Editors' ChoiceApoptosis

Deadly Redundancy

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Science's STKE  31 Oct 2006:
Vol. 2006, Issue 359, pp. tw369
DOI: 10.1126/stke.3592006tw369

Stimuli such as tumor necrosis factor (TNF) activate cell death or apoptosis by activating the cysteine proteases known as caspases. Such receptor stimulation enhances formation of the apoptosome, a protein complex that allows activation of caspase 9. But is this the only way to skin the cat? Evidently not, according to an international collaboration of leading labs in the apoptosis field. Gyrd-Hansen et al. used mouse embryo fibroblasts (MEFs) lacking components of apoptotic pathways to show that the cells required caspase 9 to undergo TNF-induced death but did not need the protein Apaf-1, a component of the apoptosome required for activation of caspase 9 by that complex. Activation of caspase 9 in this Apaf-1-independent context appeared to require its cleavage and activation by another caspase, caspase 8. Further studies with knockout MEFs showed that permeabilization of mitochondria was also not required for this apoptosome-independent cell death in response to TNF. Instead, cell death was associated with permeabilization of lysosomal membranes, an alternative means of cell destruction that depends on release of lysosomal cathepsins. Cells with complete apoptotic machinery appeared to use both the mitochondrial and the lysosomal pathways to execute cell death in response to TNF. Protection from TNF-induced death was achieved only after gene ablation or pharmacological treatments that inhibited both pathways. The authors propose that such redundant signaling of apoptosis may be common and that death-resistant cancer cells may have perturbations in multiple pathways. Understanding the underlying pathways thus may allow more effective strategies to deliver therapeutic treatments that reactivate cell death in tumor cells.

M. Gyrd-Hansen, T. Farkas, N. Fehrenbacher, L. Bastholm, M. Høyer-Hansen, F. Elling, D. Wallach, R. Flavell, G. Kroemer, J. Nylandsted, M. Jäättelä, Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Mol. Cell. Biol. 26, 7880-7891 (2006). [Abstract] [Full Text]

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