Genetics of Apoptosis

et al., 2000). This may reflect a role for Debcl in Ark-mediated facilitation of caspase
activation, or it may simply reflect a more general ability of Ark and DIAP1 to
modulate caspase activation in cells. Decreased levels of DIAP1 are found to enhance
many apoptotic inducers, probably because more active caspases are present in these
cells. Decreased Ark may simply turn the rheostat the other way.

6.

How is the mitochondrial pathway activated?

Genetic data indicate that Ark is required for some developmental apoptosis.
However, as described above, it may be that decreased Ark levels simply lower the
amount of activated caspase in the cell. Expression of Rpr, Grim, Hid, or Skl and
subsequent inhibition of DIAP1 would simply result in lower levels of active caspase
in the absence of Ark, and decrease the chance that a cell would undergo apoptosis.
This model is supported by the finding that decreased Ark levels suppress apoptosis
resulting from decreased DIAP1 activity (Rodriguez et al., 2002; Zimmermann et al.,
2002).
Alternatively, it is possible that Rpr, Grim, and Hid activate the mitochondrial
pathway, either directly or indirectly, perhaps through a caspase-mediated step. It is
possible that the Drosophila homolog of Scythe connects Rpr to the mitochondrial
pathway. Scythe is a Rpr-binding protein identified in Xenopus extracts (Thress et al.,
1998). Rpr interaction with Scythe releases a proapoptotic factor, which can release
cytochrome c from mitochondria (Thress et al., 1999). Thus, Rpr binding to Scythe
could result in Ark-mediated caspase activation through cytochrome c increases
(Figure 1).

7.

Moving upstream: regulation of Rpr, Hid, Grim, and SkI activity

Different upstream pathways regulate the proapoptotic activities of Rpr, Hid, Grim,
and Skl. These pathways include steroid hormones, DNA damage, growth factor
signaling, and many as yet uncharacterized developmental cues (Table 1). Both
transcriptional and post-translational mechanisms of regulation have been uncovered
for these genes.
In the developing embryo, the pattern of Rpr, Grim, and SkI expression
corresponds to the pattern of cell death (White et al., 1994; Chen et al., 1996;
Christich et al., 2002; Srinivasula et al., 2002; Wing et al., 2002). This suggests that
the expression of these genes is elaborately regulated by many of the pathways that
regulate other aspects of development. There are both similarities and differences in
the expression patterns of these three genes. For example, Rpr expression is upregu
lated when cells die due to defects in the normal developmental program, while SkI
expression is not increased (Nordstrom et al., 1996; Christich et al., 2002). It is not
yet clear whether developmental signals are integrated directly at the promoters of
these genes, or whether the developmental regulation of their expression reflects the

192 GENETICS OF APOPTOSIS