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MBC in Press, published online ahead of print December 19, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0624

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Submitted on June 29, 2007
Revised on October 30, 2007
Accepted on December 7, 2007

Tumor Necrosis Factor {alpha} Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

Yoshinori Takei and Ronald Laskey

MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, CB2 0XZ, United Kingdom

Monitoring Editor: Marianne Bronner-Fraser

While nerve growth factor (NGF) promotes survival of neurones, tumor necrosis factor {alpha} (TNF-{alpha}) contributes to cell death triggered by NGF depletion, through TNF-{alpha} receptor 1 (TNFR1). In contrast to this effect, TNF-{alpha} can promote neural cell survival via TNF-{alpha} receptor 2 (TNFR2). Although these findings demonstrate pivotal roles of TNF-{alpha} and NGF in cell fate decisions, cross-talk between these signaling pathways has not been clarified. We find that NGF can induce TNF-{alpha} synthesis through the NF-{kappa}B transcription factor. This provides a new basis for examining the cross-talk between NGF and TNF-{alpha}. Inhibition of TNFR2 shows opposite effects on two downstream kinases of NGF, Erk and Akt. It increases Erk activation by NGF and this increased activation induces differentiation of neuroblastoma cell lines. Reciprocally, inhibition of TNFR2 decreases Akt activation by NGF. Consistent with an essential role of Akt in survival signaling, inhibition of TNF-{alpha} signaling decreases NGF-dependent survival of neurones from rat dorsal root ganglia. Thus, NGF and NGF-induced TNF-{alpha} cooperate to activate Akt, promoting survival of normal neural cells. However, the NGF-induced TNF-{alpha} suppresses Erk activation by NGF, blocking NGF-induced differentiation of neuroblastoma cells. TNFR2 signaling could be a novel target to modulate cell responses to NGF.

Address correspondence to: Yoshinori Takei (yt215{at}cam.ac.uk)






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