Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Aubrey, Brandon J.
• dc.contributor.author Janic, Ana
• dc.contributor.author Chen, Yunshun
• dc.contributor.author Chang, Catherine
• dc.contributor.author Lieschke, Elizabeth C.
• dc.contributor.author Diepstraten, Sarah T.
• dc.contributor.author Kueh, Andrew J.
• dc.contributor.author Bernardini, Jonathan P.
• dc.contributor.author Dewson, Grant
• dc.contributor.author O’Reilly, Lorraine A.
• dc.contributor.author Whitehead, Lachlan
• dc.contributor.author Voss, Anne K.
• dc.contributor.author Smyth, Gordon K.
• dc.contributor.author Strasser, Andreas
• dc.contributor.author Kelly, Gemma L.
• dc.date.accessioned 2022-10-17T06:15:19Z
• dc.date.available 2022-10-17T06:15:19Z
• dc.date.issued 2018
• dc.description.abstract Mutations in Trp53, prevalent in human cancer, are reported to drive tumorigenesis through dominant-negative effects (DNEs) over wild-type TRP53 function as well as neomorphic gain-of-function (GOF) activity. We show that five TRP53 mutants do not accelerate lymphomagenesis on a TRP53-deficient background but strongly synergize with c-MYC overexpression in a manner that distinguishes the hot spot Trp53 mutations. RNA sequencing revealed that the mutant TRP53 DNE does not globally repress wild-type TRP53 function but disproportionately impacts a subset of wild-type TRP53 target genes. Accordingly, TRP53 mutant proteins impair pathways for DNA repair, proliferation, and metabolism in premalignant cells. This reveals that, in our studies of lymphomagenesis, mutant TRP53 drives tumorigenesis primarily through the DNE, which modulates wild-type TRP53 function in a manner advantageous for neoplastic transformation.
• dc.format.mimetype application/pdf
• dc.identifier.citation Aubrey BJ, Janic A, Chen Y, Chang C, Lieschke EC, Diepstraten ST, et al. Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development. Genes and Development. 2018 Nov 1;32(21-22):1420–9. DOI: 10.1101/gad.314286.118
• dc.identifier.doi http://dx.doi.org/10.1101/gad.314286.118
• dc.identifier.issn 0890-9369
• dc.identifier.uri http://hdl.handle.net/10230/54411
• dc.language.iso eng
• dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)
• dc.relation.ispartof Genes and Development. 2018 Nov 1;32(21-22):1420–9
• dc.rights © 2018 Aubrey et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword TRP53
• dc.subject.keyword Dominant-negative effect
• dc.subject.keyword Tumorigenesis
• dc.subject.keyword TRP53 target genes
• dc.title Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion