Nerve Growth Factor-Dependent Activation of NF-κB Contributes to Survival of Sympathetic Neurons

Abstract

Neurotrophins activate multiple signaling pathways in neurons. However, the precise roles of these signaling molecules in cell survival are not well understood. In this report, we show that nerve growth factor (NGF) activates the transcription factors NF-B and AP-1 in cultured sympathetic neurons. Activated NF-B complexes were shown to consist of heterodimers of p50 and Rel proteins (RelA, as well as c-Rel), and NF-B activation was found to occur independently of de novo protein synthesis but in a manner that required the action of the proteasome complex. Treatment with the NF-B inhibitory peptide SN50 in the continuous presence of NGF resulted in dosedependent induction of cell death. Under the conditions used, SN50 was shown to selectively inhibit NF-B activation but not the activation of other cellular transcription factors such as AP-1 and cAMP response element-binding protein. Cells treated with SN50 exhibited morphological and biochemical hallmarks of apoptosis, and the kinetics of cell killing were accelerated relative to death induced by NGF withdrawal. Finally, experiments were conducted to test directly whether NF-B could act as a survival factor for NGF-deprived neurons. Microinjection of cells with an expression plasmid encoding NF-B (c-Rel) resulted in enhanced neuronal survival after withdrawal of NGF, whereas cells that were transfected with a vector encoding a mutated derivative of c-Rel lacking the transactivation domain underwent cell death to the same extent as control cells. Together, these findings suggest that the activation of NF-B/Rel transcription factors may contribute to the survival of NGF-dependent sympathetic neurons.

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…62 In addition, NGF was incapable of preventing the death of cultured sympathetic neurons when the neurons were treated with nonspecific inhibitors of NF-kB. 11 In contrast to the findings described above, other studies suggest that NF-kB activation promotes the death of neurons under certain conditions. In models of ischemia, for example, NF-kB activation appears to contribute to brain damage and mice lacking the p50 subunit of NF-kB demonstrate decreased infarct volumes.…”

“…A growing list of signals that can activate NF-kB in neurons includes tumor necrosis factor-a (TNF), 9 the excitatory neurotransmitter glutamate, 3 nerve growth factor (NGF), 10,11 activity-dependent neurotrophic factor (ADNF), 12 a secreted form of amyloid precursor protein 13 and cell adhesion molecules. 14 These molecules can activate NF-kB through coupling to kinase cascades including calcium/calmodulindependent kinase II, 15 Akt 16,17 and protein kinase C 18 ( Figure 2).…”

Nuclear transcription factor-κB as a target for cancer drug development

“…138 Cell types (not necessarily oncogenes) that display an anti-apoptotic role for NF-B include B cells, 139,140 T cells 141,142 granulocytes, 143 macrophages, 144 neuronal cells, 145,146 and smooth muscle cells. 147 Although rare, there are systems in which NF-B has been shown to play a pro-apoptotic role in addition to its more common anti-apoptotic role.…”

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

“…Potential Akt substrates whose phosphorylation might be essential to long-term survival include inhibitor of nuclear factor-jB kinase (IKK)a via subsequent activation of nuclear factor jB or p70S6 kinase (Pullen et al 1998;Romashkova and Makarov 1999). Nuclear factor jB signaling has been shown to promote the survival of neurons (Maggirwar et al 1998). Akt might inhibit other pro-apoptotic signaling pathways besides JNK.…”