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

Abstract

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.

Social Stress Enhances Sympathetic Innervation of Primate Lymph Nodes: Mechanisms and Implications for Viral Pathogenesis

“…The present data are consistent with the hypothesis that upregulation of NGF gene expression is responsible for increased innervation density in stressed animals, but a reverse relationship is conceivable in which catecholamine signaling might causally induce NGF transcription (e.g., via cAMP-responsive promoter elements) (McCauslin et al, 2006). Using rhesus macaque PBMCs as a model of lymphocytes that circulate through the lymph node, we exposed either unstimulated or PHA-activated PBMCs to NE concentrations comparable with those measured in secondary lymphoid organs and other solid tissues (Felten et al, 1987;Lara and Belmar, 1991;Shimizu et al, 1994).…”

C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

“…Here, the addition of C1q to fA␤-injured neurons resulted in increased phosphorylation and nuclear translocation of CREB, similar to what was observed in nutrient-stressed neurons (10) and in monocytes (46). CREB is a transcription factor vital for long term memory and synaptic plasticity (34), neurogenesis (47)(48)(49), and induction of neurotrophic factors in the CNS (35). In addition, pCREB is a central transcription factor in brain-derived neurotrophic factor signaling (50) and also induces brain-derived neurotrophic factor upon activation (51).…”

Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis

“…As NGF is transcriptionally up-regulated by an intracellular cAMP-dependent signaling pathway in the brain [24][25][26][27][28], it is highly likely that the prostaglandin E2-cAMP signaling pathway, which plays key roles in the growth and inflammation of endometriotic tissues [29], may participate in the induction of NGF mRNA expression in endometriosis. Alternatively, proinflammatory cytokines including interleukin-1β and tumor necrosis factor-α may stimulate NGF production [30].…”