Table of Contents
Journal of Signal Transduction
Volume 2014, Article ID 970346, 11 pages
Research Article

TGF-β Signaling Cooperates with AT Motif-Binding Factor-1 for Repression of the α-Fetoprotein Promoter

1Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
2Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
3Department of Medical Management & Information, Hokkaido Information University, Ebetsu, Hokkaido 069-8585, Japan
4Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
5Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1

Received 18 April 2014; Accepted 23 May 2014; Published 3 July 2014

Academic Editor: Shoukat Dedhar

Copyright © 2014 Nobuo Sakata et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.