Hepatocyte nuclear factor-3 (HNF-3) binds to the insulin response sequence in the IGF binding protein-1 (IGFBP-1) promoter and enhances promoter function

Abstract

IGF binding protein-1 is an important short-term modulator of IGF bioavailability. Hepatic transcription of IGFBP-1 is increased by glucocorticoids and suppressed by insulin. We previously identified adjacent glucocorticoid and insulin response sequences approximately 90 bp 5' to the RNA cap site in the IGFBP-1 promoter. This insulin response sequence contains a sequence highly related (10/12 bases) to a consensus HNF-3 binding sequence. Gel shift and supershift studies confirm that this sequence binds HNF-3 alpha, beta and gamma. Co-expression of HNF-3 beta enhances IGFBP-1 promoter activity in NIH-3T3 cells. Mutation of this HNF-3 binding sequence disrupts this effect as well as the ability of glucocorticoids to stimulate and of insulin to inhibit IGFBP-1 promoter activity in H4IIE and HepG2 hepatoma cells. HNF-3 binding at this site may play an important role in the multihormonal regulation of hepatic IGFBP-1 gene expression.