2017 Fiscal Year Final Research Report
Regulation of gene expression by novel ERK substrates and its failure in cancer
| Project/Area Number |
15H04703
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Research Collaborator |
KUBOTA YUJI 東京大学, 医科学研究所, 助教 (70614973)
NAKAMURA TAKANORI 東京大学, 医科学研究所, 助教 (30707576)
NISHIZUMI NORIKO 東京大学, 医科学研究所, 技術専門職員 (30396882)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | エピゲノム制御 / がん / ERK |
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| Outline of Final Research Achievements |
The ERK pathway not only upregulates growth-promoting genes, but also downregulates anti-proliferative genes. In particular, ERK signaling contributes to repression of the E-cadherin gene during EMT. The CtBP co-repressor is also involved in gene silencing of E-cadherin. However, the functional relationship between ERK signaling and CtBP is unknown. In this study, we identified an ERK substrate MCRIP1, which bridges ERK signaling and CtBP-mediated gene silencing. CtBP is recruited to promoter elements of target genes by interacting with the transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, CtBP is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications. Our findings reveal a mechanism underlying ERK-induced epigenetic gene silencing of tumor suppressors and its dysregulation in cancer.
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| Free Research Field |
分子腫瘍学
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