CONVERSION OF BCL-2 TO A BAX-LIKE DEATH EFFECTOR BY CASPASES

Caspases are a family of cysteine proteases implicated in the biochemi cal and morphological changes that occur during apoptosis (programmed cell death). The loop domain of Bcl-2 is cleaved at Asp(34) by caspase -3 (CPP32) in vitro, in cells overexpressing caspase-3, and after indu ction of apoptosis by Fas ligation and interleukin-3 withdrawal. The c arboxyl-terminal Bcl-2 cleavage product triggered cell death and accel erated Sindbis virus-induced apoptosis, which was dependent on the BH3 homology and transmembrane domains of Bcl-2, Inhibitor studies indica ted that cleavage of Bcl-2 may further activate downstream caspases an d contribute to amplification of the caspase cascade. Cleavage-resista nt mutants of Bcl-2 had increased protection from interleukin-3 withdr awal and Sindbis virus-induced apoptosis. Thus, cleavage of Bcl-2 by c aspases may ensure the inevitability of cell death.