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proNGF
A
FasL
p75
Fas
death domain
FADD
JNK
pro-caspase-8
NF- kB
P
c-Jun
caspase-8
Nucleus
B
FIGURE 7.18 Members of the TNF receptor family influence neuron survival. A. A schematic shows two
members of the TNFR familly, p75 NTR and Fas. The p75 NTR is a high-affinity receptor for the proneurotrophin,
proNGF, and it may mediate either survival or apoptosis. Survival may involve the recruitment of a tran-
scription activator, nuclear factor kB (NF-kB), while apoptosis may employ Jun kinase (JNK), which phos-
phorylates the transcription factor, c-Jun. The Fas receptor is a high-affinity site for the Fas ligand (FasL), and
it may facilitate cell death through recruitment of the adaptor protein, Fas-associated death domain (FADD),
and the subsequent activation of caspase-8 from its proform. B. The images show two sympathetic neuron
cultures grown either in the presence of NGF (left) or proNGF (right). The NGF promotes survival and axon
outgrowth, whereas the proNGF induces more apoptosis, as assessed with TUNEL labeling (green dots)
through activation of the p75 NTR . (Adapted from Lee et al., 2001)
The death-promoting influence of p75 NTR can
employ the c-Jun N-terminal kinase (JNK) and its
target (the transcription factor, c-Jun) to kill cells. This
pathway can even lead to increased production of FasL
(Le-Niculescu et al., 1999). In cultures of NGF-depend-
ent sympathetic neurons, expression of c-Jun is
induced immediately after withdrawal of the neu-
rotrophin. Experimental reduction of c-Jun is sufficient
to rescue NGF-deprived neurons, and constitutive
overexpression of c-Jun is sufficient to kill neurons in
the presence of NGF (Ham et al., 1995). Similarly, rat
spinal motor neurons can be kept alive in vitro by
blocking JNK activity (Maroney et al., 1998).
THE EXPANDING WORLD OF
SURVIVAL FACTORS
The old adage about taking care not to wish for
something lest it come true has some validity in the
world of survival factors. As research on the NGF and
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