Abstract
Vasoactive intestinal polypeptide (VIP) is a pleiotropic neurotransmitter with roles in development, circadian function, immune regulation, and pain sensation. VIP gene expression is synergistically activated by elevation of cAMP and Ca2+ (Hamelink et al., J. Neurosci. 22:, 2002). The effects of these two signaling pathways on VIP gene regulation were examined in NBFL human neuroblastoma cells, which endogenously express VIP. Treatment with forskolin or the Ca2+ionophore A23187, alone modestly (10-fold) increased VIP mRNA, but together caused a synergistic (75-fold) increase in NBFL cells. Although stimulation of neuroendocrine genes by both cAMP and Ca2+ via convergence on a common cis-active element, the cyclic AMP-response element (CRE) is common, we found, unexpectedly, that the CRE of a full-length VIP luciferase reporter gene, while essential for cAMP-stimulated transcription and synergistic stimulation with cAMP and Ca2+, was dispensable for activation by Ca2+ alone. Instead, Ca2+ activation required a single element of 280 bases located 4 kb upstream from the VIP proximal promoter that was previously identified as a tissue specifier element (TSE; Hahm et al., JBC 273:,1998). The TSE of the VIP gene is a novel calcium response element in a neuron-specific gene that is independent of the CRE, but acts together with it to enable synergistic cAMP and Ca2+signaling.
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