Journal article
Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
BJ Aubrey, A Janic, Y Chen, C Chang, EC Lieschke, ST Diepstraten, AJ Kueh, JP Bernardini, G Dewson, LA O’Reilly, L Whitehead, AK Voss, GK Smyth, A Strasser, GL Kelly
Genes and Development | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2018
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 premalign..
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Awarded by Victorian Cancer Agency
Funding Acknowledgements
We thank all members of the Molecular Genetics of Cancer Division at The Walter and Eliza Hall Institute (WEHI) for support and advice; S. Haupt, Y. Haupt, A. Kallies, S. Nutt, T. Johanson, P. Hodgkin, S. Heinzel, M. Pang, P. Colman, T. Burgess, M.J. Herold, K. Rogers, C.E. Teh, D.H.D. Gray, and S. Wilcox for insightful discussion, advice, and reagents; G. Siciliano, H. Johnson, C. Gatt, and their team for animal husbandry; S. Monard and the team at the WEHI Flow Cytometry Unit; K. Rogers and team for support from the WEHI Dynamic Imaging Facility; C. Tsui, E. Tsui, and the team from the WEHI Histology Service; J. McManus and J. Corbin for hematology support; J. Zhang for providing cytokines; and D. Quilici and T. Nikolaou for irradiation service. This work was supported by Leukaemia Foundation National Research Program Clinical PhD Scholarship (to B. J. A.), National Health and Medical Research Council (NHMRC) Research Fellowship 1081421 (to A.K.V.), NHMRC project grant 1086291 (to G.L.K.), NHMRC program grant 1016701 (to A.S.), NHMRC Senior Principal Research Fellowship 1020363 (to A.S.), Leukemia and Lymphoma Society of America Specialized Center of Research (SCOR) grant 7001-13 (to A.S.), NHMRC Principal Research Fellowship 1058892 (to G.K.S.), NHMRC program grant 1054618 (to G.K.S.), Cancer Council Victoria grant-in-aids 1086157 and 1147328 (to G.L.K.), Victorian Cancer Agency Fellowship 17028 (to G.L.K), a Leukemia Foundation Australia grant (to G.L.K. and A.S.), and bequests from the Anthony Redstone Estate and Craig Perkins Cancer Research Foundation. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme.