A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells.

Abstract

We have identified and characterized two mutually exclusive nuclear proteins that interact with a single crucial element of the albumin promoter. One, albumin proximal factor (APF), is found only in liver or differentiated hepatoma cells and is probably identical to the liver-specific factors named HNFl, alTFB, or HPl-binding protein. The other, variant albumin proximal factor (vAPF), is present in dedifferentiated hepatoma cells as well as in somatic cell hybrids that show extinction of the expression of liver-specific proteins, including albumin. Reversion to the hepatic phenotype of either a dedifferentiated variant or an extinguished somatic hybrid clone is accompanied by loss of vAPF and reappearance of APF. These two proteins differ in their thermostability and in their molecular weight, while displaying identical sequence specificities. Both proteins interact with a homologous motif present in promoter regions of several other liver-specific genes. In vitro transcription assays, using a rat liver nuclear extract, indicate that the binding of APF to its target sequence is required for albumin transcription. These results suggest that a modification in the primary structure of a transcription factor is correlated with the differentiated state of the hepatic cell.

Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary

“…HNF-1beta is a transcription activator that regulates the promoters or enhancers of genes that are expressed in a liver-specific manner, such as albumin and alpha-fetoprotein. [16][17][18] In normal tissue, HNF-1beta is expressed not only in the liver, but also in the digestive tract, pancreas, and kidney, where it plays a role as a major regulator of glucose homeostasis. 19 It has been shown that the reduction of HNF-1beta expression by RNA interference induced apoptosis in ovarian clear cell carcinoma cell lines, suggesting that HNF-1beta expression is essential for the survival of clear cell carcinoma cells.…”

Novel E2F decoy oligodeoxynucleotides inhibit in vitro vascular smooth muscle cell proliferation and in vivo neointimal hyperplasia

“…Several different structures of doublestranded DNA, including unmodified oligonucleotide duplexes, ab-anomeric oligonucleotides, phosphorothioate oligonucleotide duplexes and dumbbell oligonucleotides, have been introduced as decoys for transcription factors. [1][2][3][4][5][6][7][8] The main limitation of unmodified ODN is relatively easy degradation by nucleases prevalent in sera and cells. To rectify this problem, ODNs with modified linkages, such as phosphorothioate and methylphosphonate, were developed.…”

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

“…The revertants (Rev7 cells), which occur at a frequency of 10 -9 , express nearly all of the liver-specific proteins and are morphologically similar to the original differentiated cells (Deschatrette et al 1980), perhaps because cells need several hepatocyte-specific proteins to perform gluconeogenesis and grow in media without glucose. Although the original differentiated Fao cells expressed the 88-kD form of HNF-1 found in liver extracts, the C2 cells expressed a 68-kD variant form of HNF-1 (vHNF-1) that exhibited DNA sequence specificity identical to the original HNF-1 protein Cereghini et al 1988). The Rev7 revertant cells expressed the 88-kD form of HNF-1 as well as the entire group of HNF-l-dependent genes.…”

“…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.…”