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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Detalles Bibliográficos
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
Descripción
Sumario: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.

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