vasoactive-intestinal-peptide and 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine

Ciliary neurotrophic factor (CNTF)-dependent induction of expression of the neuropeptide vasoactive intestinal peptide (VIP) gene is mediated by a 180-base pair cytokine response element (CyRE) in the VIP promoter. To elucidate the molecular mechanisms mediating the transcriptional activation by CNTF, intracellular signaling to the CyRE has been studied in a neuroblastoma cell line. It has been shown previously that CNTF induces Stat proteins to bind to a site within the CyRE. CNTF also induces a second protein to bind to a C/EBP-like site within the CyRE. In this report, we show that this inducible CyRE binding protein is composed of the AP-1 proteins c-Fos, JunB, and JunD. These proteins bind to a non-canonical AP-1 site located near the previously characterized C/EBP site. The serine/threonine kinase inhibitor H7 prevents CNTF-dependent induction of AP-1 binding and CyRE-mediated transcription, suggesting that an H7-sensitive kinase is important to mediating CNTF effects on VIP transcription. The integration at the VIP CyRE of the Jak-Stat and AP-1 signaling pathways with other pre-existing proteins provides a cellular mechanism for cell- and cytokine-specific signaling.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; Ciliary Neurotrophic Factor; Cytokines; DNA-Binding Proteins; Enzyme Inhibitors; Humans; Nerve Growth Factors; Nerve Tissue Proteins; Nuclear Proteins; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Trans-Activators; Transcription Factor AP-1; Transcription, Genetic; Vasoactive Intestinal Peptide