Functional interplay between nuclear factor-kappa B and c-Jun integrated by coactivator p300 determines the survival of nerve growth factor-dependentPC12 cells
Sb. Maggirwar et al., Functional interplay between nuclear factor-kappa B and c-Jun integrated by coactivator p300 determines the survival of nerve growth factor-dependentPC12 cells, J NEUROCHEM, 74(2), 2000, pp. 527-539
Nerve growth factor (NGF) activates the transcription factors nuclear facto
r kappa B (NF-kappa B) and activator protein-1 (AP-1) in sympathetic neuron
s. Whereas NGF-inducible NF-kappa B 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-kappa B 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 downregulation of NF-kappa B activity
. To investigate how the signal transduction pathways activating c-Jun and
NF-kappa B are differentially regulated by NGF, we performed transcriptiona
l analyses. Expression of RelA (NF-kappa B) suppressed the c-Jun-dependent
transcription of c-jun, and this effect was reversed by overexpression of t
he coactivator p300. RelA's effects on c-Jun transcription were mediated by
competitive binding of the carboxy-terminal region of RelA to the CHI doma
in of p300, which also binds to c-Jun; deletion of this region abrogated th
e ability of RelA to inhibit c-Jun activity, Furthermore, the inhibition of
endogenous NF-kappa B in NGF-maintained neuronal PC12 cells led to the ind
uction of c-Jun synthesis and a marked increase in cell death. Together, th
ese studies demonstrate a functional interaction between NF-kappa B and c-J
un and suggest a novel mechanism of NF-kappa B-mediated neuroprotection.