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et al., 1997; Rasper et al., 1998). Clustering of caspase-8 in the Fas signaling complex triggers proteolytic autoactivation of the protease encoded by this protein, which initiates a cascade of caspase activation to produce apoptosis. Other death receptors can activate caspases but produce distinct responses, probably because they associate with different adapter molecules (Table 7.18.2). The exact connections between specific death receptors and the intracellular signaling machinery is currently under study.

The execution phase of apoptosis is associated with activation of the caspase family of cysteine proteases (for reviews see Cohen, 1997; Nicholson and Thornberry, 1997). The caspases are a distinct family of cysteine proteases that cleave substrates at characteristic sequences containing aspartate in the P1 position (Table 7.18.3). Each caspase is produced as a pro-form that encodes a prodomain of variable length attached to peptides encoding the large and small catalytic subunits of the enzyme. These segments are separated by spacer segments and caspase cleavage sites. Biochemical and genetic studies have enabled the death-associated caspases to be divided into a number of subgroups. Activator caspases (caspase-8, -9, and -10) appear to function primarily by activating other downstream caspases, as their cleavage specificities closely match the cleavage sites of other caspases. This is understood most clearly in the Fas pathway, in which experimental activation of caspase-8 through oligomerization can carry out the function of the Fas signaling complex, trigger downstream caspases, and produce apoptosis (Martin et al., 1998; Muzio et al., 1998; Yang et al., 1998).

Effector caspases (caspase-3, -6, and -7) are the major active caspases present in apoptotic cells, and have specificities matching cellular substrates whose cleavage is known to be important in generating the apoptotic phenotype. Some specific features of apoptosis, such as DNA cleavage, have been linked to caspases (Enari et al., 1998; Sakahira et al., 1998). Most likely, the cleavage sites and short prodomains of effector caspases prohibit autoprocessing, making their activity dependent on upstream events (Thornberry et al., 1997). Caspase-2 has substrate preferences resembling the effector caspases but has a long prodomain that can bind the adapter molecule RAIDD through a caspase recruitment domain (CARD), a protein-protein interaction domain similar to the death effector domain (Duan and Dixit, 1997). Thus, this caspase may be a more upstream effector caspase. Studies with caspase-deficient mice created through gene targeting studies suggest that there is significant redundancy between caspases that varies between cell types. Caspase-3-deficient mice have impaired neuronal apoptosis but normal lymphocyte apoptosis (Kuida et al., 1996), whereas caspase-2-defi-cient animals seem to have a specific defect in germ-cell apoptosis (Bergeron et al., 1998).

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