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

被引：37

作者：

Aubrey, Brandon J. ^{[1
,2
,4
]}

Janic, Ana ^{[1
,2
]}

Chen, Yunshun ^{[1
,2
]}

Chang, Catherine ^{[1
]}

Lieschke, Elizabeth C. ^{[1
,2
]}

Diepstraten, Sarah T. ^{[1
,2
]}

Kueh, Andrew J. ^{[1
,2
]}

Bernardini, Jonathan P. ^{[1
,2
]}

Dewson, Grant ^{[2
]}

O'Reilly, Lorraine A. ^{[1
,2
]}

Whitehead, Lachlan ^{[1
,2
]}

Voss, Anne K. ^{[1
,2
]}

Smyth, Gordon K. ^{[1
,3
]}

Strasser, Andreas ^{[1
,2
]}

Kelly, Gemma L. ^{[1
,2
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3050, Australia

[3] Univ Melbourne, Sch Math & Stat, Melbourne, Vic 3010, Australia

[4] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

来源：

GENES & DEVELOPMENT | 2018年 / 32卷 / 21-22期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

TRP53; dominant-negative effect; tumorigenesis; TRP53 target genes; WILD-TYPE P53; BURKITT-LYMPHOMA; BREAST-CANCER; MUTATIONS; PUMA; SUPPRESSOR; MOUSE; MEDIATOR; PLATFORM; SARCOMAS;

D O I：

10.1101/gad.314286.118

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1420 / 1429

页数：10

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