title: Nerve growth factor-dependent activation of NF-kappaB contributes to survival of sympathetic neurons.
abstract: Neurotrophins activate multiple signaling pathways in neurons. However, the precise roles of these signaling molecules in cell survival are not well understood. In this report, we show that nerve growth factor (NGF) activates the transcription factors NF-kappaB and AP-1 in cultured sympathetic neurons. Activated NF-kappaB complexes were shown to consist of heterodimers of p50 and Rel proteins (RelA, as well as c-Rel), and NF-kappaB activation was found to occur independently of de novo protein synthesis but in a manner that required the action of the proteasome complex. Treatment with the NF-kappaB inhibitory peptide SN50 in the continuous presence of NGF resulted in dose-dependent induction of cell death. Under the conditions used, SN50 was shown to selectively inhibit NF-kappaB activation but not the activation of other cellular transcription factors such as AP-1 and cAMP response element-binding protein. Cells treated with SN50 exhibited morphological and biochemical hallmarks of apoptosis, and the kinetics of cell killing were accelerated relative to death induced by NGF withdrawal. Finally, experiments were conducted to test directly whether NF-kappaB could act as a survival factor for NGF-deprived neurons. Microinjection of cells with an expression plasmid encoding NF-kappaB (c-Rel) resulted in enhanced neuronal survival after withdrawal of NGF, whereas cells that were transfected with a vector encoding a mutated derivative of c-Rel lacking the transactivation domain underwent cell death to the same extent as control cells. Together, these findings suggest that the activation of NF-kappaB/Rel transcription factors may contribute to the survival of NGF-dependent sympathetic neurons.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Maggirwar
authors.forename: P D
authors.initials: PD
authors.lastname: Sarmiere
authors.forename: S
authors.initials: S
authors.lastname: Dewhurst
authors.forename: R S
authors.initials: RS
authors.lastname: Freeman
mesh_terms: D000320:Adrenergic Fibers / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004622:Embryo, Mammalian; D051863:Host Cell Factor C1; D006868:Hydrolysis; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D009414:Nerve Growth Factors / Q000494:pharmacology*; D050811:Octamer Transcription Factor-1; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020569:Proto-Oncogene Proteins c-rel; D051381:Rats; D017783:Superior Cervical Ganglion / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D051863:Host Cell Factor C1; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009414:Nerve Growth Factors; C000606206:Nfkbia protein, rat; D050811:Octamer Transcription Factor-1; D009842:Oligopeptides; D010455:Peptides; C494168:Pou2f1 protein, rat; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C118258:SN50 peptide; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D010447:Peptide Hydrolases