Nerve growth factor activation of nuclear factor kappaB through its p75 receptor is an anti-apoptotic signal in RN22 schwannoma cells.
Recent evidence indicates that nerve growth factor (NGF) produces its effects through signaling contributions from both TrkA and the p75 receptor. In contrast to its trophic actions through TrkA, NGF binding to p75 has been shown to activate programmed cell death through a mechanism involving the stress kinase JNK. However, this receptor also activates nuclear factor kappaB (NF-kappaB), the role of which has yet to be determined. We investigated the function of p75-mediated NF-kappaB stimulation in regulating cell survival in the rat schwannoma cell line RN22, which expresses p75, but not TrkA. Gel shift assays demonstrated activation of NF-kappaB in response to NGF within 30 min and lasting at least 4 h. NGF also stimulated JNK in the cells (detected by in vitro kinase assays) with a similar time course. Preventing activation of NF-kappaB with the specific inhibitor SN50 resulted in NGF-induced cell loss. Similarly, transfection of the cells with a mutant form of the endogenous NF-kappaB inhibitor (IkappaBalphaDeltaN), which cannot be degraded and therefore remains bound to NF-kappaB, preventing its activation, resulted in a significant increase in the number of apoptotic cells following NGF treatment. These results suggest that NGF activation of NF-kappaB through the p75 receptor promotes survival, counterbalancing the pro-apoptotic signal.
Gentry
J J
JJ
Department of Biochemistry and the Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
Casaccia-Bonnefil
P
P
Carter
B D
BD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009442:Neurilemmoma / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D010455:Peptides; D020800:Receptor, Nerve Growth Factor; C118258:SN50 peptide; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases