Hepatocyte nuclear factor-4 prevents silencing of hepatocyte nuclear factor-1 expression in hepatoma x fibroblast cell hybrids.
Hepatocyte nuclear factors-1alpha (HNF1alpha) and -4 (HNF4) are components of a liver-enriched transcription activation pathway which is thought to play a critical role in hepatocyte-specific gene expression, including activation of alpha1-antitrypsin gene expression. HNF1alpha, HNF4 and alpha1-antitrypsin (alpha1AT) genes are extinguished in hepatoma/fibroblast somatic cell hybrids, suggesting that fibroblasts contain a repressor-like activity. To determine the molecular basis for silencing of these genes in cell hybrids, ectopic expression of HNF1alpha and HNF4 was used. Results show that constitutive expression of HNF4 prevents extinction of HNF1alpha gene expression in hepatoma/fibroblast hybrids. In contrast, forced HNF1alpha expression failed to prevent extinction of the HNF4 locus in cell hybrids. Likewise, the alpha1AT gene remained silent in the presence of both HNF1alpha and HNF4. These results suggest that extinction of HNF1alpha is a simple lack-of-activation phenotype, whereas extinction of HNF4 andalpha1AT loci is more complex, perhaps involving negative regulation.
Bulla
G A
GA
Pediatric Research Institute, St Louis University Health Sciences Center and Cardinal Glennon Children's Hospital, 3662 Park Avenue, St Louis, MO 63110, USA. bullaga@sluvca.slu.edu
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006822:Hybrid Cells / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000502:physiology; D014162:Transfection
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta