Apoptosis
induced by DNA-damaging agents or radiation mainly proceeds through death
receptor-independent caspase activation. The release
of mitochondrial apoptogenic proteins, such as cytochrome c, into the cytoplasm leading to Apaf1-dependent
activation of caspase-9 is a key event in this pathway. The permeability of the
mitochondrial outer membrane is regulated by the various pro- and antiapoptotic Bcl-2 family proteins, and it is thought that
DNA damage triggers apoptosis through the downregulation
of antiapoptotic Bcl-2. Using murine
embryonic fibroblasts (MEF) deficient and proficient in Apaf1, we show that
DNA-damaging agents and radiation lead to a decline in Bcl-2 protein only in wt
MEF, but not in apaf1(-/-) MEF, which are defective in
the activation of effector caspases
and apoptosis. In contrast, the induction of proapoptotic
Noxa, the activation of Bax,
the cytoplasmic release of cytochrome
c, as well as a drop of the mitochondrial transmembrane
potential Deltapsim are equally observed in wt and
apaf1(-/-) MEF following DNA damage. Moreover, the loss of Bcl-2 protein
occurring in wt MEF can be prevented by caspase
inhibition. Hence, the activation of proapoptotic
Bcl-2 family proteins rather than the downregulation
of antiapoptotic Bcl-2 mediates the primary signal in
the DNA damage-induced release of mitochondrial apoptogenic
proteins in MEF.
PMID: 14534531 [PubMed - in process]
