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J. Biol. Chem., Vol. 281, Issue 26, 17681-17688, June 30, 2006

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CAAT/Enhancer-binding Protein and cAMP-response Element-binding Protein Mediate Inducible Expression of the Nerve Growth Factor Gene in the Central Nervous System^*

Christine Seitz McCauslin, Victoria Heath, Anna Maria Colangelo¹, Radek Malik, Sook Lee, Alessandra Mallei, Italo Mocchetti, and Peter F. Johnson²

From the Laboratory of Protein Dynamics and Signaling, NCI, National Institutes of Health, Frederick, Maryland 21702-1201 and the Department of Neuroscience, Georgetown University, Medical Center, Washington, D. C. 20057

Nerve growth factor (NGF) synthesis in the rat cerebral cortex is induced by the 2-adrenergic receptor agonist clenbuterol (CLE). Because NGF is a crucial neurotrophic factor for basal forebrain cholinergic neurons, defining the mechanisms that regulate its transcription is important for developing therapeutic strategies to treat pathologies of these neurons. We previously showed that the transcription factor CCAAT/enhancer-binding protein (C/EBP) contributes to NGF gene regulation. Here we have further defined the function of C/EBP and identified a role for cAMP response element-binding protein (CREB) in NGF transcription. Inhibition of protein kinase A in C6-2B glioma cells suppressed CLE induction of an NGF promoter-reporter construct, whereas overexpression of protein kinase A increased NGF promoter activity, particularly in combination with C/EBP. A CRE-like site that binds CREB was identified in the proximal NGF promoter, and C/EBP and CREB were found to associate with the NGF promoter in vivo. Deletion of the CRE and/or C/EBP sites reduced CLE responsiveness of the promoter. In addition, ectopic expression of C/EBP in combination with CLE treatment increased endogenous NGF mRNA levels in C6-2B cells. C/EBP null mice showed complete loss of NGF induction in the cerebral cortex following CLE treatment, demonstrating a critical role for C/EBP in regulating 2-adrenergic receptor-mediated NGF expression in vivo. Thus, our findings demonstrate a critical role for C/EBP in regional expression of NGF in the brain and implicate CREB in CLE-induced NGF gene transcription.

Received for publication, January 9, 2006 , and in revised form, April 12, 2006.

^* This work was supported by the Intramural Research Program of the NCI, National Institutes of Health (NIH), Center for Cancer Research, and by NIH Grant NS29664 (to I. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Laboratory of Neuroscience, Rita Levi-Montalcini, Dept. of Biotechnology and Bioscience, University of Milano-Bicocca, I-20126 Milano, Italy.

² To whom correspondence should be addressed: Laboratory of Protein Dynamics and Signaling, NCI, NIH, Bldg. 539, Rm. 122, P. O. Box B, Frederick, MD 21702-1201. Tel.: 301-846-1627; Fax: 301-846-5991; E-mail: johnsopf{at}ncifcrf.gov.

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