TY - JOUR
T1 - EBP50, a β-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma
AU - Shibata, Tatsuhiro
AU - Chuma, Makoto
AU - Kokubu, Akiko
AU - Sakamoto, Michiie
AU - Hirohashi, Setsuo
N1 - Funding Information:
Abbreviations: HCC, hepatocellular carcinoma; TCF, T-cell factor; PDZ, PSD-95, discs-large, ZO-1; cDNA, complementary DNA; GST, glutathione S-transferase; PCR, polymerase chain reaction; RT-PCR, reverse-transcription polymerase chain reaction; mRNA, messenger RNA; APC, adenomatous polyposis coli. From the Pathology Division, National Cancer Center Research Institute, Tokyo, Japan. Received July 15, 2002; accepted April 3, 2003. Supported in part by a grant-in-aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, Japan. Address reprint requests to: Setsuo Hirohashi, M.D., Pathology Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. E-mail: shirohas@ncc.go.jp; fax: (81) 3-3248-2463. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3801-0023$30.00/0 doi:10.1053/jhep.2003.50270
PY - 2003/7/1
Y1 - 2003/7/1
N2 - Wnt signaling mediated by β-catenin plays crucial roles in the development of hepatocellular carcinoma and other cancers such as colorectal cancer. β-catenin associates with T-cell factor (TCF) transcription factors and functions as a transcriptional activator in the nucleus. By protein interaction screening, we identified EBP50, a cytoplasmic protein with 2 PDZ domains, as a β-catenin-associating molecule. EBP50 interacted with β-catenin through its carboxyl-PDZ domain in vitro and in vivo. Northern blot and RT-PCR analysis revealed an increase of EBP50 messenger RNA (mRNA) in hepatocellular carcinoma (HCC) cell lines and surgical specimens of human HCC. Over-expression of EBP50 protein with focal nuclear localization was detected in human HCC. In human HCC and colorectal cancer cell lines, EBP50 enhanced β-catenin/TCF-dependent transcription in a dose-dependent manner. In an HCC cell line, over-expression of the carboxyl PDZ domain resulted in a decrease of endogenous β-catenin/TCF transactivation. EBP50 promoted β-catenin-mediated transactivation only in cells in which β-catenin was already stabilized, suggesting that EBP50 may work with stabilized β-catenin for transcriptional regulation. In conclusion, the EBP50/β-catenin complex promotes Wnt signaling, and over-expression of EBP50 may work cooperatively with β-catenin in the development of liver cancer.
AB - Wnt signaling mediated by β-catenin plays crucial roles in the development of hepatocellular carcinoma and other cancers such as colorectal cancer. β-catenin associates with T-cell factor (TCF) transcription factors and functions as a transcriptional activator in the nucleus. By protein interaction screening, we identified EBP50, a cytoplasmic protein with 2 PDZ domains, as a β-catenin-associating molecule. EBP50 interacted with β-catenin through its carboxyl-PDZ domain in vitro and in vivo. Northern blot and RT-PCR analysis revealed an increase of EBP50 messenger RNA (mRNA) in hepatocellular carcinoma (HCC) cell lines and surgical specimens of human HCC. Over-expression of EBP50 protein with focal nuclear localization was detected in human HCC. In human HCC and colorectal cancer cell lines, EBP50 enhanced β-catenin/TCF-dependent transcription in a dose-dependent manner. In an HCC cell line, over-expression of the carboxyl PDZ domain resulted in a decrease of endogenous β-catenin/TCF transactivation. EBP50 promoted β-catenin-mediated transactivation only in cells in which β-catenin was already stabilized, suggesting that EBP50 may work with stabilized β-catenin for transcriptional regulation. In conclusion, the EBP50/β-catenin complex promotes Wnt signaling, and over-expression of EBP50 may work cooperatively with β-catenin in the development of liver cancer.
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U2 - 10.1053/jhep.2003.50270
DO - 10.1053/jhep.2003.50270
M3 - Article
C2 - 12830000
AN - SCOPUS:0038121958
SN - 0270-9139
VL - 38
SP - 178
EP - 186
JO - Hepatology
JF - Hepatology
IS - 1
ER -
