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

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 back...

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Autores: Aubrey, Brandon J., Janic, Ana, Chen, Yunshun, Chang, Catherine, Lieschke, Elizabeth C., Diepstraten, Sarah T., Kueh, Andrew J., Bernardini, Jonathan P., Dewson, Grant, O’Reilly, Lorraine A., Whitehead, Lachlan, Voss, Anne K., Smyth, Gordon K., Strasser, Andreas, Kelly, Gemma L.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/54411
Acceso en línea:http://hdl.handle.net/10230/54411
http://dx.doi.org/10.1101/gad.314286.118
Access Level:acceso abierto
Palabra clave:TRP53
Dominant-negative effect
Tumorigenesis
TRP53 target genes
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spelling Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor developmentAubrey, Brandon J.Janic, AnaChen, YunshunChang, CatherineLieschke, Elizabeth C.Diepstraten, Sarah T.Kueh, Andrew J.Bernardini, Jonathan P.Dewson, GrantO’Reilly, Lorraine A.Whitehead, LachlanVoss, Anne K.Smyth, Gordon K.Strasser, AndreasKelly, Gemma L.TRP53Dominant-negative effectTumorigenesisTRP53 target genesMutations 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.Cold Spring Harbor Laboratory Press (CSHL Press)202220222018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/54411http://dx.doi.org/10.1101/gad.314286.118reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésGenes and Development. 2018 Nov 1;32(21-22):1420–9© 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/.http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/544112026-06-12T07:21:37Z
dc.title.none.fl_str_mv Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
title Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
spellingShingle Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
Aubrey, Brandon J.
TRP53
Dominant-negative effect
Tumorigenesis
TRP53 target genes
title_short Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
title_full Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
title_fullStr Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
title_full_unstemmed Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
title_sort Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
dc.creator.none.fl_str_mv Aubrey, Brandon J.
Janic, Ana
Chen, Yunshun
Chang, Catherine
Lieschke, Elizabeth C.
Diepstraten, Sarah T.
Kueh, Andrew J.
Bernardini, Jonathan P.
Dewson, Grant
O’Reilly, Lorraine A.
Whitehead, Lachlan
Voss, Anne K.
Smyth, Gordon K.
Strasser, Andreas
Kelly, Gemma L.
author Aubrey, Brandon J.
author_facet Aubrey, Brandon J.
Janic, Ana
Chen, Yunshun
Chang, Catherine
Lieschke, Elizabeth C.
Diepstraten, Sarah T.
Kueh, Andrew J.
Bernardini, Jonathan P.
Dewson, Grant
O’Reilly, Lorraine A.
Whitehead, Lachlan
Voss, Anne K.
Smyth, Gordon K.
Strasser, Andreas
Kelly, Gemma L.
author_role author
author2 Janic, Ana
Chen, Yunshun
Chang, Catherine
Lieschke, Elizabeth C.
Diepstraten, Sarah T.
Kueh, Andrew J.
Bernardini, Jonathan P.
Dewson, Grant
O’Reilly, Lorraine A.
Whitehead, Lachlan
Voss, Anne K.
Smyth, Gordon K.
Strasser, Andreas
Kelly, Gemma L.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TRP53
Dominant-negative effect
Tumorigenesis
TRP53 target genes
topic TRP53
Dominant-negative effect
Tumorigenesis
TRP53 target genes
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/54411
http://dx.doi.org/10.1101/gad.314286.118
url http://hdl.handle.net/10230/54411
http://dx.doi.org/10.1101/gad.314286.118
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Genes and Development. 2018 Nov 1;32(21-22):1420–9
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press (CSHL Press)
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press (CSHL Press)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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