Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-β signaling, as a target of the β-catenin pathway in colorectal tumor cells
Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-β signaling, as a target of the β-catenin pathway in colorectal tumor cells
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DOI：
10.1074/jbc.m310876200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Akiyama, T
中科院分区：
文献类型：
--
作者：
Sekiya, T;Adachi, S;Akiyama, T
Wnt信号通路在大多数人结直肠肿瘤中被激活。肿瘤抑制性腺瘤性结肠息肉病（APC）中的突变失活以及β-连环蛋白的激活导致β-连环蛋白的积累，其进而与T细胞因子/淋巴增强因子（TCF/LEF）家族的转录因子相关并激活其靶基因的转录。在这里，我们表明，β-连环蛋白激活BMP和激活素膜结合抑制剂（BAMBI）/NMA基因的转录。BAMBI在大肠癌和肝细胞癌中的表达水平明显高于相应的非癌组织。结直肠肿瘤细胞系中BAMBI的表达被TCF-4的显性负突变体或β-连环蛋白-TCF相互作用的抑制剂抑制，表明β-连环蛋白是结直肠肿瘤细胞中BAMBI异常表达的原因。此外，过表达BAMBI抑制肿瘤细胞对转化生长因子β信号传导的反应。这些结果表明，β-连环蛋白通过诱导BAMBI的表达干扰转化生长因子β介导的生长停滞，这可能有助于结直肠和肝细胞肿瘤的发生。
The Wnt signaling pathway is activated in most human colorectal tumors. Mutational inactivation in the tumor suppressor adenomatous polyposis coli (APC), as well as activation of beta-catenin, causes the accumulation of beta-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that beta-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in colorectal tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of beta-catenin-TCF interaction, suggesting that beta-catenin is responsible for the aberrant expression of BAMBI in colorectal tumor cells. Furthermore, overexpression of BAMBI inhibited the response of tumor cells to transforming growth factor-beta signaling. These results suggest that beta-catenin interferes with transforming growth factor-beta-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to colorectal and hepatocellular tumorigenesis.