title: TGF- β Signaling Cooperates with AT Motif-Binding Factor-1 for Repression of the α -Fetoprotein Promoter.
abstract: α-Fetoprotein (AFP) is known to be highly produced in fetal liver despite its barely detectable level in normal adult liver. On the other hand, hepatocellular carcinoma often shows high expression of AFP. Thus, AFP seems to be an oncogenic marker. In our present study, we investigated how TGF-β signaling cooperates with AT motif-binding factor-1 (ATBF1) to inhibit AFP transcription. Indeed, the expression of AFP mRNA in HuH-7 cells was negatively regulated by TGF-β signaling. To further understand how TGF-β suppresses the transcription of the AFP gene, we analyzed the activity of the AFP promoter in the presence of TGF-β. We found that the TGF-β signaling and ATBF1 suppressed AFP transcription through two ATBF1 binding elements (AT-motifs). Using a heterologous reporter system, both AT-motifs were required for transcriptional repression upon TGF-β stimulation. Furthermore, Smads were found to interact with ATBF1 at both its N-terminal and C-terminal regions. Since the N-terminal (ATBF1N) and C-terminal regions of ATBF1 (ATBF1C) lack the ability of DNA binding, both truncated mutants rescued the cooperative inhibitory action by the TGF-β signaling and ATBF1 in a dose-dependent manner. Taken together, these findings indicate that TGF-β signaling can act in concert with ATBF1 to suppress the activity of the AFP promoter through direct interaction of ATBF1 with Smads.
authors.affiliation: Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Nobuo
authors.identifier: 0000-0001-9967-8409
authors.initials: N
authors.lastname: Sakata
authors.affiliation: Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Ikeno
authors.affiliation: Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Department of Medical Management & Information, Hokkaido Information University, Ebetsu, Hokkaido 069-8585, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nakabayashi
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Dong
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1.
authors.forename: Taiki
authors.initials: T
authors.lastname: Tamaoki
authors.affiliation: Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakano
authors.affiliation: Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Susumu
authors.identifier: 0000-0002-7967-0730
authors.initials: S
authors.lastname: Itoh
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