CASPASE-3-GENERATED FRAGMENT OF GELSOLIN - EFFECTOR OF MORPHOLOGICAL CHANGE IN APOPTOSIS

The caspase-3 (CPP32, apopain, YAMA) family of cysteinyl proteases has been implicated as key mediators of apoptosis in mammalian cells, Gel solin was identified as a substrate for caspase-3 by screening the tra nslation products of small complementary DNA pools for sensitivity to cleavage by caspase-3. Gelsolin was cleaved in vivo in a caspase-depen dent manner in cells stimulated by Fas. Caspase-cleaved gelsolin sever ed actin filaments in vitro in a Ca2+-independent manner, Expression o f the gelsolin cleavage product in multiple cell types caused the cell s to round up, detach from the plate, and undergo nuclear fragmentatio n. Neutrophils isolated from mice lacking gelsolin had delayed onset o f both blebbing and DNA fragmentation, following apoptosis induction, compared with wild-type neutrophils. Thus, cleaved gelsolin may be one physiological effector of morphologic change during apoptosis.