Zheng, T. S., Hunot, S., Kuida, K., Momoi, T., Srinivasan, A., Nicholson, D. W., Lazebnik, Y., Flavell, R. A. (2000) Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nature Medicine, 6 (11). pp. 1241-1247. ISSN 1078-8956
Abstract
Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. Using an established in vivo model of Fas-mediated apoptosis, we demonstrate here that elimination of certain caspases was compensated in vivo by the activation of other caspases. Hepatocyte apoptosis and mouse death induced by the Fas agonistic antibody Jo2 required proapoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pathway of caspase activation; deficiency in caspases essential for this pathway, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of alternate caspases after injection of Jo2, and therefore failed to protect mice against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, also elicited compensatory activation of caspases in cultured caspase-3(-/-) hepatocytes, indicating that the compensatory caspase activation was mediated through the mitochondria. Our findings provide direct experimental evidence for compensatory pathways of caspase activation. This issue should therefore be considered in developing caspase inhibitors for therapeutic applications.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Antibodies Antigens, CD95 Apoptosis Caspase 1 Caspase 3 Caspase 9 Caspases Cells, Cultured Enzyme Activation Hemorrhage Hepatocytes Humans Liver Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Mitochondria, Liver |
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions |
| CSHL Authors: | |
| Communities: | CSHL labs > Labeznik lab |
| Depositing User: | Matt Covey |
| Date: | 2000 |
| Date Deposited: | 12 Dec 2012 17:31 |
| Last Modified: | 12 Dec 2012 17:31 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26387 |
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