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Published online 19 February 2001. doi:10.1083/jcb.152.4.753
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© The Rockefeller University Press, 0021-9525/2001//753 $5.00
The Journal of Cell Biology, Volume 152, Number 4, , 2001 753-764

Original Article

Activation of Nuclear Factor {kappa}b and bcl-x Survival Gene Expression by Nerve Growth Factor Requires Tyrosine Phosphorylation of I{kappa}B{alpha}



Nguyen Truc Buia, Antonia Livolsic, Jean-Francois Peyronc, and Jochen H.M. Prehna,b

a Interdisciplinary Center for Clinical Research, Research Group "Apoptosis and Cell Death,", D-48149 Münster, Germany
b Department of Pharmacology and Toxicology, Faculty of Medicine, Westphalian Wilhelms-University, D-48149 Münster, Germany
c Institut National de la Santé et de la Recherche Médicale U526 "Hematopoietic Cell Activation, " Faculte de Medecine Pasteur, 06107 Nice, France
Interdisciplinary Center for Clinical Research (IZKF), Research Group "Apoptosis and Cell Death," Faculty of Medicine, Westphalian Wilhelms-University, Röntgenstrasse 21, D-48149 Münster, Germany.49-251-83-5225049-251-83-52251

prehn{at}uni-muenster.de

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-{kappa}B (NF{kappa}B). We investigated the effect of NGF on the expression of Bcl-xL, an anti–apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1–10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NF{kappa}B activity after treatment with NGF that was associated with increased nuclear translocation of the active NF{kappa}B p65 subunit. NGF-induced NF{kappa}B activity and Bcl-xL expression were inhibited in cells overexpressing the NF{kappa}B inhibitor, I{kappa}B{alpha}. Unlike tumor necrosis factor-{alpha} (TNF-{alpha}), however, NGF-induced NF{kappa}B activation occurred without significant degradation of I{kappa}Bs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein–tagged I{kappa}B{alpha}. Moreover, in contrast to TNF-{alpha}, NGF failed to phosphorylate I{kappa}B{alpha} at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of I{kappa}B{alpha} potently suppressed NFG-, but not TNF-{alpha}–induced NF{kappa}B activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-{alpha}–, but not NGF-induced NF{kappa}B activation. We conclude that NGF and TNF-{alpha} induce different signaling pathways in neurons to activate NF{kappa}B and bcl-x gene expression.

Key Words: nerve growth factor • nuclear factor-{kappa}B • Bcl-xL • tumor necrosis factor-{alpha} • I{kappa}B

© 2001 The Rockefeller University Press

Abbreviations used in this paper: COX-2, cyclooxygenase-2; EGFP, enhanced green fluorescent protein; NF{kappa}B, nuclear factor-{kappa}B; P-Ser32-I{kappa}B{alpha}, serine 32-phosphorylated I{kappa}B{alpha}; RT, reverse transcription; SEAP, secreted form of human placental alkaline phosphatase; TNF-{alpha}, tumor necrosis factor-{alpha}; TRAF6 dn, dominant negative tumor necrosis factor receptor-associated factor-6.


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