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COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors
Yuanyuan Xie, … , Ping Chi, Yu Chen
Yuanyuan Xie, … , Ping Chi, Yu Chen
Published January 23, 2018
Citation Information: J Clin Invest. 2018;128(4):1442-1457. https://doi.org/10.1172/JCI94840.
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Research Article Oncology Article has an altmetric score of 16

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

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Abstract

Aberrant activation of MAPK signaling leads to the activation of oncogenic transcriptomes. How MAPK signaling is coupled with the transcriptional response in cancer is not fully understood. In 2 MAPK-activated tumor types, gastrointestinal stromal tumor and melanoma, we found that ETV1 and other Pea3-ETS transcription factors are critical nuclear effectors of MAPK signaling that are regulated through protein stability. Expression of stabilized Pea3-ETS factors can partially rescue the MAPK transcriptome and cell viability after MAPK inhibition. To identify the players involved in this process, we performed a pooled genome-wide RNAi screen using a fluorescence-based ETV1 protein stability sensor and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 or DET1 loss led to decoupling between MAPK signaling and the downstream transcriptional response, where MAPK inhibition failed to destabilize Pea3 factors and fully inhibit the MAPK transcriptome, thus resulting in decreased sensitivity to MAPK pathway inhibitors. We identified multiple COP1 and DET1 mutations in human tumors that were defective in the degradation of Pea3-ETS factors. Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling–dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition.

Authors

Yuanyuan Xie, Zhen Cao, Elissa W.P. Wong, Youxin Guan, Wenfu Ma, Jenny Q. Zhang, Edward G. Walczak, Devan Murphy, Leili Ran, Inna Sirota, Shangqian Wang, Shipra Shukla, Dong Gao, Simon R.V. Knott, Kenneth Chang, Justin Leu, John Wongvipat, Cristina R. Antonescu, Gregory Hannon, Ping Chi, Yu Chen

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Figure 9

Functional characterization of cancer-derived COP1 mutations.

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Functional characterization of cancer-derived COP1 mutations.
(A) FACS p...
(A) FACS plot of mCherry fluorescence in A375 cells expressing mCherry-nETV1 and the indicated sgCOP1 guide RNA or sgCON (lentiCRISPRv2 vector with no guide RNA). (B) FACS plot of mCherry fluorescence in A375 cells expressing mCherry-nETV1 and the indicated sgCOP1 guide RNA or sgCON control treated with DMSO or 1 μM vemurafenib for 24 hours. (C) Immunoblot of HA in A375 melanoma cells expressing WT or mutant HA-COP1. Mutations that showed decreased function are in red. (D) FACS plots of EGFP and mCherry fluorescence in A375 cells expressing mCherry-nETV1 and either EGFP alone or the indicated COP1 mutation treated with 1 μM vemurafenib or DMSO for 24 hours. (E) Model of the structure of the COP1 WD40 domain together with peptide (DEQFVPDY). The protein backbone is shown as cartoons and the surface is in white, with key interface side chains labeled and rendered as sticks. The ETV1 peptide backbone is shown in green, with nitrogen atoms in blue and oxygen atoms in red. Functional COP-mutant amino acids are labeled in black, and loss-of-function mutant amino acids are in red. FSC-A, forward scatter area.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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