The hepatocyte nuclear factor 3 beta stimulates the transcription of the human insulin-like growth factor I gene in a direct and indirect manner

Promoter 1 (P1) of the human insulin-like growth factor I (IGF-I) gene is most active in adult liver. In this study we show that HNF-3 beta, a member of the winged helix protein family of Liver-enriched transcription factors, has a strong stimulatory effect on the activity of P1. Transient transfection experiments in combination with bandshift and DNase I footprinting analysis revealed the presence of two HNF-3 binding sites in the proximal promoter region of P1. Both binding sites, which are well conserved in evolution, are required for maximal transactivation. Studies employing HNF-3 mutant constructs indicated that IGF-I expression is also regulated indirectly by HNF-3 beta as a consequence of enhanced expression of HNF-1 alpha. This liver-enriched transcription factor bets previously been shown to transactivate P1. Thus, HNF-3 beta regulates the expression of the human IGF-I gene via two distinct mechanisms.