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| Status |
Public on Nov 28, 2023 |
| Title |
Combined absence of Trp53 target genes Zmat3, Puma and p21 cause a high incidence of cancer in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
To investigate the impact of combined loss of Zmat3, Puma and p21 in Trp53-mediated tumour suppression we crossed Zmat3 -/- (ZKO) with Puma -/- p21 -/- mice to obtain Puma -/- p21 -/- Zmat3 -/- animals /TKOs).
Whole thymus from 8-12 week old mice were isolated and single cell suspension made by gentle mashing with a 70uL filter. 5 million cells were used for RNA extraction.
We then performed gene expression profiling using RNA-seq data
We were interested in the expression differences between Zmat3 KO mice and those with a triple KO (Zmat3, p21 & Puma). We also compared each of them to wild-type samples.
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| Contributor(s) |
Brennan MS, Brinkmann K, Sola GR, Healey G, Gibson L, Gangoda L, Potts M, Lieschke E, Wilcox S, Strasser A, Herold MJ, Janic A |
| Citation(s) |
38110554 |
| BioProject |
PRJNA1043715 |
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| Submission date |
Nov 27, 2023 |
| Last update date |
Feb 15, 2024 |
| Contact name |
Gerard Romero |
| E-mail(s) |
grspianus1999@gmail.com
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| Organization name |
Universitat Pompeu Fabra
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| Department |
Dpt of Medicine and Life Sciences, Universitat Pompeu Fabra (MELIS/UPF)
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| Street address |
Doctor Aiguader, 88
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| City |
Barcelona |
| State/province |
Catalonia |
| ZIP/Postal code |
08003 |
| Country |
Spain |
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| Platforms (1) |
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| Samples (11)
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE248747_Raw_counts_matrix.txt.gz |
617.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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