Cytokine regulation of the liver transcription factor hepatocyte nuclear factor-3 beta is mediated by the C/EBP family and interferon regulatory factor 1.
Three distinct hepatocyte nuclear factor-3 (HNF-3) proteins (alpha, beta, and gamma) regulate the transcription of numerous liver-enriched genes. The HNF-3 proteins bind DNA via a homologous winged helix motif common to a number of proteins known to be critical for determination events in embryogenesis. We have demonstrated previously that two binding sites in the -184 HNF-3 beta promoter are recognized by widely distributed factors and that there is also a critical autoregulatory site, we identified a binding site for a cell-specific factor, LF-H3 beta, that may function in restricting HNF-3 beta gene expression to hepatocytes. Our present study demonstrates that members of the C/EBP and proline and acidic amino acid-rich subfamilies of basic region leucine zipper transcription factors bind the LF-H3 beta site, and cotransfection of HepG2 cells shows that these factors are able to activate an HNF-3 beta promoter reporter construct. The LF-H3 beta-C/EBP binding sequence also confers HNF-3 beta promoter stimulation in response to interleukin (IL)-1 and IL-6. Upstream of this HNF-3 beta proximal promoter region, an IFN-stimulated response element core sequence (-231 to -210) was found that mediates transcriptional induction by IFN-gamma but not IFN-alpha. Gel mobility supershift assay demonstrates that an IFN-gamma-induced protein-DNA complex is disrupted by an antibody specific for interferon regulatory factor-1/interferon-stimulated gene factor-2. Consistent with this finding, we observed that IFN-gamma induction requires ongoing protein synthesis. Surprisingly, the effect of the three cytokines (IL-1, IL-6, and IFN-gamma) in combination as assayed by the same model is not synergistic. HNF-3beta joins the C/EBP family on the list of liver-enriched transcription factors, the expression of which is modulated by cytokines.
Samadani
U
U
Department of Biochemistry, University of Illinois at Chicago 60612-7334, USA.
Porcella
A
A
Pani
L
L
Johnson
P F
PF
Burch
J B
JB
Pine
R
R
Costa
R H
RH
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D006528:Carcinoma, Hepatocellular; D016207:Cytokines / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D051790:G-Box Binding Factors; D015870:Gene Expression / Q000276:immunology; D006367:HeLa Cells / Q000276:immunology; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016350:Leucine Zippers / Q000235:genetics; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D010750:Phosphoproteins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000276:immunology*
D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; D051790:G-Box Binding Factors; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; D015850:Interleukin-6; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta