3对外源性细胞色素c激活的反应性与胞质caspase-3不同。我们的结果表明，细胞内膜可通过一种受Bcl-2抑制的机制产生活性caspase-3，并且膜中caspase激活的调控与在细胞质中观察到的不同。这些数据表明，Bcl-2可能部分通过阻断膜相关procaspases的激活来控制细胞质事件。
