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mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation

Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovere...

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Autores principales: Jana, Sujata, Deo, Rucha, Hough, Rowan P., Liu, Yuzhen, Horn, Jessie L., Wright, Jonathan L., Lam, Hung-Ming, Webster, Kevin R., Chiang, Gary G., Sonenberg, Nahum, Hsieh, Andrew C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262354/
https://www.ncbi.nlm.nih.gov/pubmed/34032633
http://dx.doi.org/10.1172/jci.insight.144920
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author Jana, Sujata
Deo, Rucha
Hough, Rowan P.
Liu, Yuzhen
Horn, Jessie L.
Wright, Jonathan L.
Lam, Hung-Ming
Webster, Kevin R.
Chiang, Gary G.
Sonenberg, Nahum
Hsieh, Andrew C.
author_facet Jana, Sujata
Deo, Rucha
Hough, Rowan P.
Liu, Yuzhen
Horn, Jessie L.
Wright, Jonathan L.
Lam, Hung-Ming
Webster, Kevin R.
Chiang, Gary G.
Sonenberg, Nahum
Hsieh, Andrew C.
author_sort Jana, Sujata
collection PubMed
description Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model, we show that this single posttranslational modification is critical for bladder cancer initiation and progression, despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis, and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation.
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spelling pubmed-82623542021-07-13 mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation Jana, Sujata Deo, Rucha Hough, Rowan P. Liu, Yuzhen Horn, Jessie L. Wright, Jonathan L. Lam, Hung-Ming Webster, Kevin R. Chiang, Gary G. Sonenberg, Nahum Hsieh, Andrew C. JCI Insight Research Article Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model, we show that this single posttranslational modification is critical for bladder cancer initiation and progression, despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis, and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation. American Society for Clinical Investigation 2021-06-08 /pmc/articles/PMC8262354/ /pubmed/34032633 http://dx.doi.org/10.1172/jci.insight.144920 Text en © 2021 Jana et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Jana, Sujata
Deo, Rucha
Hough, Rowan P.
Liu, Yuzhen
Horn, Jessie L.
Wright, Jonathan L.
Lam, Hung-Ming
Webster, Kevin R.
Chiang, Gary G.
Sonenberg, Nahum
Hsieh, Andrew C.
mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation
title mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation
title_full mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation
title_fullStr mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation
title_full_unstemmed mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation
title_short mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation
title_sort mrna translation is a therapeutic vulnerability necessary for bladder epithelial transformation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262354/
https://www.ncbi.nlm.nih.gov/pubmed/34032633
http://dx.doi.org/10.1172/jci.insight.144920
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