Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis.
J Biol Chem
; 277(33): 29803-9, 2002 Aug 16.
Article
in En
| MEDLINE
| ID: mdl-12065594
ABSTRACT
DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for caspase-2 in etoposide-induced cytochrome c release. In particular, Jurkat T-lymphocytes treated with an irreversible caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-caspase-2 antisense (Casp-2/AS) are refractory to cytochrome c release stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining caspase-2 activity results in an attenuation of downstream events, such as pro-caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Apoptosis
/
Caspases
/
Cytochrome c Group
/
Etoposide
/
Mitochondria
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2002
Document type:
Article
Affiliation country:
Sweden