Recent evidence indicates that
nerve growth factor (
NGF) produces its effects through signaling contributions from both TrkA and the p75 receptor. In contrast to its trophic actions through TrkA,
NGF binding to p75 has been shown to activate programmed cell death through a mechanism involving the stress
kinase JNK. However, this receptor also activates
nuclear factor kappaB (
NF-kappaB), the role of which has yet to be determined. We investigated the function of p75-mediated
NF-kappaB stimulation in regulating cell survival in the rat
schwannoma cell line RN22, which expresses p75, but not TrkA. Gel shift assays demonstrated activation of
NF-kappaB in response to
NGF within 30 min and lasting at least 4 h.
NGF also stimulated JNK in the cells (detected by in vitro
kinase assays) with a similar time course. Preventing activation of
NF-kappaB with the specific inhibitor SN50 resulted in
NGF-induced cell loss. Similarly, transfection of the cells with a mutant form of the endogenous
NF-kappaB inhibitor (IkappaBalphaDeltaN), which cannot be degraded and therefore remains bound to
NF-kappaB, preventing its activation, resulted in a significant increase in the number of apoptotic cells following
NGF treatment. These results suggest that
NGF activation of
NF-kappaB through the p75 receptor promotes survival, counterbalancing the pro-apoptotic signal.