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Nuclear Factor κB/p49 Is a Negative Regulatory Factor in Nerve Growth Factor‐Induced Choline Acetyltransferase Promoter Activity in PC12 Cells
Author(s) -
ToliverKinsky T.,
Wood T.,
PerezPolo J. R.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0752241.x
Subject(s) - choline acetyltransferase , nerve growth factor , biology , basal forebrain , cholinergic , cholinergic neuron , nuclear protein , microbiology and biotechnology , medicine , endocrinology , transcription factor , receptor , biochemistry , gene
A novel nuclear factor κB (NF‐κB) binding sitehas been identified within the promoter region of the mouse gene encodingcholine acetyltransferase (ChAT), the enzyme that synthesizes acetylcholineand has been implicated in the cognitive deficits associated with aging andAlzheimer's disease. This binding site, which is located within the nervegrowth factor (NGF)‐responsive enhancer element, was recognized by theNF‐κB protein p49 but not p65 or p50. p49 from both basal forebrain andPC12 nuclear extracts interacted with this specific sequence inelectrophoretic mobility shift assays. Mutation of the NF‐κB site causedan increase in NGF‐induced promoter activation, whereas overexpression of p49in NGF‐differentiated PC12 cells caused a decrease in endogenous ChAT enzymeactivity and a decrease in promoter activity that was specifically mediatedthrough this NF‐κB binding site. Treatment of PC12 cells with NGFresulted in a drastic reduction in nuclear p49 binding to the ChAT NF‐κBsite after 24 h, but nuclear p49 levels were not altered, suggesting that lateNGF‐mediated events prevent binding of p49 to the ChAT promoter by an unknownmechanism other than nuclear translocation. Decreased ChAT expression andincreased NF‐κB activity in the brain are associated with aging andAlzheimer's disease. These data indicate that p49 is a negative regulator ofChAT expression and suggest a possible mechanism for aging‐associated declinesin cholinergic function.