Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice

Brennan, Margs S.; Brinkmann, Kerstin; Romero Sola, Gerard; Healey, Geraldine; Gibson, Leonie; Gangoda, Lahiru; Potts, Margaret A.; Lieschke, Elizabeth C.; Wilcox, Stephen; Strasser, Andreas; Herold, Marco J.; Janic, Ana

Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice

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dc.contributor.author Brennan, Margs S.
dc.contributor.author Brinkmann, Kerstin
dc.contributor.author Romero Sola, Gerard
dc.contributor.author Healey, Geraldine
dc.contributor.author Gibson, Leonie
dc.contributor.author Gangoda, Lahiru
dc.contributor.author Potts, Margaret A.
dc.contributor.author Lieschke, Elizabeth C.
dc.contributor.author Wilcox, Stephen
dc.contributor.author Strasser, Andreas
dc.contributor.author Herold, Marco J.
dc.contributor.author Janic, Ana
dc.date.accessioned 2024-01-26T06:39:11Z
dc.date.available 2024-01-26T06:39:11Z
dc.date.issued 2024
dc.description.abstract Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the PUMA and p21, the critical effectors of TRP53-mediated apoptosis and cell cycle arrest respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma-/-p21-/-Zmat3-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma-/-Zmat3-/- or p21-/-Zmat3-/-deficient mice. Interestingly, we observed that the triple knockout and Puma-/-Zmat3-/- double deficient animals succumbed to lymphoma, while p21-/-Zmat3-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.
dc.description.sponsorship This work was supported by grants and fellowships from the Australian Phenomics Network (APN), the Australian National Health and Medical Research Council (NHMRC) to MJH and AS (1143105), Programme Grant to AS (1016701), Investigator grant to AS (2007887), Investigator Grant to MJH (2017971); the Leukaemia and Lymphoma Society of America to AS and MJH (LLS SCOR 7015-18); the Cancer Council of Victoria Project grant to AS (1052309) and Venture Grant to MJH and AS; support to AS from the estate of Anthony (Toni) Redstone OAM; support to AJ from Spanish Ministry of Economy and Development Grant (PID2021-127710OB-I00) and Programa Captació de Talent Investigador ‘La Caixa’ foundation (51110009). AJ is supported by Ramon y Cajal Research Fellowship (RYC2018-025244-I), AS and MJH are supported by NHMRC Fellowships (1020363 and 1156095), MSB is supported by Cancer Council Victoria Postdoctoral Fellowship and Swedish Cancer Society (21 0355 PT). This work was made possible through the Victorian Government Operational Infrastructure Support and Australian Government, the ‘Unidad de Excelencia María de Maeztu’ funded by the Spanish Government.
dc.format.mimetype application/pdf
dc.identifier.citation Brennan MS, Brinkmann K, Romero Sola G, Healey G, Gibson L, Gangoda L, et al. Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice. Cell Death Differ. 2024 Feb;31(2):159-69. DOI: 10.1038/s41418-023-01250-w
dc.identifier.doi http://dx.doi.org/10.1038/s41418-023-01250-w
dc.identifier.issn 1350-9047
dc.identifier.uri http://hdl.handle.net/10230/58822
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Cell Death Differ. 2024 Feb;31(2):159-69
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-127710OB-I00
dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Cancer
dc.subject.keyword Cancer genetics
dc.subject.keyword Cancer models
dc.title Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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