文章基本信息

标题：CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop
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作者：Yibo Ren ; Zhenlin Ouyang ; Zhanwu Hou 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：11
页码：1-31
DOI：10.1016/j.isci.2020.101635
语种：English
出版社：Elsevier
摘要：SummaryDUSP6 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 threecis-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.Graphical AbstractDisplay OmittedHighlights•CIC represses DUSP6 transcription through direct promoter binding•p90RSK phosphorylates CIC at S173 and S301 sites•S173/S301 phosphorylated CIC binds to 14-3-3 to promote its nuclear export•ERK/p90RSK signaling regulates the subcellular localization of CIC-DUX4 proteinBiochemistry; Structural Biology; Cancer