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Functional Interplay Between Nuclear Factor‐κB and c‐Jun Integrated by Coactivator p300 Determines the Survival of Nerve Growth Factor‐Dependent PC12 Cells

Abstract: Nerve growth factor (NGF) activates the transcription factors nuclear factor κB (NF‐κB) and activator protein‐1 (AP‐1) in sympathetic neurons. Whereas NGF‐inducible NF‐κB is required for the survival of neurons, c‐Jun has the ability to promote neuronal death. In this report, we have examined the effect of NGF withdrawal on c‐Jun and NF‐κB transcription factors in PC12 cells differentiated to a neuronal phenotype. We show that the withdrawal of NGF from these cultures results in de novo synthesis of c‐Jun, increase in AP‐1 activity, and down‐regulation of NF‐κB activity. To investigate how the signal transduction pathways activating c‐Jun and NF‐κB are differentially regulated by NGF, we performed transcriptional analyses. Expression of RelA (NF‐κB) suppressed the c‐Jun‐dependent transcription of c‐jun, and this effect was reversed by overexpression of the coactivator p300. RelA’s effects on c‐Jun transcription were mediated by competitive binding of the carboxy‐terminal region of RelA to the CH1 domain of p300, which also binds to c‐Jun; deletion of this region abrogated the ability of RelA to inhibit c‐Jun activity. Furthermore, the inhibition of endogenous NF‐κB in NGF‐maintained neuronal PC12 cells led to the induction of c‐Jun synthesis and a marked increase in cell death. Together, these studies demonstrate a functional interaction between NF‐κB and c‐Jun and suggest a novel mechanism of NF‐κB‐mediated neuroprotection.