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) in creases nerve growth factor (NGF) biosynthesis in the rat cerebral cor tex but not in other regions of the brain. We have explored the transc ription 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, s uggesting that other transcription factors govern the brain area-speci fic 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 NG F expression is induced by BAR agonists, (i) CLE increased C/EBP delta -binding activity, (ii) NGF mRNA levels were increased by overexpressi ng C/EBP delta, and (iii) C/EBP delta increased the activity of an NGF promoter-reporter construct. Moreover, DNase footprinting and deletio n 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-media ted activation of the NGF gene in vivo, since CLE elicited a time-depe ndent increase in C/EBP delta-binding activity in the cerebral cortex only. Our data suggest that, while AP-1 may regulate basal levels of N GF expression, C/EBP delta is a critical component determining the are a-specific expression of NGF in response to BAR stimulation.