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Mol Cell. 2015 Apr 2;58(1):35-46. doi: 10.1016/j.molcel.2015.01.023. Epub 2015 Feb 26.

MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP.

Author information

1
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan; Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
2
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan.
3
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
4
Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
5
Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: h-saito@ims.u-tokyo.ac.jp.
6
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: takekawa@ims.u-tokyo.ac.jp.

Abstract

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.

PMID:
25728771
DOI:
10.1016/j.molcel.2015.01.023
[Indexed for MEDLINE]
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