期刊
MOLECULAR CELL
卷 58, 期 1, 页码 35-46出版社
CELL PRESS
DOI: 10.1016/j.molcel.2015.01.023
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Takeda Science Foundation
- Toray Science Foundation
- Global COE Program from MEXT, Japan
- Grants-in-Aid for Scientific Research [25440043, 15K19003, 15H01205, 15H04703, 24390079, 15J07710, 22117003, 22117001, 25650003] Funding Source: KAKEN
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.
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