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.
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An ERK12-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS on.pdf - Accepted Version Download (13MB) | Preview |
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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