Analysis of the NF-κB and PI 3-Kinase/Akt Survival Pathways in Nerve Growth Factor-Dependent Neurons

Abstract

Nerve growth factor (NGF) readdition to NGF-deprived neurons can halt Jun N-terminal kinase (JNK) activation, cytochrome c release, and cell death through mechanisms that may involve phosphatidylinositol (PI) 3-kinase, Akt, and nuclear factor kappa B (NF-κB). We found that expression of the NF-κB protein c-Rel in NGF-deprived neurons blocks cytochrome c release but does not inhibit c-Jun phosphorylation. Conversely, inhibition of NF-κB in NGF-maintained neurons promotes cytochrome c release and cell death. In contrast to c-Rel, activated PI 3-kinase and Akt inhibit c-Jun phosphorylation but have only a small effect on cytochrome c release. Finally, although c-Rel can protect neurons from death caused by inhibitors of PI 3-kinase or Akt, NF-κB function is not critical for Akt-promoted survival. These results suggest that the PI 3-kinase/Akt and NF-κB survival pathways target distinct cell death events in neurons.