CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop.
CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop.
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CIC 是 ERK1/2-DUSP6 负反馈环的中介者
DOI：
10.1016/j.isci.2020.101635
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发表时间：
2020-11-20
期刊：
影响因子：
5.8
通讯作者：
Shao Y
中科院分区：
文献类型：
--
作者：
Ren Y;Ouyang Z;Hou Z;Yan Y;Zhi Z;Shi M;Du M;Liu H;Wen Y;Shao Y
DUSP6是MAPK/ERK信号通路中一个重要的负反馈成分。尽管DUSP6的表达受到ERK1/2信号的严格调控，但这种调控的分子机制尚不完全清楚。在这项工作中，我们发现转录抑制物CIC在ERK1/2信号的下游发挥作用，负调控DUSP6的表达。CIC通过结合DUSP6启动子中的三个顺式调控元件（CREs）直接抑制DUSP6的转录。ERK1/2的下游靶点p90RSK磷酸化CIC的S173和S301位点，形成14-3-3识别基序，导致14-3-3介导的CIC核输出和DUSP6的抑制。最后，我们证明了致癌的CIC-DUX4融合蛋白作为DUSP6的转录激活因子，其核/细胞质分布仍然受到ERK1/2信号的调节。这些结果完成了ERK1/2/p90RSK/CIC/DUSP6负反馈回路，并阐明了RTK/MAPK信号如何在哺乳动物细胞中利用CIC的转录抑制活性的分子机制。CIC通过直接启动子结合抑制DUSP6转录p90RSK在S173和S301位点磷酸化CIC， S173/S301磷酸化CIC结合14-3-3促进其核输出ERK/p90RSK信号调控CIC- dux4蛋白的亚细胞定位生化；结构生物学;癌症
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. 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 protein Biochemistry; Structural Biology; Cancer
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