Caspase Cascade

Apoptosis or programmed cell death is triggered by a variety of stimuli, including cell surface receptors like FAS, the mitochondrial response to stress, and factors released from cytotoxic T cells. The caspases comprise a class of cysteine proteases many members of which are involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that subsequently degrade cellular targets that lead to cell death. The activating caspases include caspase-8 and caspase-9. Caspase-8 is the initial caspase activated in response to receptors with a death domain that interacts with FADD. The mitochondrial stress pathway begins with the release of cytochrome c from mitochondria, which then interacts with Apaf-1, causing self-cleavage and activation of caspase-9. The effector caspases, caspase-3, -6 and-7 are downstream of the activator caspases and act to cleave various cellular targets. Granzyme B and perforin, proteins released by cytotoxic T cells, induce apoptosis in target cells by forming transmembrane pores and triggering apoptosis, perhaps through cleavage of caspases. Caspase independent mechanisms of granzyme B-mediated apoptosis have been suggested.

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References:

Earnshaw, W.C., et al., Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Ann. Rev. Biochem., 68, 383-424 (1999).

Adrain, C., and Martin, S.J., The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem. Sci., 26, 390-397 (2001).