Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/134248
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Type: | Journal article |
Title: | Rpl24(Bst) mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K |
Author: | Knight, J.R.P. Vlahov, N. Gay, D.M. Ridgway, R.A. Faller, W.J. Proud, C. Mallucci, G.R. von der Haar, T. Smales, C.M. Willis, A.E. Sansom, O.J. |
Citation: | eLife, 2021; 10:e69729-1-e69729-25 |
Publisher: | eLife Sciences Publications Ltd |
Issue Date: | 2021 |
ISSN: | 2050-084X 2050-084X |
Statement of Responsibility: | John RP Knight, Nikola Vlahov, David M Gay, Rachel A Ridgway, William James Faller, Christopher Proud, Giovanna R Mallucci, Tobias von der Haar, Christopher Mark Smales, Anne E Willis, Owen J Sansom |
Abstract: | Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24(Bst) mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24(Bst) also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24(Bst) mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24(Bst) mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models. |
Keywords: | Cancer Biology |
Rights: | © 2021, Knight et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. |
DOI: | 10.7554/eLife.69729 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.7554/elife.69729 |
Appears in Collections: | Medicine publications |
Files in This Item:
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hdl_134248.pdf | Published version | 1.85 MB | Adobe PDF | View/Open |
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