The signal transduction pathway underlying ion channel gene regulation by SP1-C-Jun interactions.
During neuronal differentiation, an exquisitely controlled program of signal transduction events takes place, leading to the temporally and spatially regulated expression of genes associated with the differentiated phenotype. A critical class of genes involved in this phenomenon is that made up of genes encoding neurotransmitter-gated ion channels that play a central role in signal generation and propagation within the nervous system. We used the well established PC12 cell line to investigate the molecular details underlying the expression of the neuronal nicotinic acetylcholine receptor class of ion channels. Neuronal differentiation of PC12 cells can be induced by nerve growth factor, leading to an increase in neuronal nicotinic acetylcholine receptor gene expression. Nerve growth factor initiates several signal transduction cascades. Here, we show that the Ras-dependent mitogen-activated protein kinase and phosphoinositide 3-kinase pathways are critical for the nerve growth factor-mediated increase in the transcriptional activity of a neuronal nicotinic acetylcholine receptor gene promoter. In addition, we show that a component of the Ras-dependent mitogen-activated protein kinase pathway, nerve growth factor-inducible c-Jun, exerts its effects on receptor gene promoter activity most likely through protein-protein interactions with Sp1. Finally, we demonstrate that the target for nerve growth factor signaling is an Sp1-binding site within the neuronal nicotinic acetylcholine receptor gene promoter.
Melnikova
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Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01613, USA.
Gardner
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D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D004330:Drosophila; D007473:Ion Channels / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D016716:PC12 Cells; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
D007473:Ion Channels; D016755:Proto-Oncogene Proteins c-jun; D011950:Receptors, Cholinergic; D016329:Sp1 Transcription Factor; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins