Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K.
Gay, David M
Ridgway, Rachel A
Faller, William James
Smales, Christopher Mark
eLife Sciences Publications, Ltd
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Knight, J. R., Vlahov, N., Gay, D. M., Ridgway, R. A., Faller, W. J., Proud, C., Mallucci, G., et al. (2021). Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K.. Elife, 10 https://doi.org/10.7554/eLife.69729
Funder: National Health and Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000925
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.
Research Article, Cancer Biology, Cell Biology, translation, protein sythesis, intestinal cancer, in vivo models, RPL24, eEF2K, Mouse
Wellcome Trust (via MRC) (201487/Z/16/Z)
Cancer Research UK (via Beatson Institute for Cancer Research) (C20673/A24388)
External DOI: https://doi.org/10.7554/eLife.69729
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331896