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

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Journal of Signal Transduction - Volume 2014 2014, Article ID 970346, 11 pages -

Research Article

Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan

Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan

Department of Medical Management & Information, Hokkaido Information University, Ebetsu, Hokkaido 069-8585, Japan

Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA

Department 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.

Autor: Nobuo Sakata, Satoshi Kaneko, Souichi Ikeno, Yutaka Miura, Hidekazu Nakabayashi, Xue-Yuan Dong, Jin-Tang Dong, Taiki Tamaok



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