title: Molecular mechanisms of hereditary persistence of alpha-fetoprotein (AFP) in two Japanese families A hepatocyte nuclear factor-1 site mutation leads to induction of the AFP gene expression in adult livers.
abstract: alpha-Fetoprotein (AFP) is produced abundantly in fetal liver but is hardly detectable in adults. In this study, we investigated two unrelated Japanese families with hereditary persistence of AFP. A g-->a substitution at nucleotide -119 (-119g-->a) in the hepatocyte nuclear factor (HNF)-1 binding site of the AFP promoter was identified in both families. The activity of the wild- or variant-type human AFP promoter was evaluated by in vitro and in vivo transfection experiments. This substitution in the AFP promoter significantly stimulated its transcriptional activity in human hepatoma cells, regardless of their prior AFP production. The variant-type AFP promoter was also active in adult mouse livers in vivo. Additionally, overexpression of HNF-1alpha stimulated the activity of both the wild- and variant-type AFP promoters in hepatoma cells. HNF-1alpha expression also activated both AFP promoters even in nonhepatoma cells, and this activation was suppressed by nuclear factor (NF)-I overexpression. These results indicate that an HNF-1 binding site mutation leads to induction of the AFP gene expression in adult liver, and suggest that competition between HNF-1 and NF-I in this region is involved in transcriptional regulation of the AFP gene during hepatic development.
authors.affiliation: Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagata-Tsubouchi
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uto
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Numata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Moriuchi
authors.forename: Ildeok
authors.initials: I
authors.lastname: Kim
authors.forename: Satoru
authors.initials: S
authors.lastname: Hasuike
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagata
authors.forename: Toru
authors.initials: T
authors.lastname: Sekiya
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tsubouchi