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

• Main Authors: Yibo Ren, Zhenlin Ouyang, Zhanwu Hou, Yuwei Yan, Zhe Zhi, Mengjin Shi, Mengtao Du, Huadong Liu, Yurong Wen, Yongping Shao
• Format: Article
• Language: English
• Published: Elsevier 2020-11-01
• Series: iScience
• Subjects: Biochemistry; Structural Biology; Cancer
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004220308270

Summary: 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.