Characterization of a neuregulin-1 gene promoter: positive regulation of type I isoforms by NF-kappaB.

The neuregulin-1 (Nrg1) gene encodes for a group of growth factors with multiple functions during mammalian development. Overexpression of Nrg1 is found in many different cancer types and correlates with cancer progression and an aggressive phenotype. In this study we identified the promoter of Nrg1 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 Sp1 increased promoter activity, while ZBP-89 decreased the activity. Overexpression of the NF-kappaB subunit p65 (RelA) led to a strong activation of the promoter mediated through a single NF-kappaB binding site. Reflecting that the transcriptional activity of NF-kappaB and Sp1 are increased upon Nrg-stimulation in breast cancer cells this study suggests a potential mechanism of a positive feedback loop/autoregulation of neuregulin.