The role of MDM4 in tumors
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ABSTRACT:
PROVIDER: PRJNA1016372 | ENA |
REPOSITORIES: ENA
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Project description:We transfected GFP and MDM4 into colon cancer cell SW480, and performed transcriptomic analysis.
2023-09-17 | GSE243108 | GEO
Project description:MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors
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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
Project description:Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. We screened several MRT cell lines each with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin and ATSP-7041, we show that MRT cells are more sensitive than other p53 wild-type cancer cell lines to MDM2 and dual MDM2/4 inhibition in vitro. These compounds cause significant upregulation of the p53 pathway in MRT cells, and sensitivity is ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitizes cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-day idasanutlin pulse causing marked regression of all xenografts including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene p53, and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.
2019-02-04 | GSE124508 | GEO
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: 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:Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activated the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoforms witch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.
2018-05-08 | GSE108651 | GEO
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:Transcriptional profiling of mouse embryonic kidneys lacking Mdm4 function in the ureteric bud lineage
2020-06-01 | GSE137994 | GEO
Project description:Protein Arginine MethylTransferase 5 (PRMT5) is known to mediate epigenetic control on chromatin and to functionally regulate components of the splicing machinery. In this study we show that selective deletion of PRMT5 in different organs leads to cell cycle arrest and apoptosis. At the molecular level, PRMT5 depletion results in reduced methylation of Sm proteins, aberrant constitutive splicing and in the Alternative Splicing (AS) of specific mRNAs. We identify Mdm4 as one of these mRNAs, which due to its weak 5’-Donor site, acts as a sensor of splicing defects and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in PRMT5 conditional knockout mice. Our data demonstrate a key role of PRMT5, together with p53, as guardians of the transcriptome. This will have fundamental implications in our understanding of PRMT5 activity, both in physiological conditions, as well as pathological conditions, including cancer and neurological diseases. Total RNA was extracted from control Prmt5F/F, and Prmt5 depleted Prmt5F/FNes (Nestin-Cre) Neural Stem/Progenitors Cells (NPCs). The final cRNA samples were hybridized to Illumina MouseRef-8 V2 arrays in quadruplicates.
2013-09-13 | E-GEOD-45269 | biostudies-arrayexpress