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J Biol Chem. 1994 Feb 18;269(7):5420-7.

A transcriptional regulatory element common to a large family of hepatic cytochrome P450 genes is a functional binding site of the orphan receptor HNF-4.

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Department of Physiology and Biophysics, University of Illinois, Urbana 61801.


Hepatic cytochrome P450 (CYP) genes, including members of CYP1 to CYP4 families, comprise the majority of the CYP gene superfamily. Previous study has demonstrated that HepG2-specific transcriptional activation of two CYP2C genes was dependent on a common element that bound a HepG2 nuclear protein designated HPF-1 (Venepally, P., Chen, D., and Kemper, B. (1992) J. Biol. Chem. 267, 17333-17338). This cis-acting element is highly homologous to the hepatocyte nuclear factor 4 (HNF-4) binding motif and is present in the promoters of more than 20 other CYP2 genes. To investigate the relationship between HPF-1 and HNF-4, we have compared their tissue distribution, DNA binding, and immunochemical characteristics, as well as transcriptional activity of their recognition elements. DNase I footprint analyses and gel-shift assays indicated that HPF-1, like HNF-4, was present in liver and kidney, but not brain and spleen. Both factors bound to either the HPF-1 site in the CYP2C2 promoter or an HNF-4 site in the human apolipoprotein CIII promoter. These complexes could be "supershifted" by an antiserum specific for HNF-4. When the sequence of the HPF-1 site in the CYP2C2 promoter was changed to that of the apolipoprotein CIII HNF-4 site, comparable transcriptional activities were obtained with the wild-type promoter and the HNF-4 mutant in transfected HepG2 cells. Cotransfection of HNF-4 with CYP2C2 promoter-luciferase constructs in COS-1 cells indicated that HNF-4 could trans-activate the promoters containing the HPF-1 site. These results indicate that the HPF-1 motif is a functional HNF-4-binding site, and the common immunological properties indicate that HPF-1 and HNF-4 are closely related and possibly identical. HNF-4, therefore, may act as a common regulator for the liver-specific expression of many CYP2 genes.

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