TY - JOUR
T1 - Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K
AU - Knight, John R.P.
AU - Vlahov, Nikola
AU - Gay, David M.
AU - Ridgway, Rachel A.
AU - Faller, William James
AU - Proud, Christopher
AU - Mallucci, Giovanna R.
AU - von der Haar, Tobias
AU - Smales, Christopher Mark
AU - Willis, Anne E.
AU - Sansom, Owen J.
N1 - Funding 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). We thank Daniel Murphy for kindly supplying antibodies for ACC and P-ACC. We thank Fiona Warrander for critical reading of the manuscript.
Publisher Copyright:
© Knight et al.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122018853&partnerID=8YFLogxK
U2 - 10.7554/eLife.69729
DO - 10.7554/eLife.69729
M3 - Article
C2 - 34895463
AN - SCOPUS:85122018853
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e69729
ER -
