scholarly journals The Mouse Alpha-Fetoprotein Promoter is Repressed in HepG2 Hepatoma Cells by Hepatocyte Nuclear Factor-3 (FOXA)

2002 ◽  
Vol 21 (8) ◽  
pp. 561-569 ◽  
Author(s):  
Mei-Chuan Huang ◽  
Kelly Ke Li ◽  
Brett T. Spear
Keyword(s):  
Hepatoma Cells ◽  
Alpha Fetoprotein ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor

scholarly journals Functional Activity of Human Hepatoma Cells Transfected with Adenovirus-Mediated Hepatocyte Nuclear Factor (HNF)-4 Gene

2004 ◽  
Vol 13 (4) ◽  
pp. 393-404 ◽  
Author(s):  
Takafumi Naiki ◽  
Masahito Nagaki ◽  
Yoshihiro Shidoji ◽  
Hisanori Kojima ◽  
Hisataka Moriwaki
Keyword(s):  
Functional Activity ◽  
Hepatoma Cells ◽  
Nuclear Factor ◽  
Human Hepatoma ◽  
Hepatocyte Nuclear Factor ◽  
Human Hepatoma Cells

scholarly journals Overproduction of a truncated hepatocyte nuclear factor 3 protein inhibits expression of liver-specific genes in hepatoma cells.

1995 ◽  
Vol 15 (10) ◽  
pp. 5453-5460 ◽  
Author(s):  
V Vallet ◽  
B Antoine ◽  
P Chafey ◽  
A Vandewalle ◽  
A Kahn
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Sites ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatoma Cells ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Regulatory Regions ◽  
Truncated Protein ◽  
Fork Head

Transcription of hepatocyte-specific genes requires the interaction of their regulatory regions with several nuclear factors. Among them is the hepatocyte nuclear factor 3 (HNF3) family, composed of the HNF3 alpha, HNF3 beta, and HNF3 gamma proteins, which are expressed in the liver and have very similar fork head DNA binding domains. The regulatory regions of numerous hepatocyte-specific genes contain HNF3 binding sites. We examined the role of HNF3 proteins in the liver-specific phenotype by turning off the HNF3 activity in well-differentiated mhAT3F hepatoma cells. Cells were stably transfected with a vector allowing the synthesis of an HNF3 beta fragment consisting of the fork head DNA binding domain without the transactivating amino- and carboxy-terminal domains. The truncated protein was located in the nuclei of cultured hepatoma cells and competed with endogenous HNF3 proteins for binding to cognate DNA sites. Overproduction of this truncated protein, lacking any transactivating activity, induced a dramatic decrease in the expression of liver-specific genes, including those for albumin, transthyretin, transferrin, phosphoenolpyruvate carboxykinase, and aldolase B, whereas the expression of the L-type pyruvate kinase gene, containing no HNF3 binding sites, was unaltered. Neither were the concentrations of various liver-specific transcription factors (HNF3, HNF1, HNF4, and C/EBP alpha) affected. In partial revertants, with a lower ratio of truncated to full-length endogenous HNF3 proteins, previously extinguished genes were re-expressed. Thus, the transactivating domains of HNF3 proteins are needed for the proper expression of a set of liver-specific genes but not for expression of the genes encoding transcription factors found in differentiated hepatocytes.

scholarly journals Liver-enriched transcription factors uncoupled from expression of hepatic functions in hepatoma cell lines.

1997 ◽  
Vol 17 (11) ◽  
pp. 6311-6320 ◽  
Author(s):  
D Chaya ◽  
C Fougère-Deschatrette ◽  
M C Weiss
Keyword(s):  
Transcription Factors ◽  
Hepatoma Cell ◽  
Hepatoma Cells ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatic Differentiation ◽  
Hepatoma Cell Lines ◽  
Differentiated Cells ◽  
Heritable Phenotype ◽  
Nuclear Factor 1

Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver.

scholarly journals Hepatocyte Nuclear Factor 4 Provokes Expression of Epithelial Marker Genes, Acting As a Morphogen in Dedifferentiated Hepatoma Cells

1998 ◽  
Vol 140 (4) ◽  
pp. 935-946 ◽  
Author(s):  
Gerald F. Späth ◽  
Mary C. Weiss
Keyword(s):  
Epithelial Cell ◽  
Hepatoma Cells ◽  
Stable Expression ◽  
Junctional Complex ◽  
Cell Phenotype ◽  
Marker Genes ◽  
Specific Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
E Cadherin

Abstract. We have recently shown that stable expression of an epitope-tagged cDNA of the hepatocyte- enriched transcription factor, hepatocyte nuclear factor (HNF)4, in dedifferentiated rat hepatoma H5 cells is sufficient to provoke reexpression of a set of hepatocyte marker genes. Here, we demonstrate that the effects of HNF4 expression extend to the reestablishment of differentiated epithelial cell morphology and simple epithelial polarity. The acquisition of epithelial morphology occurs in two steps. First, expression of HNF4 results in reexpression of cytokeratin proteins and partial reestablishment of E-cadherin production. Only the transfectants are competent to respond to the synthetic glucocorticoid dexamethasone, which induces the second step of morphogenesis, including formation of the junctional complex and expression of a polarized cell phenotype. Cell fusion experiments revealed that the transfectant cells, which show only partial restoration of E-cadherin expression, produce an extinguisher that is capable of acting in trans to downregulate the E-cadherin gene of well-differentiated hepatoma cells. Bypass of this repression by stable expression of E-cadherin in H5 cells is sufficient to establish some epithelial cell characteristics, implying that the morphogenic potential of HNF4 in hepatic cells acts via activation of the E-cadherin gene. Thus, HNF4 seems to integrate the genetic programs of liver-specific gene expression and epithelial morphogenesis.

scholarly journals Hepatocyte nuclear factor 4 expression overcomes repression of the hepatic phenotype in dedifferentiated hepatoma cells.

1997 ◽  
Vol 17 (4) ◽  
pp. 1913-1922 ◽  
Author(s):  
G F Späth ◽  
M C Weiss
Keyword(s):  
Target Genes ◽  
Hepatoma Cells ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Enhanced Expression ◽  
Alpha1 Antitrypsin ◽  
Hepatocyte Nuclear Factor 4 ◽  
Well Differentiated ◽  
Dedifferentiated Hepatoma ◽  
Hepatic Genes

The capacity of the liver-enriched transcription factor hepatocyte nuclear factor 4 (HNF4) to direct redifferentiation of dedifferentiated rat hepatoma cells was investigated by stable transfection of epitope-tagged HNF4 cDNA into H5 variant cells. HNF4-producing cells expressed the previously silent HNF1 gene and showed activation of some hepatic functions, including alpha1-antitrypsin, beta-fibrinogen, and transthyretin, but not of the endogenous HNF4 gene. Expression of the other hepatocyte-enriched transcription factors was not modified. Treatment of the HNF4tag-expressing cells with dexamethasone induced expression of the transgene by 10-fold, resulting in enhanced expression of target genes of both glucocorticoid hormones and HNF4. The set of activated hepatic genes was extended by treatment of cells with the demethylating agent 5-azacytidine followed by selection in dexamethasone-containing glucose-free medium. Some of the colonies that developed reexpressed the entire set of hepatic functions tested. Fusion of HNF4tag-producing H5 cells with well-differentiated Fao cells showed that only those hybrids which maintained expression of HNF4tag were protected from complete extinction, including that of the Fao HNF4 gene. Thus, H5 cells must produce an extinguisher of the HNF4 gene. In addition, this result implies that HNF4 itself, or its target HNF1, is a positive regulator of HNF4. In conclusion, HNF4tag expression overcomes repression of the hepatic phenotype of the H5 cell without abolishing its potential to extinguish an active genome. Taken together, these results predict that expression of HNF4 should be sufficient to establish heritable expression of many parameters of the hepatic differentiated state.

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