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Samadani U , Porcella A , Pani L , Johnson PF , Burch JBE , Pine R , Costa RH
Cytokine Regulation of the Liver Transcript Factor Hepatocyte Nuclear Factor-3-Beta Is Mediated by the C/Ebp Family and Interferon Regulatory Factor-1
Cell Growth & Differentiation. 1995 Jul;6(7) :879-890
AbstractThree distinct hepatocyte nuclear factor-3 (HNF-3) proteins (alpha, beta, and gamma) regulate the transcription of numerous liver-enriched genes. The HNF3 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 present that is recognized by members of the HNF-3 family. Adjacent to the 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-3 beta joins the C/EBP family on the list of liver-enriched transcription factors, the expression of which is modulated by cytokines.
NotesTimes Cited: 28 Article RH190 CELL GROWTH DIFFER