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An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene

Azman, Muhammad S; Alard, Emilie L; Dodel, Martin; Capraro, Federica; Faraway, Rupert; Dermit, Maria; Fan, Wanling; ... Mardakheh, Faraz K; + view all (2023) An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene. The EMBO Journal , 42 (11) , Article e110902. 10.15252/embj.2022110902. Green open access

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Abstract

Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA-binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of nucleolin and highlight a crucial role for this mechanism in RAS-mediated tumorigenesis.

Type: Article
Title: An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.2022110902
Publisher version: https://doi.org/10.15252/embj.2022110902
Language: English
Additional information: ©2023 The Authors. Published under the terms of the CC BY 4.0 license.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Nucleolin, pancreatic ductal adenocarcinoma, RAS, ribosome biogenesis, RNA-binding proteins, POLYMERASE-I TRANSCRIPTION, PROTEIN-KINASE CK2, MESSENGER-RNA, COMPUTATIONAL PLATFORM, DEPENDENT REGULATION, PHOSPHORYLATION, CANCER, ACTIVATION, TRANSLATION, REVEALS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10174364
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