Transcriptional Regulation of the Neuropeptide Y Gene by Nerve Growth Factor: Antagonism by Glucocorticoids and Potentiation by Adenosine 3′,5′-Monophosphate and Phorbol Ester

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Abstract
The regulation of the preproneuropeptide Y gene (NPY gene) by nerve growth factor (NGF) and second messenger systems in PC12 rat pheochromocytoma cells was studied by means of steady state NPY mRNA and nuclear run-on transcription analyses. Treatment of cells with 2.5S NGF increased the NPY mRNA abundance up to 100-fold over 1-6 days. Glucocorticoids (e.g.dexamethasone) potentiated by up to 3-fold the stimulation by NGF at early times (.ltoreq. 7H), but strongly suppressed it at later times (.gtoreq. 25 h). The response to NGF was blocked by cycloheximide, indicating a requirement for ongoing protein synthesis. Treatment of cells for 24-48 h with combinations of NGF, forskolin to elevate cAMP levels, and phorbol-12-myristate-13-acetate (PMA) to activate protein kinase C synergistically elevated NPY mRNA levels. The rate of NPY gene transcription in PC12 nuclei was increased by NGF, forskolin plus PMA, or NGF plus forskolin plus PMA, indicating that these regulators act at least in part at a transcriptional level. .beta.-Actin gene transcription also was elevated synergistically by forskolin and PMA. In summary, NPY gene transcription and NPY mRNA levels are controlled by multiple, potentially interacting regulatory systems. The striking antagonism between NGF and glucocorticoid may reflect the hormonal control of phenotypic choice during neural crest differentiation.