Whole kidneys at embryonic day 14.5: wildtype (WT) versus Hoxb7Cre transgene mediated conditional Mdm4 knockout kidneys
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PROVIDER: PRJNA574125 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptional profiling of mouse embryonic kidneys lacking Mdm4 function in the ureteric bud lineage
2020-06-01 | GSE137994 | GEO
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Project description:Defects in the splicing machinery have been implicated in various diseases, including cancer. We identified a general reduction in the expression spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced and telomere uncapping-induced senescence. Supporting the notion that defective splicing contributes to senescence, we showed that the splicing inhibitors herboxidiene and pladienolide B induce senescence both in normal and cancer cell lines. Furthermore, the individual depletion of several spliceosome components also promoted senescence. We noted an alternative splicing shift in MDM4, from the full-length MDM4-FL variant to MDM4-S during replicative and stress-induced senescence. This shift was replicated by splicing inhibition and the depletion of individual spliceosome components. Importantly, decreasing the level of MDM4-FL promoted senescence, while cell survival was improved both by reducing the level of MDM4-FL and by overexpressing MDM4-S. Overall, our work establishes that defects in the splicing machinery alter the alternative splicing of MDM4 to promote senescence.
2024-10-11 | GSE245356 | GEO
Project description:BACKGROUND: Lim1 is a homeobox gene that is essential for nephrogenesis. During metanephric kidney development, Lim1 is expressed in the nephric duct, ureteric buds, and the induced metanephric mesenchyme. Conditional ablation of Lim1 in the metanephric mesenchyme blocks the formation of nephrons at the nephric vesicle stage, leading to the production of small, non-functional kidneys that lack nephrons. METHODS: In the present study, we used Affymetrix probe arrays to screen for nephron-specific genes by comparing the expression profiles of control and Lim1 conditional mutant kidneys. Kidneys from two developmental stages, embryonic day 14.5 (E14.5) and 18.5 (E18.5), were examined. RESULTS: Comparison of E18.5 kidney expression profiles generated a list of 465 nephron-specific gene candidates that showed a more than 2-fold increase in their expression level in control kidney versus the Lim1 conditional mutant kidney. Computational analysis confirmed that this screen enriched for kidney-specific genes. Furthermore, at least twenty-eight of the top fifty (56%) candidates (or their vertebrate orthologs) were previously reported to have a nephron-specific expression pattern. Our analysis of E14.5 expression data yielded 41 candidate genes that are up-regulated in the control kidneys compared to the conditional mutants. Three of them are related to the Notch signaling pathway that is known to be important in cell fate determination and nephron patterning. CONCLUSIONS: Therefore, we demonstrate that Lim1 conditional mutant kidneys serve as a novel tissue source for comprehensive expression studies and provide a means to identify nephron-specific genes. Keywords: tissue specificity, time course, development, kidney, metanephric mesenchyme, nephron, Lim1, knockout mice, conditional knockout
2006-02-13 | GSE4230 | GEO
Project description:Background: The expression of MDM4, a well-known p53-inhibitor, is positively associated with chemotherapy response and overall survival in epithelial ovarian cancer (EOC). The basis of this association remains elusive. Since the occurrence of metastasis is one of the factors responsible for the high death rate of this cancer, we analyzed MDM4 involvement in EOC metastatic process. Methods: In vivo and in vitro models, based on 2D and 3D assays, were employed to assess the activity of MDM4 in ovarian cancer progression. A 3D-bioprinting co-culture system was ad hoc developed for this study. Proteomic analysis was conducted on 3D multicellular tumour spheroids to assess pathways triggered by MDM4 overexpression. Results: In mouse models, increased MDM4 reduced intraperitoneal dissemination of human and murine EOC cells, independently of p53 and in a cell-autonomous way. Consistently, high MDM4 correlates with increased overall survival probability in large public data sets. 2D and 3D assays indicated that MDM4 impairs the early steps of the metastatic process. The 3D-bioprinting co-culture system showed reduced dissemination and intravasation into vessel-like structures of MDM4-expressing cells. Proteomic analysis of EOC spheroids revealed that MDM4 reduces protein synthesis and decreases mTOR signaling. Accordingly, MDM4 did not further inhibit EOC cell migration when its activity towards mTOR is blocked genetically or pharmacologically. Conversely, increased MDM4 reduced the efficacy of mTOR inhibitors in constraining EOC cell migration. Conclusions: Overall, these data clarify the antagonism of MDM4 towards EOC progression and suggest the usefulness of MDM4 assessment for tailored application of mTOR targeted therapy.
2021-05-27 | PXD019935 | Pride
Project description:We transfected GFP and MDM4 into colon cancer cell SW480, and performed transcriptomic analysis.
2023-09-17 | GSE243108 | GEO
Project description:Single Cell analysis of Cells from a IL10 B cell conditional KO Kidneys
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Project description:Epicardial cells are progenitors giving rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during cardiac development, and critically modulating heart morphogenesis and coronary development. An integral phase of epicardial cell fate transition is epithelial-to-mesenchymal transition (EMT), which confers motility and facilitates cell fate transition. We identify a pathway involving protein arginine methyltransferase 1 (PRMT1) and its downstream p53 signaling that drives epicardial EMT and invasion. We show that PRMT1 determines the half-life of p53 through regulating alternative splicing of Mdm4, which is a key controller of p53 degradation. Loss of PRMT1 promotes the expression of Mdm4 short form, which inhibits p53 degradation. Accumulation of p53 subsequently enhances Slug degradation and blocks epicardial EMT. We further demonstrated that the PRMT1-Mdm4-p53 pathway drives epicardial cell fate transition into cardiac fibroblasts, coronary smooth muscle cells and pericytes in vivo, and modulates ventricular morphogenesis and coronary vessel formation. Together, our results establish critical functions of the PRMT1-Mdm4-p53 pathway in epicardial EMT, invasion and cell fate transition.
2020-08-18 | GSE122200 | GEO
Project description:Microsatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increased MDM4 exon 6 inclusion, cell proliferation, and augmented resistance to the MDM inhibitor Nutlin-3A. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, RPL22 loss is a driver of oncogenic MDM4 induction and key to a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
2024-07-22 | GSE263237 | GEO