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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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | エピゲノム制御 / がん / ERK / MAPキナーゼ / CtBP / 転写制御 / シグナル伝達 / 遺伝子 / 癌 / 発現制御 / リン酸化 / 生体分子 / EMT |
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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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Report
(4 results)
Research Products
(111 results)
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[Journal Article] Genomic loss of DUSP4 contributes to the progression of intraepithelial neoplasm of pancreas to invasive carcinoma.2016
Author(s)
Hijiya N, Tsukamoto Y, Nakada C, Tung NL, Kai T, Matsuura K, Shibata K, Inomata M, Uchida T, Tokunaga A, Amada K, Shirao K, Yamada Y, Mori H, Takeuchi I, Seto M, Aoki M, Takekawa M, Moriyama M.
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Journal Title
Cancer Res.
Volume: 76
Issue: 9
Pages: 2612-2625
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Genomic loss of DUSP4 contributes to the progression of intraepitherial neoplasm of pancreas to invasive carcinoma2016
Author(s)
Hijiya N, Tsukamoto Y, Nakada C, Tung NL, Kai T, Matsuura K, Shibata K, Inomata M, Uchida T, Tokunaga A, Amada K, Shirao K, Yamada Y, Mori H, Takeuchi I, Seto M, Aoki M, Takekawa M, and Moriyama M
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Journal Title
Cancer Res
Volume: In press
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Presentation] DUSP4の発現低下は膵上皮内癌から浸潤癌への進展に関与する2016
Author(s)
Naoki Hijiya, Yoshiyuki Tsukamoto, Chisato Nakata, Tomoki Kai, Keiko Matsuura, Masafumi Inomata, Kuniaki Shirao, Hiromu Mori, Masao Seto, Masahiro Aoki, Mutsuhiro Takekawa, Masatsugu Moriyama
Organizer
第75回日本癌学会学術総会
Place of Presentation
パシフィコ横浜（横浜）
Year and Date
2016-10-06
Related Report
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