MUC1-C Oncoprotein Induces TCF7L2 Transcription Factor Activation and Promotes Cyclin D1 Expression in Human Breast Cancer Cells
MUC1-C Oncoprotein Induces TCF7L2 Transcription Factor Activation and Promotes Cyclin D1 Expression in Human Breast Cancer Cells
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DOI：
10.1074/jbc.m111.323311
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发表时间：
2012-03-23
影响因子：
4.8
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
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作者：
Rajabi, Hasan;Ahmad, Rehan;Kufe, Donald
MUC1是一种异源二聚体糖蛋白，在乳腺癌中过度表达。目前的研究表明，致癌的MUC1C端亚单位(MUC1C)与TCF7L2转录因子有关。MUC1-C细胞质结构域(MUC1-CD)直接与TCF7L2 C-末端区域结合。MUC1-C阻断TCF7L2与C端结合蛋白(CtBP)之间的相互作用，CBP是TCF7L2介导的转录抑制因子。TCF7L2和MUC1-C在细胞周期蛋白D1基因启动子上形成复合体，MUC1-C通过募集β-catenin和p300促进TCF7L2介导的转录。沉默人乳腺癌细胞中的MUC1-C下调细胞周期蛋白D1启动子的激活，并降低细胞周期蛋白D1的表达。此外，MUC1-C抑制剂阻断了与TCF7L2的相互作用，并抑制了细胞周期蛋白D1的水平。这些发现表明，MUC1-C癌蛋白参与了TCF7L2的激活，从而促进了乳腺癌细胞中细胞周期蛋白D1的表达。
MUC1 is a heterodimeric glycoprotein that is overexpressed in breast cancers. The present studies demonstrate that the oncogenic MUC1 C-terminal subunit (MUC1-C) associates with the TCF7L2 transcription factor. The MUC1-C cytoplasmic domain (MUC1-CD) binds directly to the TCF7L2 C-terminal region. MUC1-C blocks the interaction between TCF7L2 and the C-terminal-binding protein (CtBP), a suppressor of TCF7L2-mediated transcription. TCF7L2 and MUC1-C form a complex on the cyclin D1 gene promoter and MUC1-C promotes TCF7L2-mediated transcription by the recruitment of beta-catenin and p300. Silencing MUC1-C in human breast cancer cells down-regulated activation of the cyclin D1 promoter and decreased cyclin D1 expression. In addition, a MUC1-C inhibitor blocked the interaction with TCF7L2 and suppressed cyclin D1 levels. These findings indicate that the MUC1-C oncoprotein contributes to TCF7L2 activation and thereby promotes cyclin D1 expression in breast cancer cells.