2026-04-17T16:15:13Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/544112025-12-18T01:19:21Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Aubrey, Brandon J. author Janic, Ana author Chen, Yunshun author Chang, Catherine author Lieschke, Elizabeth C. author Diepstraten, Sarah T. author Kueh, Andrew J. author Bernardini, Jonathan P. author Dewson, Grant author O’Reilly, Lorraine A. author Whitehead, Lachlan author Voss, Anne K. author Smyth, Gordon K. author Strasser, Andreas author Kelly, Gemma L. author 2022-10-17T06:15:19Z 2022-10-17T06:15:19Z 2018 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. TRP53 Dominant-negative effect Tumorigenesis TRP53 target genes Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development