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CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop
Yibo Ren1, Zhenlin Ouyang2, Zhanwu Hou3
1Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
Iscience
|October 26, 2020
Summary
The study reveals how ERK1/2 signaling regulates DUSP6 expression via the CIC protein. Phosphorylation of CIC by p90RSK leads to its nuclear export, derepressing DUSP6 and completing a negative feedback loop.
Area of Science:
- Molecular Biology
- Cell Signaling
- Gene Regulation
Background:
- DUSP6 is a negative feedback regulator in the MAPK/ERK pathway.
- The precise molecular mechanisms controlling DUSP6 expression by ERK1/2 signaling are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism by which ERK1/2 signaling regulates DUSP6 expression.
- To identify the role of the transcriptional repressor CIC in this regulatory pathway.
Main Methods:
- Investigated CIC's role as a downstream effector of ERK1/2 signaling.
- Analyzed CIC's direct binding to DUSP6 promoter cis-regulatory elements (CREs).
- Examined the effect of p90RSK-mediated phosphorylation of CIC on its subcellular localization and DUSP6 regulation.
Main Results:
- CIC directly represses DUSP6 transcription by binding to its promoter.
- p90RSK phosphorylates CIC at S173 and S301, promoting 14-3-3-mediated nuclear export.
- Nuclear export of CIC derepresses DUSP6 expression, completing an ERK1/2/p90RSK/CIC/DUSP6 negative feedback circuit.
- The oncogenic CIC-DUX4 fusion protein activates DUSP6 transcription.
Conclusions:
- Established a novel negative feedback circuit involving ERK1/2, p90RSK, CIC, and DUSP6.
- Elucidated the mechanism of transcriptional repression and derepression of DUSP6 by CIC.
- Demonstrated context-dependent regulation of DUSP6 by CIC, including its oncogenic fusion form.
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