Inhibition of Ced-3/ICE-Related Proteases Does Not Prevent Cell Death Induced by Oncogenes, DNA Damage, or the Bcl-2 Homologue Bak

There is increasing evidence for a central role in mammalian apoptosis of the interleukin-1β-converting enzyme (ICE) family of cysteine proteases, homologues of the product of the nematode "death" gene, ced-3. Ced-3 is thought to act as an executor rather than a regulator of programmed cel...

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Bibliographic Details
Published in:The Journal of cell biology 1997-01, Vol.136 (1), p.215-227
Main Authors: McCarthy, Nicola J., Moira K. B. Whyte, Gilbert, Christopher S., Evan, Gerard I.
Format: Article
Language:English
Subjects:
Actins
Amino Acid Chloromethyl Ketones - pharmacology
Animals
Apoptosis
Apoptosis - physiology
bcl-2 Homologous Antagonist-Killer Protein
Blood
Caenorhabditis elegans Proteins
Caspase 1
Caspases
Cell culture techniques
Cell death
Cell Line
Cell lines
Cell Membrane
Cells
Cellular biology
Cultured cells
Cysteine Endopeptidases - physiology
Cysteine Proteinase Inhibitors - pharmacology
Deoxyribonucleic acid
DNA
DNA Damage
Fibroblasts
Gene Expression
Genes, myc - physiology
Helminth Proteins - antagonists & inhibitors
Helminth Proteins - physiology
Ice
Insulin-Like Growth Factor I - physiology
Lamins
Membrane Proteins - genetics
Microscopy, Video
Nuclear Proteins - metabolism
Phosphatidylserines - analysis
Poly(ADP-ribose) Polymerases - metabolism
Proto-Oncogene Proteins c-bcl-2 - genetics
Rats
T lymphocytes
Tamoxifen - analogs & derivatives
Tamoxifen - pharmacology
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Summary:There is increasing evidence for a central role in mammalian apoptosis of the interleukin-1β-converting enzyme (ICE) family of cysteine proteases, homologues of the product of the nematode "death" gene, ced-3. Ced-3 is thought to act as an executor rather than a regulator of programmed cell death in the nematode. However, it is not known whether mammalian ICE-related proteases (IRPs) are involved in the execution or the regulation of mammalian apoptosis. Moreover, an absolute requirement for one or more IRPs for mammalian apoptosis has yet to be established. We have used two cell-permeable inhibitors of IRPs, Z-Val-Ala-Asp.fluoromethylketone (ZVAD.fmk) and t-butoxy carbonyl-Asp.fluoromethylketone (BD.fmk), to demonstrate a critical role for IRPs in mammalian apoptosis induced by several disparate mechanisms (deregulated oncogene expression, ectopic expression of the Bcl-2 relative Bak, and DNA damage-induced cell death). In all instances, ZVAD.fmk and BD.fmk treatment inhibits characteristic biochemical and morphological events associated with apoptosis, including cleavage of nuclear lamins and poly-(ADP-ribose) polymerase, chromatin condensation and nucleosome laddering, and external display of phosphatidylserine. However, neither ZVAD.fmk nor BD.fmk inhibits the onset of apoptosis, as characterized by the onset of surface blebbing; rather, both act to delay completion of the program once initiated. In complete contrast, IGF-I and Bcl-2 delay the onset of apoptosis but have no effect on the kinetics of the program once initiated. Our data indicate that IRPs constitute part of the execution machinery of mammalian apoptosis induced by deregulated oncogenes, DNA damage, or Bak but that they act after the point at which cells become committed to apoptosis or can be rescued by survival factors. Moreover, all such blocked cells have lost proliferative potential and all eventually die by a process involving cytoplasmic blebbing.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.136.1.215