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J Biol Chem, Vol. 273, Issue 45, 30024-30032, November 6, 1998
From the
Retinoic Acid Mediates Down-regulation of the
-Fetoprotein
Gene through Decreased Expression of Hepatocyte Nuclear Factors
,,
Department of Pathology, Harbor-UCLA Medical
Center, Torrance, California 90509 and the § Department
of Pathology, University of Pittsburgh,
Pittsburgh, Pennsylvania 15261
-Fetoprotein (AFP), a protein highly induced
during fetal liver development, is down-regulated by retinoids in the
human hepatoma cell line Hep3B, in contrast to up-regulation observed in other cell types. Previously, we have documented that such up-regulation involves direct effects through cis-retinoid
X receptor-binding sites in the AFP enhancer. In this report, we show a
distinctive effect of all-trans-retinoic acid (RA) in Hep3B
cells. RA caused a marked decrease in AFP transcripts. Deletion
analysis of the upstream regulatory region of the AFP gene revealed
that cis-acting sites required for down-regulation resided
near the promoter. Gel mobility shift assays for factors binding to key
elements in the AFP promoter region demonstrated that hepatocyte
nuclear factor (HNF) 1 binding was diminished in nuclear extracts from RA-treated cells. In addition, HNF4, which is not known to bind to the
AFP promoter but does regulate HNF1, was also diminished. The levels of
HNF1 and HNF4 mRNA were also decreased following RA treatment. AFP
promoter-chloramphenicol acetyltransferase transient transfection
assays demonstrated that the level of HNF1 had a direct impact on basal
transcription as well as RA-mediated down-regulation of the AFP gene,
and that co-transfection of HNF1 and HNF4, but not transfection of
either factor alone, reversed the RA-mediated inhibition. Taken
together these data point to an interaction among the RA, HNF1, and
HNF4 signals, which is reflected in decreased expression of AFP.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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