Interaction of a Liver-Specific Nuclear Factor with the Fibrinogen and α ₁ -Antitrypsin Promoters

Abstract

The orderly and sequential activation of genes during development is hypothesized to be related to the selective expression of groups of regulatory proteins acting primarily at the level of transcription. A nuclear protein was found in hepatocytes, but not other cell types, that binds to a sequence required for hepatocyte-specific transcription of the gene for the beta chain of fibrinogen. This protein, hepatocyte nuclear factor 1 (HNF1), also interacts with homologous sequences required for optimal promoter function of the genes for the alpha chain of fibrinogen and alpha 1-antitrypsin. The promoter or enhancer regions for several viral and cellular genes not expressed in the liver did not compete for this binding. The restricted expression of HNF1 and its selective interaction with the control regions of several liver-specific genes indicate that it is involved in developmentally regulated gene expression in the liver.

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

“…TCF1 and TCF2, respectively, encode the transcription factors hepatocyte nuclear factor 1a and b (HNF1a and HNF1b), two POU-homeodomain proteins that bind to an essential element in the proximal promoter sequences of albumin and many other tissue-specific genes and are associated with development, metabolism and cancer (Cereghini et al, 1987;Courtois et al, 1987;Frain et al, 1989;Rey-Campos et al, 1991). For instance, TCF2 defects cause developmental abnormalities in multiple tissues, including kidney and pancreas (Horikawa et al, 1997;Haumaitre et al, 2005), and Bluteau et al (2002) identified biallelic mutations of TCF1 in hepatic adenomas (Bluteau et al, 2002).…”

HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro.

“…Nuclear extracts were prepared from mouse and rat tissues with minor modification of published methods (Courtois et al 1987). Briefly, tissues were excised immediately after the animals were sacrificed and homogenized in ice-cold buffer A [10 mM HEPES (pH 7.8 at 4°C), 15 mM KC1, 2 mM MgC12, 1 mM DTT, 0.1 mM EDTA, 1 mM PMSF, 10 lag/ml leupeptin, and 1 txg/ml antipain].…”

“…Furthermore, we find that heterodimerization is regulated in a tissue-specific manner, as freely exchangeable heterodimers are formed in transfected Jurkat human T cells but stable nonexchangeable homodimers are present in liver extracts. For simplicity we will use the terms HNF-I~ for the original HNF-1 protein (Courtois et al 1987) and HNF-I~ for the newly cloned vHNF-1 Cereghini et al 1988).…”

“…Hepatocyte nuclear factor-1 (HNF-1) (Courtois et al 1987), also called APF (Cereghini et al 1988), LFB1 (Hardon et al 1988), HP (Schorpp et al 1988), and A box factor (Maire et al 1989), is a homeo domain-containing protein that acts as a transcriptional activator in vivo and in vitro to regulate the expression of a large group of genes that have the common characteristic of being expressed in hepatocytes . Consistent with the presence of a homeo domain and sequences related to the POU-specific region {Frain et al 1989;Baumhueter et al 1990), HNF-1 has been suggested to play a role in establishing the hepatocyte phenotype.…”

Cloning, sequencing and characterization of the human Alpha glutathione S-transferase gene corresponding to the cDNA clone pGTH2

“…Upstream of this region at position -86 and -107 the nucleotide sequence contains two half-recognition sites for the nuclear factor NFl: consensus sequence, 5'-TGG(A/C)N5G-CCAA-3' [23]. An absolute homology was found to the ATTAAC motif reported to mediate liver-specific expression by hepatocyte nuclear factor HNF1 [24] at position -171 to -176. DISCUSSION H.p.l.c.…”