Genetics of Apoptosis

fragment that promotes the characteristic rounding-up of cells (Kothakota et al.,
1997). PAK2, a serine/threonine kinase, is activated by caspase cleavage (Rudel and
Bokoch, 1997). As PAK2 is involved in the regulation of the actin cytoskeleton, its
activation seems to help formation of apoptotic bodies. Thus, cleavage of specific
proteins by caspases mediates the characteristic morphologic changes and ultimate
death of the cell.
Prosurvival members of the Bcl-2 family, including Bcl-2 and Bcl-xL proteins, are
also cleaved by caspases during apoptosis, and the fragments generated by the cleavage
appear to enhance apoptotic changes in the dying cells (Cheng et al., 1997; Clem et
al., 1998). Although initiator caspases mainly target effector caspases for cleavage and
activation, there are some examples where a cellular protein is directly cleaved by
activated initiator caspase. For example, caspase-2 and caspase-8 cleave Bid, a BH3-
only protein (Li et al., 1998a; Luo et al., 1998; Guo et al., 2002). As discussed above,
the cleaved Bid translocates to mitochondria and initiates cytochrome c release,
thereby linking the receptor pathway to the mitochondrial pathway of apoptosis, As
the intrinsic and extrinsic pathways of apoptosis are independent of each other, the
bridging via Bid probably serves as an amplification loop for caspase activation, rather
than an initiating event.

8.

Function of individual caspases

8.1

Caspase mutations and gene knockouts

In C. elegans, the loss of function mutations results in a complete inhibition of
developmental cell death (Chapter 10). In Drosophila melanogaster, specific mutants
are only available for dcp-1 and dredd. Most dcp-1 mutant embryos die during larval
stages, and the larvae that survive lack imaginal disks and gonads, and have melanotic
tumors (Song et al., 1997). The dcp-1 m u ta ti o n a l so c au s e s f e m a l e s te r i l i t y by d e f e c t i v e
transfer of the cytoplasmic contents from nurse cells to developing oocytes, a process
which requires apoptosis (McCall and Steller, 1998). The loss of dredd function
suggests a role for this caspase primarily in the regulation of innate immune response
in the fly (Leulier et al., 2000; Stoven et al., 2000). Although dronc mutants are
currently not available, RNA interference studies suggest that dronc is essential for
programmed cell death in the embryos and cell lines (Quinn et al., 2000; Cakouros
et al., 2002).
Caspase gene k/o data in the mouse emphasizes the complexity of the caspase-
activation pathways. The phenotypes of the casp9-/- and casp3-/- mice are very similar,
suggesting that these caspases are in the same pathway. Both casp9-/- and casp3-/-
mutations are lethal during embryogenesis or shortly after birth (Kuida et al., 1996,
1998; Hakem et al., 1998; Woo et al., 1998). The most profound defect of these
mice is hyperplasia in the brain resulting from decreased apoptosis. Defective neural

THE ROLE OF CASPASES IN APOPTOSIS 45