Chicken Ovalbumin Upstream Promoter-Transcription Factor, Hepatocyte Nuclear Factor 3, and CCAAT/Enhancer Binding Protein Control the Far-Upstream Enhancer of the Rat α-Fetoprotein Gene

Abstract

We have further characterized the most distal of the three alpha-fetoprotein (AFP) enhancers required for expression of the AFP gene in fetal hepatocytes and yolk sac endodermal cells. Almost total rat AFP enhancer 3 (E3) activity is driven by a 160-bp fragment at -6 kb containing three target regions for nuclear proteins that cooperate to stimulate transcription from the AFP and the thymidine kinase promoters in HepG2 hepatoma cells. Region 1, recently shown to be crucial for correct function of the enhancer in liver of transgenic mice, is recognized by two sets of transcription factors that bind to partly overlapping sites, 1a and 1b, in a noncooperative and nonexclusive manner. Site 1a contains a motif, AGGTCA, which is recognized by chicken ovalbumin upstream promoter transcription factors (COUP-TFs), but not by hepatocyte nuclear factor 4. Hepatocyte nuclear factor 3 (HNF3) and CCAAT/enhancer binding protein (C/EBP), which bind to regions 2 and 3, respectively, are likely responsible for the liver-specific E3 action. They play a key role by acting in synergy. The participation of nuclear receptors such as COUP-TFs, with C/EBP and HNF3, in the tight control of the distal AFP enhancer is a new, and perhaps key, step toward understanding the regulation and function of this enhancer, which may remain active throughout development.

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

“…Forty-five base pairs 3Ј of this HNF3 site is a C͞EBP binding site (26). Upstream of the HNF-3 site is a chicken ovalbumin upstream promoter-transcription factor (COUP-TF) binding site (27). Deletion studies have shown that all three of these sites contribute to MERIII activity in HepG2 cells (27).…”

“…Upstream of the HNF-3 site is a chicken ovalbumin upstream promoter-transcription factor (COUP-TF) binding site (27). Deletion studies have shown that all three of these sites contribute to MERIII activity in HepG2 cells (27). Of these factors, COUP-TF and HNF-3 are particularly interesting because both of these, although generally associated with positive regulation, have been shown to be repressors in some situations (28)(29)(30).…”

Glucocorticoids are insufficient for neonatal gene induction in the liver

“…The discrepancy between the two transgenic analyses is likely to be due to the action of factors binding to sequences neighboring the GRE. Interestingly, the same set of transcription factors interacts with the two regulatory sequences that confer neonatal induction, the Tat GRUs and the sequences used in the transgenic study of Montoliu et al (16): the dimeric GRE they used is also a dimeric Ets-binding site (11) and the Afp enhancers contain numerous binding sites for C͞EBP and HNF-3 that could synergize with this dimeric GRE (32)(33)(34). Such an interpretation is supported by the observation that the Afp sequences contribute to the expression patterns of the construct in the liver, because a typical predominance in the pericentral region was seen (16).…”

The Mouse Alpha-Albumin (Afamin) Promoter Is Differentially Regulated by Hepatocyte Nuclear Factor 1α and Hepatocyte Nuclear Factor 1β

“…Many of the liver-enriched factors that have been identified, including hepatocyte nuclear factor 1 (HNF1), FoxA, HNF4, HNF6, and C/EBP, have been found to regulate members of this gene family (Gorski et al, 1986;Chevrette et al, 1987;Lichtsteiner et al, 1987;Cereghini et al, 1988;Feuerman et al, 1989;Zhang et al, 1991;Milos and Zaret, 1992;Bois-Joyeux and Danan, 1994;Thomassin et al, 1996;Song et al, 1998). These transcription factors are also expressed in tissues other than the liver, suggesting that the combined action of multiple factors is required for the liver-restricted expression of target genes, including members of the albumin family.…”