Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

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dc.contributor.authorChu, Jennifer
dc.contributor.authorZhang, Wenhan
dc.contributor.authorCencic, Regina
dc.contributor.authorO'Connor, Patrick B. F.
dc.contributor.authorRobert, Francis
dc.contributor.authorDevine, William G.
dc.contributor.authorSelznick, Asher
dc.contributor.authorHenkel, Thomas
dc.contributor.authorMerrick, William C.
dc.contributor.authorBrown, Lauren E.
dc.contributor.authorBaranov, Pavel V.
dc.contributor.authorPorco, John A. Jr
dc.contributor.authorPelletier, Jerry
dc.contributor.funderHealth Research Boarden
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderWellcome Trusten
dc.contributor.funderCanadian Institutes of Health Researchen
dc.contributor.funderNational Institutes of Healthen
dc.date.accessioned2022-07-15T14:30:37Z
dc.date.available2022-07-15T14:30:37Z
dc.date.issued2020-02
dc.date.updated2022-07-15T13:37:54Z
dc.description.abstractRocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5′ leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.en
dc.description.sponsorshipCanadian Institutes of Health Research (Foundation Grant FDN-148366); National Institute of Health (Research grants R35 GM118173, R24 GM-111625, and R01 GM-067041)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationChu, J., Zhang, W., Cencic, R., O'Connor, P. B. F., Robert, F., Devine, W. G., Selznick, A., Henkel, T., Merrick, W. C., Brown, L. E., Baranov, P. V., Porco, J. A., Jr and Pelletier, J. (2020) 'Rocaglates induce gain-of-function alterations to eIF4A and eIF4F', Cell Reports, 30(8), pp. 2481-2488.e5. doi: 10.1016/j.celrep.2020.02.002en
dc.identifier.doi10.1016/j.celrep.2020.02.002en
dc.identifier.endpage2488.e5en
dc.identifier.issn2211-1247
dc.identifier.issued8en
dc.identifier.journaltitleCell Reportsen
dc.identifier.startpage2481en
dc.identifier.urihttps://hdl.handle.net/10468/13372
dc.identifier.volume30en
dc.language.isoenen
dc.publisherElsevier B.V.en
dc.relation.projectinfo:eu-repo/grantAgreement/WT/Molecular Basis of Cell Function/210692//Molecular memory in human AMD1 gene: mechanisms and functions./en
dc.rights© 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjecteIF4Aen
dc.subjecteIF4Fen
dc.subjectInterfacial inhibitoren
dc.subjectRocaglatesen
dc.subjectTranslation initiationen
dc.titleRocaglates induce gain-of-function alterations to eIF4A and eIF4Fen
dc.typeArticle (peer-reviewed)en
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