The Hepatocyte Nuclear Factor 3β Stimulates the Transcription of the Human Insulin-like Growth Factor I Gene in a Direct and Indirect Manner

Abstract

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-3beta, 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-3beta as a consequence of enhanced expression of HNF-1alpha. This liver-enriched transcription factor has previously been shown to transactivate P1. Thus, HNF-3beta regulates the expression of the human IGF-I gene via two distinct mechanisms.