Consequences of Zmat3 loss in c-MYC- and mutant KRAS-driven tumorigenesis
AuthorBest, SA; Vandenberg, CJ; Abad, E; Whitehead, L; Guiu, L; Ding, S; Brennan, MS; Strasser, A; Herold, MJ; Sutherland, KD; ...
Source TitleCell Death and Disease
University of Melbourne Author/sVandenberg, Cassandra; Janic, Ana; Strasser, Andreas; Herold, Marco; Sutherland, Kate
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsBest, S. A., Vandenberg, C. J., Abad, E., Whitehead, L., Guiu, L., Ding, S., Brennan, M. S., Strasser, A., Herold, M. J., Sutherland, K. D. & Janic, A. (2020). Consequences of Zmat3 loss in c-MYC- and mutant KRAS-driven tumorigenesis. CELL DEATH & DISEASE, 11 (10), https://doi.org/10.1038/s41419-020-03066-9.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575595
TP53 is a critical tumor suppressor that is mutated in approximately 50% of human cancers. Unveiling the downstream target genes of TP53 that fulfill its tumor suppressor function is an area of intense investigation. Zmat3 (also known as Wig-1 or PAG608) is one such downstream target of p53, whose loss in hemopoietic stem cells lacking the apoptosis and cell cycle regulators, Puma and p21, respectively, promotes the development of leukemia. The function of Zmat3 in tumorigenesis however remains unclear. Here, to investigate which oncogenic drivers co-operate with Zmat3 loss to promote neoplastic transformation, we utilized Zmat3 knockout mice in models of c-MYC-driven lymphomagenesis and KrasG12D-driven lung adenocarcinoma development. Interestingly, unlike loss of p53, Zmat3 germline loss had little impact on the rate of tumor development or severity of malignant disease upon either the c-MYC or KrasG12D oncogenic activation. Furthermore, loss of Zmat3 failed to rescue KrasG12D primary lung tumor cells from oncogene-induced senescence. Taken together, we conclude that in the context of c-MYC-driven lymphomagenesis or mutant KrasG12D-driven lung adenocarcinoma development, additional co-occurring mutations are required to resolve Zmat3 tumor suppressive activity.
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