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dc.contributor.authorKnight, John Rp
dc.contributor.authorVlahov, Nikola
dc.contributor.authorGay, David M
dc.contributor.authorRidgway, Rachel A
dc.contributor.authorFaller, William James
dc.contributor.authorProud, Christopher
dc.contributor.authorMallucci, Giovanna
dc.contributor.authorvon der Haar, Tobias
dc.contributor.authorSmales, Christopher Mark
dc.contributor.authorWillis, Anne
dc.contributor.authorSansom, Owen J
dc.date.accessioned2022-01-04T14:32:28Z
dc.date.available2022-01-04T14:32:28Z
dc.date.issued2021-12-13
dc.date.submitted2021-04-24
dc.identifier.issn2050-084X
dc.identifier.other69729
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331896
dc.descriptionFunder: National Health and Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000925
dc.description.abstractIncreased 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.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.subjectResearch Article
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjecttranslation
dc.subjectprotein sythesis
dc.subjectintestinal cancer
dc.subjectin vivo models
dc.subjectRPL24
dc.subjecteEF2K
dc.subjectMouse
dc.titleRpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K.
dc.typeArticle
dc.date.updated2022-01-04T14:32:27Z
prism.publicationNameElife
prism.volume10
dc.identifier.doi10.17863/CAM.79346
dcterms.dateAccepted2021-11-26
rioxxterms.versionofrecord10.7554/eLife.69729
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Frame, Margaret C
datacite.contributor.supervisorsenior_editor: Ron, David
dc.contributor.orcidKnight, John Rp [0000-0002-8771-5484]
dc.contributor.orcidMallucci, Giovanna [0000-0001-8504-1191]
dc.contributor.orcidvon der Haar, Tobias [0000-0002-6031-9254]
dc.contributor.orcidWillis, Anne [0000-0002-1470-8531]
dc.contributor.orcidSansom, Owen J [0000-0001-9540-3010]
dc.identifier.eissn2050-084X
pubs.funder-project-idWellcome Trust (via MRC) (201487/Z/16/Z)
pubs.funder-project-idCancer Research UK (via Beatson Institute for Cancer Research) (C20673/A24388)
cam.issuedOnline2021-12-13


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