MCRIP1, an ERK Substrate, Mediates ERK-Induced Gene Silencing during Epithelial-Mesenchymal Transition by Regulating the Co-Repressor CtBP
MCRIP1, an ERK Substrate, Mediates ERK-Induced Gene Silencing during Epithelial-Mesenchymal Transition by Regulating the Co-Repressor CtBP
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DOI：
10.1016/j.molcel.2015.01.023
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发表时间：
2015-04-02
期刊：
影响因子：
16
通讯作者：
Takekawa, Mutsuhiro
中科院分区：
文献类型：
--
作者：
Ichikawa, Kenji;Kubota, Yuji;Takekawa, Mutsuhiro
ERK通路不仅上调促生长基因，而且下调抗增殖和肿瘤抑制基因。特别是，ERK信号转导有助于抑制上皮-间质转化（EMT）过程中的E-钙粘蛋白基因。CtBP转录辅阻遏物也参与E-钙粘蛋白的基因沉默。然而，ERK信号转导和CtBP之间的功能关系是未知的。在这里，我们确定了ERK底物，命名为MCRIP 1，它桥接ERK信号传导和CtBP介导的基因沉默。CtBP通过与DNA结合转录抑制子ZEB 1相互作用被募集到靶基因的启动子元件。我们发现MCRIP 1与CtBP结合，从而竞争性抑制CtBP-ZEB 1相互作用。当被ERK磷酸化时，MCRIP 1与CtBP解离，使CtBP与ZEB 1相互作用。以这种方式，CtBP共阻遏物复合物通过诱导染色质修饰被募集到E-钙粘蛋白启动子并使其沉默。我们的研究结果揭示了ERK诱导的表观遗传基因沉默在EMT及其在癌症中的失调的分子机制。
The ERK pathway not only upregulates growth-promoting genes, but also downregulates anti-proliferative and tumor-suppressive genes. In particular, ERK signaling contributes to repression of the E-cadherin gene during epithelial-mesenchymal transition (EMT). The CtBP transcriptional co-repressor is also involved in gene silencing of E-cadherin. However, the functional relationship between ERK signaling and CtBP is unknown. Here, we identified an ERK substrate, designated MCRIP1, which bridges ERK signaling and CtBP-mediated gene silencing. CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications. Our findings reveal a molecular mechanism underlying ERK-induced epigenetic gene silencing during EMT and its dysregulation in cancer.