The signal transduction pathway underlying ion channel gene regulation by Sp1-c-Jun interactions

During neuronal differentiation, an exquisitely controlled program of signa l 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 g enes 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 under lying 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 acetylcho line receptor gene expression, Nerve growth factor initiates several signal transduction cascades. Here, we show that the Pas-dependent mitogen-activa ted protein kinase and phosphoinositide 3-kinase pathways are critical for the nerve growth factor-mediated increase in the transcriptional activity o f a neuronal nicotinic acetylcholine receptor gene promoter. In addition, w e show that a component of the Ras-dependent mitogen-activated protein kina se pathway, nerve growth factor-inducible c-Jun, exerts its effects on rece ptor gene promoter activity most likely through protein-protein interaction s with Spl. Finally, we demonstrate that the target for nerve growth factor signaling is an Spl-binding site within the neuronal nicotinic acetylcholi ne receptor gene promoter.