: Nat Med 2000 Nov;6(11):1241-7 Related Articles, Books, LinkOut
Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation.
Zheng TS, Hunot S, Kuida K, Momoi T, Srinivasan A, Nicholson DW, Lazebnik Y, Flavell RA
[1] Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] T.S.Z. present address: Biogen, 14 Cambridge Center, Cambridge Massachusetts 02142, USA [3] T.S.Z. and S.H. contributed equally to this work.
[Medline record in process]
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.
PMID: 11062535, UI: 20517633 |
