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Science  23 Aug 2002:
Vol. 297, Issue 5585, pp. 1233
DOI: 10.1126/science.297.5585.1233r

Cells responding to cytotoxic stresses like DNA damage are thought to activate apoptosis-inducing caspases only after the mitochondria are permeabilized and release their cytochrome c, which functions as a caspase activator. Lassus et al. (p. 1352; see the Perspective by Kumar and Vaux) present experimental results challenging this view. They monitored apoptosis caused by DNA damage in human fibroblasts transformed with the adenoviral oncogene E1A and in other human tumor cell lines. When small interfering RNA (siRNA) was used to block expression of caspase-2, release of pro-apoptotic factors from the mitochondria was inhibited and the percentage of cells undergoing apoptosis was reduced. Apoptosis was restored by the expression of mutant caspase-2 RNA that was designed not to interact with siRNA. Thus, even “intrinsic” death-inducing pathways activated by DNA damage includes caspase activation as an early event in order to permeabilize the mitochondria.

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