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. Gelsolin was identified as a substrate for caspase-3 by screening the translation products of small complementary DNA pools for sensitivity to cleavage by caspase-3. Gelsolin was cleaved in vivo in a caspase-dependent manner in cells stimulated by Fas. Caspase-cleaved gelsolin severed actin filaments in vitro in a Ca2+-independent manner. Expression of the gelsolin cleavage product in multiple cell types caused the cells to round up, detach from the plate, and undergo nuclear fragmentation. Neutrophils isolated from mice lacking gelsolin had delayed onset of 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.
Kothakota
S
S
Chiron Corporation, Emeryville, CA 94608, USA.
Azuma
T
T
Reinhard
C
C
Klippel
A
A
Tang
J
J
Chu
K
K
McGarry
T J
TJ
Kirschner
M W
MW
Koths
K
K
Kwiatkowski
D J
DJ
Williams
L T
LT
D000199:Actins / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases; D002460:Cell Line; D048429:Cell Size; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D053938:DNA Fragmentation; D018260:Gelsolin / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology
D000199:Actins; D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D018260:Gelsolin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D003513:Cycloheximide; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases