EBP50, a β-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma
EBP50, a β-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma
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DOI：
10.1053/jhep.2003.50270
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发表时间：
2003-07-01
期刊：
影响因子：
13.5
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Shibata, T;Chuma, M;Hirohashi, S
β-连环蛋白介导的WNT信号在肝细胞癌和其他肿瘤如结直肠癌的发生发展中起着重要作用。癌症。β-连环蛋白与T细胞因子(TCF)转录因子结合，在细胞核内作为转录激活因子发挥作用。通过蛋白质相互作用筛选，我们确定EBP50是一个含有两个PDZ结构域的细胞质蛋白，是一个β-连环蛋白结合分子。EBP50通过其羧基PDZ结构域在体内外与β-连环蛋白相互作用。Northern印迹和RT-PCR分析显示，EBP50信使RNA在肝细胞癌细胞系和人肝癌手术标本中表达增加。在人肝细胞癌中检测到EBP50蛋白的高表达并定位于核。在人肝癌和结直肠癌细胞系中，EBP50以剂量依赖的方式促进β-连环蛋白/TCF依赖的转录。在肝癌细胞系中，羧基PDZ结构域的过度表达导致内源性β-连环蛋白/TCF反式激活的减少。EBP50只在P-catenin已经稳定的细胞中促进β-catenin介导的反式激活，这表明EBP50可能与稳定的β-catenin一起作用于转录调节。综上所述，EBP50/β-catenin复合体促进Wnt信号转导，EBP50的过度表达可能与β-catenin协同作用于肝癌的发生发展。
Wnt signaling mediated by beta-catenin plays crucial roles in the development of hepatocellular carcinoma and other cancers such as colorectal. cancer. beta-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 beta-catenin-associating molecule. EBP50 interacted with beta-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 beta-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 beta-catenin/TCF transactivation. EBP50 promoted beta-catenin-mediated transactivation only in cells in which P-catenin was already stabilized, suggesting that EBP50 may work with stabilized beta-catenin for transcriptional regulation. In conclusion, the EBP50/beta-catenin complex promotes Wnt signaling, and over-expression of EBP50 may work cooperatively with beta-catenin in the development of liver cancer.