NGF induces the expression of the VGF gene through a cAMP response element

NGF is a peptide growth factor that plays a key role in the differentiation and survival of neurons in both the PNS and CNS. NGF acts through both transcription-dependent and transcription-independent mechanisms to regulate the differentiation of PC12 cells. To better understand the regulation of gene expression by NGF, we have defined a cis-acting sequence that is immediately upstream of the transcription start site of the VGF (a2/NGF33.1) gene that is required for induction by NGF. Within this sequence is a consensus cAMP response element (CRE) embedded in a 14 base pair palindrome. Mutations in this CRE eliminate induction of the VGF gene both by NGF and by agents that act via cAMP. Although this sequence confers transcriptional induction by both NGF and cAMP, it is not sufficient to allow induction by epidermal growth factor, acidic or basic fibroblast growth factor, or phorbol 12-myristate 13-acetate (PMA). Thus, this sequence defines an element that is selectively activated by NGF and cAMP. Promoter fragments from the VGF gene that include the core CRE efficiently bind the inducible transcription factor CREB, while fragments bearing mutations that eliminate NGF and cAMP inducibility fail to do so. Sequence comparisons and hybridization studies indicate that there are at least two alternatively spliced forms of VGF mRNA, and the accumulation of both of these forms is similarly regulated by NGF and cAMP.