Original Article

Activation of Nuclear Factor B and bcl-x Survival Gene Expression by Nerve Growth Factor Requires Tyrosine Phosphorylation of IB

Correspondence to: Jochen H.M. Prehn, Interdisciplinary Center for Clinical Research (IZKF), Research Group “Apoptosis and Cell Death,” Faculty of Medicine, Westphalian Wilhelms-University, Röntgenstrasse 21, D-48149 Münster, Germany. Tel:49-251-83-52251 Fax:49-251-83-52250 E-mail:prehn{at}uni-muenster.de.

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-B (NFB). 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 NFB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFB p65 subunit. NGF-induced NFB activity and Bcl-xL expression were inhibited in cells overexpressing the NFB inhibitor, IB. Unlike tumor necrosis factor- (TNF-), however, NGF-induced NFB activation occurred without significant degradation of IBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein–tagged IB. Moreover, in contrast to TNF-, NGF failed to phosphorylate IB at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IB potently suppressed NFG-, but not TNF-–induced NFB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-–, but not NGF-induced NFB activation. We conclude that NGF and TNF- induce different signaling pathways in neurons to activate NFB and bcl-x gene expression.

Key Words: nerve growth factor, nuclear factor-B, Bcl-xL, tumor necrosis factor-, IB

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