Characterization of a neuregulin-1 gene promoter: Positive regulation of type I isoforms by NF-kB

摘要

The neuregulin-1 (Nrgl) gene encodes for a group of growth factors with multiple functions during mammalian development. Overexpression of Nrgl is found in many different cancer types and correlates with cancer progression and an aggressive phenotype. In this study we identified the promoter of Nrgl type I isoforms. Reporter gene assays revealed that 850 bp upstream from the translation initiation codon are necessary for high transcriptional activity in murine Neuro-2A neuroblastoma cells. The core promoter is highly conserved among mammals, has multiple transcription start sites and is located in a CpG island. The conserved promoter region contains GC-and GT-box elements and overexpression of Spl increased promoter activity, while ZBP-89 decreased the activity. Overexpression of the NF-kB subunit p65 (RelA) led to a strong activation of the promoter mediated through a single NF-kB binding site. Reflecting that the transcriptional activity of NF-kB and Spl are increased upon Nrg-stimulation in breast cancer cells this study suggests a potential mechanism of a positive feedback loop/autoregulation of neuregulin.