Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
Details
Publication Year 2018-11-01, Volume 32, Issue #21-22, Page 1420-1429
Journal Title
Genes & Development
Publication Type
Journal Article
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.
Publisher
CSH Press
WEHI Research Division(s)
Molecular Genetics Of Cancer; Bioinformatics; Cell Signalling And Cell Death; Systems Biology And Personalised Medicine; Development And Cancer
PubMed ID
30366906
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-11-20 09:12:47
Last Modified: 2018-11-20 11:16:56
An error has occurred. This application may no longer respond until reloaded. Reload 🗙