Healthcare and Medicine Reference
In-Depth Information
understand how receptors are activated in vivo if we are
to evaluate the contribution of each of the cytoplasmic
kinases.
A complete description of the intracellular path-
ways mediating survival may still be lacking, but
many of the candidates that pass the signal from mem-
brane to nucleus have now been identified. The impor-
tance of each candidate molecule is likely to range
broadly from one neuron type to another. Fortunately,
these remaining mysteries need not be solved in order
for us to consider the cytoplasmic weapons that
neurons use to kill themselves.
NGF
PC12 cells
+ NGF
- NGF
+ JNK activator
+ ERK activator
- NGF
CASPASES: AGENTS OF DEATH
The discovery of specific genes that are directly
involved in apoptosis was made in experiments on the
nematode, Caenorhabditis elegans . In 2002, Robert
Horvitz shared the Nobel Prize for Physiology or Med-
icine for uncovering the discrete genetic steps that
support apoptosis, which came to be known as pro-
grammed cell death (PCD). Two genes, ced-3 and ced-
4 , must be expressed by each C. elegans cell if it is to die
during development ( ced stands for cell death abnor-
mal) (Yuan and Horvitz, 1990). When either of these
genes is mutated, almost all of the PCD is prevented
(Figure 7.25). Analysis of mosaic animals (i.e., animals
in which the ced gene is expressed in only a few iden-
tified cells) indicates that the gene product acts within
the cell that produces it, showing that PCD proceeds
by suicide rather than a violent neighbor. What are
these gene products, and how do they control the life
or death decision?
Proteases appear to be a common weapon of choice
for cell death. Although it has been known for some time
that one can rescue injured cells by blocking proteolytic
enzymes, the evidence for protease involvement in nor-
mally occurring cell death came only recently. In fact, one
of the gene products that kills C. elegans neurons, CED-3,
turns out to be a cysteine protease, an enzyme that specif-
ically cuts up proteins after an aspartate residue. In
mammals, there is a CED-3-like protease called inter-
leukin-1b-converting enzyme (ICE). While ICE plays a
life-affirming role in processing pro-interleukin-1b for
the purposes of blood cell production, it also serves as an
angel of death in the developing nervous system. New
cysteine proteases have been identified in many species,
and they are now generally referred to as C ysteine
requiring ASP artate prote ASE s, or caspases (Figure
7.25). Thus, ICE is now called caspase-1.
In C. elegans , the ced-4 gene product is also a necessary
constituent of the death pathway. CED-4 binds to the
FIGURE 7.24 ERK and JNK mediate the effects of NGF. When
NGF is withdrawn from the culture media, PC12 cells die (center).
NGF is not able to support PC12 cell survival when the MAP kinase,
JNK, is constitutively activated (left). In contrast, when ERK is con-
stitutively activated in PC12 cells, they are able to survive even in
the absence of NGF (right). (Adapted from Xia et al., 1995)
cells through BDNF activation of TrkB (Xing et al.,
1996; Riccio et al., 1999; Bonni et al., 1999).
The extent to which CREB-dependent transcription
contributes to neuron survival in vivo remains to be
determined (Lonze and Ginty, 2002). In any event,
other transcription pathways are likely to play a sig-
nificant role. For example, Akt phosphorylates a tran-
scription factor, called forkhead, preventing it from
translocating to the nucleus and upregulating Fas
ligand (Brunet et al., 1999).
Although we have tried to present a unified picture of
cell survival signaling, it is likely that different neurons
will employ specific cytoplasmic mechanisms. For
example, Ras appears to be a principal cytoplasmic
signal for NGF signaling in DRG neurons. However, it is
also known that NGF-dependent sympathetic neurons
from caudal regions of nervous system are not saved by
Ras injection, wherease sympathetic neurons from the
rostral SCG are saved (Markus et al., 1997).
The many molecular pathways between receptor and
nucleus interact with one another, producing another
level of complexity. For example, activation of ERK
requires binding and activation of both Shc and phos-
pholipase C-g1 (PLC-g1) (Stephens et al., 1994). However,
the PLC-g1 pathway seems to be more involved in neurite
outgrowth (see Chapter 5). Therefore, it will be crucial to
 
 
 
 
 
 
 
 
 
 
 
 
 
Search Pocayo ::




Custom Search