Liver-specific expression of human insulin-like growth factor binding protein 1: functional role of transcription factor HNF1 in vivo.

Abstract

Tissue-specific expression of insulin-like growth factor binding protein 1 (IGFBP-1) in the liver has been studied using differentiated (H41H and C2Rev7) and dedifferentiated (Hs and C2) rat hepatoma cell lines. Northern blot analysis showed that endogenous IGFBP-1 mRNA was expressed only in the differentiated cell lines. The first 341 base pairs 5' to the transcription initiation site of the human IGFBP-1 gene were inserted upstream of the chloramphenicol acetyltransferase reporter gene (pBP-1341). Expression of this gene from the human IGFBP-1 promoter was 10-16 times more efficient in the H411 line than in the other hepatoma cell lines and 40 and -12 times more so than in rat fibroblasts (FR3T3) and a human cervical carcinoma cell line (C33), respectively.Cotransfection of pBP-1341 and pRSV-HNF1 and/or pRSV-v-HNF1 (eukaryotic expression vectors that drive the synthesis of the liver-enriched trans-acting factor HNF1 or of v-HNF1, a related form) in C33 recipient cells yielded a 6-fold increase in IGFBP-1 promoter activity by HNF1 and a 2-fold increase by v-HNF1. These increases were dependent on the integrity of an HNF1 binding site located 58-74 nucleotides upstream of the cap site. Stimulation of promoter activity by cotransfection of both HNF1 and v-HNF1 fell between these values. Our results indicate that HNF1 is instrumental in human IGFBP-1 promoter activity in vivo and that v-HNF1 modulates this functional role.

Physiology and pathophysiology of IGFBP-1 and IGFBP-2 – Consensus and dissent on metabolic control and malignant potential

“…The 3 0 untranslated region contains ATTTA motifs that are characteristic of mRNA species with a very short half-life. IGFBP-1 mRNA is expressed in fetal liver and in post-natal tissues, primarily in the secretory endometrium, pregnancy decidua and liver [28], but is not found in human fetal and post-natal kidney. IGFBP-1 mRNA and protein expression has also been described in human osteoblastic cells and appears to be triggered by stimulation through glucocorticoids yet inhibited by insulin as aforementioned in hepatocytes, suggesting that IGFBP-1 produced by osteoblasts in vivo can modulate the local actions of IGF on bone formation in response to changes in glucocorticoid and insulin concentrations [29].…”

Hepatocyte Nuclear Factor 1 and the Glucocorticoid Receptor Synergistically Activate Transcription of the Rat Insulin-like Growth Factor Binding Protein-1 Gene

“…Since cotransfection of HNF-1␣ had no effect on dexamethasone stimulation, we wanted to verify that functional HNF-1␣ was expressed. Overexpression of HNF-1␣ (37) or HNF-1␤ (39) had been reported to enhance basal activity of the human (h)IGFBP-1 promoter in several human cell lines, irrespective of whether the cells expressed HNF-1. We examined the effect of HNF-1␣ overexpression on basal promoter activity of the rIGFBP-1 gene in H4-II-E cells (Fig.…”

Interleukin-6-Induced STAT3 and AP-1 Amplify Hepatocyte Nuclear Factor 1-Mediated Transactivation of Hepatic Genes, an Adaptive Response to Liver Injury

“…DNase I hypersensitivity analyses identified clusters of liver-restricted nuclease sensitive sites in the promoter region, Ϫ100 to Ϫ300, Ϫ2300, Ϫ3100, and Ϫ5000, along with other weak sites (9). This tissue-specific pattern of expression may be regulated in part by members of hepatocyte nuclear factor (HNF-1) family of proteins, as the HNF-1 forms are responsible for the basal IGFBP-1 promoter activity in hepatoma cells via a conserved site just upstream of the RNA initiation site (1,2,46,53). HNF-1␣, a homeodomain protein, regulates the expression of a number of hepatic genes, and contains a variant homeodomain that binds to DNA either as a homodimer or as a heterodimer with HNF-1␤ (4,60).…”