Sb. Maggirwar et al., Nerve growth factor-dependent activation of NF-kappa B contributes to survival of sympathetic neurons, J NEUROSC, 18(24), 1998, pp. 10356-10365
Neurotrophins activate multiple signaling pathways in neurons. However, the
precise roles of these signaling molecules in cell survival are not well u
nderstood. In this report, we show that nerve growth factor (NGF) activates
the transcription factors NF-kappa B and AP-1 in cultured sympathetic neur
ons. Activated NF-kappa B complexes were shown to consist of heterodimers o
f p50 and Rel proteins (RelA, as well as c-Rel), and NF-kappa B activation
was found to occur independently of de novo protein synthesis but in a mann
er that required the action of the proteasome complex. Treatment with the N
F-kappa B inhibitory peptide SN50 in the continuous presence of NGF resulte
d in dose-dependent induction of cell death. Under the conditions used, SN5
0 was shown to selectively inhibit NF-kappa B activation but not the activa
tion of other cellular transcription factors such as AP-1 and cAMP response
element-binding protein. Cells treated with SN50 exhibited morphological a
nd biochemical hallmarks of apoptosis, and the kinetics of cell killing wer
e accelerated relative to death induced by NGF withdrawal. Finally, experim
ents were conducted to test directly whether NF-kappa B could act as a surv
ival factor for NGF-deprived neurons. Microinjection of cells with an expre
ssion plasmid encoding NF-kappa B (c-Rel) resulted in enhanced neuronal sur
vival after withdrawal of NGF, whereas cells that were transfected with a v
ector encoding a mutated derivative of c-Rel lacking the transactivation do
main underwent cell death to the same extent as control cells. Together, th
ese findings suggest that the activation of NF-kappa B/Rel transcription fa
ctors may contribute to the survival of NGF-dependent sympathetic neurons.