Rpl24 Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Knight, J. R.P. et al. (2021) Rpl24 Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K. eLife, 10, e69729. (doi: 10.7554/elife.69729) (PMID:34895463) (PMCID:PMC8668188)

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Abstract

Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24Bst 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 Rpl24Bst 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, Rpl24Bst 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 Rpl24Bst 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.

Item Type:Articles
Additional Information:The Sansom laboratory was funded by CRUK (A17196, A24388, and A21139), The European Research Council ColonCan (311301). This work was also funded by a Wellcome Trust Collaborative Award in Science (201487) to GM, CMS, TvdH, AEW, and OS. We are grateful to the Advanced Technologies and Core Services at the Beatson Institute (funded by CRUK C596/A17196 and A31287), particularly the Biological Services Unit, Histology Services and Transgenic Technology Laboratory. CGP is supported by funding from the National Health and Medical Research Council (Australia).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Faller, Dr William and Ridgway, Dr Rachel and Sansom, Professor Owen
Creator Roles:
Ridgway, R.Investigation
Faller, W.Investigation
Sansom, O.Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing
Authors: 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., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
First Published:First published in eLife 10:e69729
Publisher Policy:Reproduced under a Creative Commons License

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