Beta-Adrenergic Receptor-Induced Activation of Nerve Growth Factor Gene Transcription in Rat Cerebral Cortex Involves Ccaat/Enhancer-Binding Protein Delta

Stimulation of beta-adrenergic receptors (BAR) by clenbuterol (CLE) increases nerve growth factor (NGF) biosynthesis in the rat cerebral cortex but not in other regions of the brain. We have explored the transcription mechanisms that may account for the cortex-specific activation of the NGF gene. Although the NGF promoter contains an AP-1 element, AP-1-binding activity in the cerebral cortex was not induced by CLE, suggesting that other transcription factors govern the brain area-specific induction of NGF. Because BAR activation increases cAMP levels, we examined the role of CCAAT/enhancer-binding proteins (C/EBP), some of which are known to be cAMP-inducible, In C6-2B glioma cells, whose NGF expression is induced by BAR agonists, (i) CLE increased C/EBP delta-binding activity, (ii) NGF mRNA levels were increased by overexpressing C/EBP delta, and (iii) C/EBP delta increased the activity of an NGF promoter-reporter construct. Moreover, DNase footprinting and deletion analyses identified a C/EBP delta site in the proximal region of the NGF promoter. C/EBP delta appears to be responsible for the BAR-mediated activation of the NGF gene in vivo, since CLE elicited a time-dependent increase in C/EBP delta-binding activity in the cerebral cortex only. Our data suggest that, while AP-1 may regulate basal levels of NGF expression, C/EBP delta is a critical component determining the area-specific expression of NGF in response to BAR stimulation. [References: 45]

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