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Pro-apoptotic regulator
Anti-apoptotic regulator
Mitochondria permeability
cyt c
cyt c
Activating factor
Initiator protease
Effector protease
FIGURE 7.26 Regulation of cell death machinery in three species. (Left) In C. elegans , the effector pro-
tease that leads to apoptosis (CED-3) is activated by CED-4. An anti-apoptotic regulator (CED-9) can complex
with CED-4 and interfere with CED-3 activation. A pro-apoptotic regulator (EGL-1) can bind to CED-9, and
facilitate the processing of CED-3. (Middle) Many of the same components are present in mammals, includ-
ing pro- and anti-apoptotic regulators (Bax and Bcl-2). However, Caspase-3 is activated by an initiator pro-
tease (Caspase-9) that is processed in molecular complex with cytochrome c and Apaf-1. An additional
regulatory component consists of IAP, which prevents Caspase-9 activation, and Smac, which can inhibit IAP
and permit the apoptotic pathway to progress. (Right) In the fruit fly, the pathway is relatively similar to that
described for mammals.
raises a question about the specificity of caspases: is
their activity imprecise, or do they break down specific
substrates? The evidence suggests great specificity, par-
ticularly for proteins that are involved in genome regu-
lation, such as DNA repair, DNA replication, and RNA
splicing enzymes (Lazebnik et al., 1994; Loetscher et al.,
1997; Nicholson and Thornberry, 1997). Structural pro-
teins of the nucleus and cytoskeleton, such as actin and
fodrin, are also targets for cleavage. One example of
caspase target is the DNA repair enzyme called poly
(ADP-ribose) polymerase (PARP), suggesting that cell
death is achieved by compromising the neuron's tran-
scription machinery. A second set of targets, of some
interest to those studying Alzheimer's disease, are the
transmembrane proteins called presenilins that are
apparently involved in the Notch signaling pathway
(see Chapter 2: Induction). Although NGF-deprived
PC12 cells normally die, they can be rescued by trans-
fection with presenilin 2 antisense mRNA.
While no final arrests have been made, caspases
appear to be a primary felon in the developing nervous
system. However, conspiracy theorists can take
comfort in the many other death mechanisms that
underlie normal cell death. We have learned that the
release of a mitochondrial flavoprotein, AIF, can act
directly to fragment DNA without the intermediate
involvement of caspases. A second caspase-independ-
ent pathway involves the regulation of superoxide
(O 2 · - ), which accumulates as a result of oxygen usage
in the mitochondrial respiratory chain. Free radicals
such as O 2 · - have unpaired electrons, making them an
extremely reactive species. Excess O 2 · - can disrupt
membrane integrity, inhibit pumps, and fragment
DNA. Superoxide dismutase (SOD) is the endogenous
enzyme that eliminates O 2 · - by catalyzing a reaction to
O 2 and H 2 O 2 . Interestingly, sympathetic neurons can
survive for a longer period of time after NGF depri-
vation if injected with SOD. Although a caspase medi-
ates the cell death process initiated by trophic factor
deprivation, it is not responsible for the death initiated
by free radicals (Troy et al., 1997).
Thus, for each developing population of neurons,
the naturally occurring period of cell death may
invoke a distinctive set of molecular mechanisms.
In fact, one of the most varied features of cell death
involves the regulatory proteins that determine
whether or not caspases cross the threshold to their
active state.
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