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CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop.


ABSTRACT: DUSP6 functions as an important negative feedback component of the MAPK/ERK signaling pathway. Although DUSP6 expression is tightly regulated by ERK1/2 signaling, the molecular mechanism of this regulation remains partially understood. In this work, we show that the transcriptional repressor CIC functions downstream of the ERK1/2 signaling to negatively regulate DUSP6 expression. CIC directly represses DUSP6 transcription by binding to three cis-regulatory elements (CREs) in DUSP6 promoter. p90RSK, a downstream target of ERK1/2, phosphorylates CIC at S173 and S301 sites, which creates a 14-3-3 recognition motif, resulting in 14-3-3-mediated nuclear export of CIC and derepression of DUSP6. Finally, we demonstrate that the oncogenic CIC-DUX4 fusion protein acts as a transcriptional activator of DUSP6 and its nuclear/cytoplasmic distribution remains regulated by ERK1/2 signaling. These results complete an ERK1/2/p90RSK/CIC/DUSP6 negative feedback circuit and elucidate the molecular mechanism of how RTK/MAPK signaling harnesses the transcriptional repressor activity of CIC in mammalian cells.

SUBMITTER: Ren Y 

PROVIDER: S-EPMC7578760 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop.

Ren Yibo Y   Ouyang Zhenlin Z   Hou Zhanwu Z   Yan Yuwei Y   Zhi Zhe Z   Shi Mengjin M   Du Mengtao M   Liu Huadong H   Wen Yurong Y   Shao Yongping Y  

iScience 20201003 11


DUSP6 functions as an important negative feedback component of the MAPK/ERK signaling pathway. Although DUSP6 expression is tightly regulated by ERK1/2 signaling, the molecular mechanism of this regulation remains partially understood. In this work, we show that the transcriptional repressor CIC functions downstream of the ERK1/2 signaling to negatively regulate DUSP6 expression. CIC directly represses DUSP6 transcription by binding to three <i>cis</i>-regulatory elements (CREs) in DUSP6 promote  ...[more]

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