Nerve Growth Factor Activation of Nuclear Factor κB through Its p75 Receptor Is an Anti-apoptotic Signal in RN22 Schwannoma Cells

Abstract

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 κB (NF-κB), the role of which has yet to be determined. We investigated the function of p75-mediated NF-κB 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-κB in response to NGF within 30 min and lasting at least 4 h. NGF also stimulated JNK in the cells (detected by <i>in vitro</i> kinase assays) with a similar time course. Preventing activation of NF-κB with the specific inhibitor SN50 resulted in NGF-induced cell loss. Similarly, transfection of the cells with a mutant form of the endogenous NF-κB inhibitor (IκBαΔN), which cannot be degraded and therefore remains bound to NF-κB, 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-κB through the p75 receptor promotes survival, counterbalancing the pro-apoptotic signal.