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Volume 16, Number 18, Issue of September 15, 1996 pp. 5654-5660
Copyright ©1996 Society for Neuroscience

Bcl-2 Expression in Neural Cells Blocks Activation of ICE/CED-3 Family Proteases during Apoptosis

Received March 12, 1996; revised June 19, 1996; accepted July 2, 1996.

Anu Srinivasan1, , Lyndon M. Foster1, , Maria-Pia Testa1, Tõnis Örd1, Robert W. Keane2, Dale E. Bredesen1, and Celik Kayalar1

1 Program on Aging, The Burnham Institute, La Jolla, California 92037, and 2 Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33101

The ICE/CED-3 family of proteases has been implicated in playing a fundamental role in programmed cell death. Bcl-2 protein represses a number of apoptotic death programs, but the biochemical mechanism of its action is not known. We investigated the activation of ICE/CED-3 proteases induced by three apoptotic stimuli (staurosporine, ceramide, and serum withdrawal) in the neuronal cell line GT1-7 and in cells overexpressing Bcl-2. Rapid activation of a 17 kDa subunit of an activated member of the ICE/CED-3 family is demonstrated by affinity-labeling GT1-7 extracts from apoptotic controls cells with a biotinylated ICE/CED-3 inhibitor. This activation corresponds to an increased ICE/CED-3-like protease activity in extracts measured by a fluorogenic substrate assay. In a cell-free system, these extracts induce apoptotic morphological changes in intact nuclei. All three activities are readily inhibited by treatment of control extracts with ICE/CED-3-like protease inhibitors. Overexpressed Bcl-2 inhibits the activation of the 17 kDa protein, the ICE/CED-3-like protease activity in the fluorogenic assay, and the induction of apoptotic morphological changes in HeLa nuclei in the cell-free system, similar to results obtained with ICE/CED-3 protease inhibitors. At the mRNA level, overexpression of Bcl-2 did not alter expression of five members of the ICE/CED-3 family: CPP32, ICE, Mch 2, Nedd 2, and TX. Overexpression of Bcl-2 prevented the apoptosis-induced processing of pro-Nedd 2 to the cleaved form. These data suggest that Bcl-2 participates upstream from the function of ICE/CED-3 proteases and may inhibit apoptosis by preventing the post-translational activation of ICE/CED-3 proteases.

Key words: apoptosis; programmed cell death; neural cells; Bcl-2; ICE/CED-3 proteases; ceramide; staurosporine; serum withdrawal




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