Caspase-3 Controls both Cytoplasmic and Nuclear Events Associated with Fas-Mediated Apoptosis in vivo

Both caspase-1- and caspase-3-like activities are required for Fas-mediated apoptosis. However, the role of caspase-1 and caspase-3 in mediating Fas-induced cell death is not clear. We assessed the contributions of these caspases to Fas signaling in hepatocyte cell death in vitro. Although wild-type...

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Published in:Proceedings of the National Academy of Sciences - PNAS 1998-11, Vol.95 (23), p.13618-13623
Main Authors: Zheng, Timothy S., Schlosser, Stephan F., Dao, Tao, Hingorani, Ravi, Crispe, I. Nicholas, Boyer, James L., Flavell, Richard A.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Antibodies
Apoptosis
Biological Sciences
Caspase 3
Caspases - metabolism
Cell death
Cell lines
Cell nucleus
Cell Nucleus - metabolism
Cell Nucleus - pathology
Cellular biology
Coculture techniques
Cytoplasm - metabolism
Cytoplasm - pathology
Deoxyribonucleic acid
DNA
DNA fragmentation
Fas Ligand Protein
fas Receptor - metabolism
Fibroblasts
Hepatocytes
Liver - metabolism
Liver - pathology
Membrane Glycoproteins - metabolism
Mice
Plasma
Rabbits
Thymocytes
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Summary:Both caspase-1- and caspase-3-like activities are required for Fas-mediated apoptosis. However, the role of caspase-1 and caspase-3 in mediating Fas-induced cell death is not clear. We assessed the contributions of these caspases to Fas signaling in hepatocyte cell death in vitro. Although wild-type, caspase-1-/-, and caspase-3-/-hepatocytes were killed at a similar rate when cocultured with FasL expressing NIH 3T3 cells, caspase-3-/-hepatocytes displayed drastically different morphological changes as well as significantly delayed DNA fragmentation. For both wild-type and caspase-1-/-apoptotic hepatocytes, typical apoptotic features such as cytoplasmic blebbing and nuclear fragmentation were seen within 6 hr, but neither event was observed for caspase-3-/-hepatocytes. We extended these studies to thymocytes and found that apoptotic caspase-3-/-thymocytes exhibited similar ``abnormal'' morphological changes and delayed DNA fragmentation observed in hepatocytes. Furthermore, the cleavage of various caspase substrates implicated in mediating apoptotic events, including gelsolin, fodrin, laminB, and DFF45/ICAD, was delayed or absent. The altered cleavage of these key substrates is likely responsible for the aberrant apoptosis observed in both hepatocytes and thymocytes deficient in caspase-3.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.23.13618