BETA-ADRENERGIC RECEPTOR-INDUCED ACTIVATION OF NERVE GROWTH-FACTOR GENE-TRANSCRIPTION IN RAT CEREBRAL-CORTEX INVOLVES CCAAT ENHANCER-BINDING-PROTEIN-DELTA/
Am. Colangelo et al., BETA-ADRENERGIC RECEPTOR-INDUCED ACTIVATION OF NERVE GROWTH-FACTOR GENE-TRANSCRIPTION IN RAT CEREBRAL-CORTEX INVOLVES CCAAT ENHANCER-BINDING-PROTEIN-DELTA/, Proceedings of the National Academy of Sciences of the United Statesof America, 95(18), 1998, pp. 10920-10925
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.