PRMT1-Mdm4-p53 pathway controls epicardial invasion and cell fate transition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA503912 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8162740.fastq.gz | Fastqsanger.gz | |||
| SRR8162750.fastq.gz | Fastqsanger.gz | |||
| SRR8162741.fastq.gz | Fastqsanger.gz | |||
| SRR8162751.fastq.gz | Fastqsanger.gz | |||
| SRR8162742.fastq.gz | Fastqsanger.gz |
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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:To study the role of PRMT1 in epicardial fate decision during development using Single cell RNA-seq analysis
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| S-EPMC7425665 | biostudies-literature
Project description:We report 6 unrelated individuals with variable BMF phenotypes and hypocellular MDS. The median age at presentation was 10 years (4 weeks - 53 years). Unbiased genomic analysis revealed germline heterozygous variants in MDM4, including 4 null (frameshift, nonsense, and splice-site resulting in premature truncation confirmed by RNA sequencing) and 2 missense variants. Mechanistically, MDM4 mutations lead to loss-of-function with enhanced p53 activation. We used CRISPR/Cas9 to delete MDM4 in healthy donor hematopoietic stem and progenitor cells (HSPCs). The resulting MDM4-haploinsufficient HSPCs exhibited increased p53 activity, impaired colony-forming capacity, and reduced engraftment potential in immunodeficient mice. Complementation studies revealed the functional necessity of both p53-binding and RING-finger domains in MDM4-mediated hematopoietic regulation. To study variant effect in a genetic background free of potential confounders, we introduced patient-specific MDM4 variants into induced pluripotent stem cells (iPSCs). MDM4-mutant iPSCs yielded significantly reduced erythroid and myeloid cell populations and exhibited increased p53 activity, as evidenced by elevated p21 expression, confirming the role of MDM4 in regulating hematopoiesis through p53 modulation. Transcriptome analysis of iPSC-derived hematopoietic cells revealed upregulation of p53 pathway. Importantly, one patient acquired TP53 mutations, suggesting clonal rescue in the context of MDM4 deficiency. Our findings establish MDM4 deficiency as a new “TP53-opathy” BMF syndrome with variable hematopoietic manifestations. This study also highlights the critical role of the MDM4-p53 axis in maintaining hematopoietic homeostasis.
2025-10-16 | GSE279650 | GEO
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: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:The aim of this experiment has been to investigate the transcriptional profile of HCT116 cells treated with Peptide-3 (Pep3) compared to untreated (NT), treated with solvent (DMSO) or with a mutated peptide (Pep3M) cells. Peptide-3 is a dodecapeptide able to interact with MDM2 at the levels of the interaction region of the MDM4 and MDM2 proteins, thereby interfering with the coopeartivy function of the proteins in the regulation of p53. This peptide is indeed able to specifically activate p53 and to cause apoptotis in different cancer cell lines and tumor growth inhibition in xenograft models.
2017-04-18 | GSE62855 | GEO
Project description:Through an shRNA screen we have identified Prmt1 as a genetic vulnerability of p53/Rb-null murine osteosarcoma cells. Depletion of Prmt1 in p53-deficient cells impairs tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways are enriched for Prmt1 downstream targets, implicating a role of Prmt1 in translation control. In particular, we have shown that loss of Prmt1 leads to a the decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. We also observed that p53/Rb-null cells are sensitive to p53-induced translation stress. Analysis of the human tumor cell Achilles data set further reveals that Prmt1 and translation-associated pathways converge on the same functional networks. We propose that targeted therapy directed to inhibition of Prmt1 and its associated translation-related pathways represents a novel and promising therapeutic strategy for p53-deficient cancer cells that exhibit dependencies on translation stress response.
2018-01-06 | GSE93309 | GEO
Project description:The aim of this experiment has been to investigate the transcriptional profile of HCT116 cells treated with Peptide-3 (Pep3) compared to untreated (NT), treated with solvent (DMSO) or with a mutated peptide (Pep3M) cells. Peptide-3 is a dodecapeptide able to interact with MDM2 at the levels of the interaction region of the MDM4 and MDM2 proteins, thereby interfering with the coopeartivy function of the proteins in the regulation of p53. This peptide is indeed able to specifically activate p53 and to cause apoptotis in different cancer cell lines and tumor growth inhibition in xenograft models. Three different experimental conditions have been analysed compared to untreated cells at time 0 (NT cells, the starting point of the treatment): cells treated with DMSO solvent (DMSO); treated with peptide-3 (Pep3) and with control peptide (Pep3M). The analysis has been performed at 24 and 48 hours after treatment. In addition, untreated cells after 24 hours of growth have been analysed as further control. All analyses have been performed in triplicates.
2017-04-18 | E-GEOD-62855 | biostudies-arrayexpress
Project description:Ubiquitination plays an important role in proliferating and invasive characteristic of glioblastoma (GBM), similar to many other cancers. Tripartite motif 25 (TRIM25) is a member of the TRIM family of proteins, which are involved in tumorigenesis through substrate ubiquitination. Here, we found TRIM25 is upregulated in GBM and promotes glioblastoma cell growth and invasion, both in vitro and in vivo. Subsequently, we screened a panel of proteins that interact with TRIM25; mass spectrometry and co-immunoprecipitation showed that NONO was a potential substrate of TRIM25. TRIM25 knockdown reduced the K63-linked ubiquitination of NONO, which suppressed the splicing function of NONO. The dysfunctional NONO further leads to the retention of the second intron in the pre-mRNA of PRMT1 and inhibit the activation of the PRMT1/c-MYC pathway. In summary, we demonstrated that TRIM25 promotes glioblastoma cell growth and invasion by regulating the PRMT1/c-MYC pathway through mediation of the splicing factor NONO. Efforts to target the E3 ligase activity of TRIM25 or the complex interactions between TRIM25 and NONO may be useful in the treatment of GBM.
2023-07-11 | GSE236661 | GEO