Mice deficient in Zfp871 are prone to early death and steatohepatitis in part through the p53-Mdm2 axis
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ABSTRACT:
PROVIDER: PRJNA736737 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14783107_1.fastq.gz | Fastqsanger.gz | |||
| SRR14783107_2.fastq.gz | Fastqsanger.gz | |||
| SRR14783108_1.fastq.gz | Fastqsanger.gz | |||
| SRR14783108_2.fastq.gz | Fastqsanger.gz | |||
| SRR14783109_1.fastq.gz | Fastqsanger.gz |
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Project description:p53 transcription factor is activated upon exposure to various cellular stresses, leading to growth suppression. However, aberrant activation of p53 can lead to defects in embryonic development and other abnormalities. Here, we identified zinc finger protein Zfp871 as a p53 target gene. We showed that as an RNA-binding protein, Zfp871 binds to Mdm2 3’UTR and stabilizes Mdm2 mRNA, which in turn suppresses p53 expression through increased expression of Mdm2 E3 ubiquitin ligase. Consistently, Zfp871 deficiency increases p53 expression, leading to growth suppression in a p53-dependent manner. To determine the role of Zfp871 in the p53 pathway, we utilized Zfp871-deficient mouse model and found that Zfp871-null mice were prone to embryonic/pre-weaning lethality, which can be partially rescued by simultaneous deletion of Trp53. We also found that mice heterozygous for Zfp871 had a short lifespan and were susceptible to steatohepatitis but not to spontaneous tumors. To determine the underlying mechanism, RNA-seq analysis was performed and showed that an array of genes involved in development, lipid metabolism and inflammation are regulated by Zfp871 in conjunction with p53. Taken together, we conclude that the Zfp871-Mdm2-p53 pathway plays a critical role in tumor-free survival and development.
2021-06-11 | GSE176582 | GEO
Project description:We reported for the first time that DMKG plus B87 kills cancer cells through a MDM2-dependent cell death mechanism (unpublished results). Moreover, we demonstrated that this effect is reverted by MDM2 inhibitors. We investigated if this effect is transcriptional.
2020-12-20 | GSE108406 | GEO
Project description:Pathogenesis and factors for determining progression of alcoholic and non-alcoholic steatosis to steatohepatitis with risk of further progression to liver cirrhosis and cancer are poorly understood. In the present study, we aimed to identify potential molecular signatures for discrimination of steatohepatitis from steatosis. Global gene expression analysis was applied to unravel differentially expressed genes between steatohepatitis compared to steatosis and control samples. For functional annotation as well as the identification of disease-relevant biological processes of the differentially expressed genes the gene ontology (GO) database was used. Genes down-regulated in steatohepatitis were mainly involved in metabolic processes. Genes up-regulated in steatohepatitis samples were associated with cancer progression and proliferation. Further statistical and pathway analysis lead to the selection of 46 candidate genes which were validated in two sample cohorts by quantitative real-time PCR. In surgical liver resection samples 39 genes and in percutaneous liver biopsies 30 genes were significantly up-regulated in steatohepatitis. Conclusion: The development of steatohepatitis is characterized by distinct molecular changes. 44 human liver tissue surgical samples (normal n=13; steatosis n=19; steatohepatitis n=12, 8/2 cirrhotic/non-cirrhotic) obtained from patients undergoing liver surgery for HCC, other malignancy/metastatic disease, benign tumors of the liver and organ dedicated to transplantation. Virtually normal control samples in this cohort were taken from patients undergoing surgical resection of liver metastasis, but the surrounding liver tissue used for the molecular analyses was normal, non-tumorous liver tissue without detectable pathological changes. The samples were provided by the Biobank at the Medical University of Graz. This dataset is part of the TransQST collection.
2012-12-10 | E-GEOD-33814 | biostudies-arrayexpress
Project description:The MDM2 oncoprotein is an essential component of the p53 pathway. Although MDM2 has been widely described as a major negative regulator of the p53 tumor suppressor, growing evidences support the notion that Mdm2 functions are also mediated through p53 independent mechanisms. We found that MDM2 is recruited on chromatin. By ChIP-Seq (using MDM2 antibody) of H1299 cells exhibiting MDM2 recruitment on chromatin, we identified at the whole genome level MDM2 binding sites. Both input and IPped-DNA were exhaustively sequenced and mapped on human genome
2016-06-09 | GSE64439 | GEO
Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.
2013-04-02 | E-GEOD-37031 | biostudies-arrayexpress
Project description:Adult cardiomyocytes (CM) are terminally differentiated cells with minimal regenerative capacity, making cardiac tissue particularly vulnerable to injury. Thus, defining the roadblocks responsible for adult CM cell cycle arrest lies at the core of developing therapies to regenerate myocyte loss following injurious events such as myocardial infarction. We have previously shown that inactivating the p53/Mdm2 tumor suppressor circuitry, specifically in the heart (using the Cre-loxP recombination system of bacteriophage P1), can allow differentiated CMs to regain proliferative capacity, through an upregulation of factors involved in cell cycle re-entry. These factors are repressed in quiescent CMs, in part through the action of microRNAs (miRNAs). Notably, knockout of either p53 or Mdm2 individually was insufficient to promote CM proliferation. Therefore, we hypothesized that inactivation of p53/Mdm2-regulated miRNAs could promote the expression of cell cycle activators and induce proliferation of adult murine CMs. To identify miRNAs regulated by both p53 and Mdm2, total miRNA expression profiles from cardiac specific p53/Mdm2 double knockout (DKO) mouse hearts were compared with those from cardiac-specific single knockouts (p53KO and Mdm2KO), and vehicle-injected controls using the Nanostring nCounter mouse miRNA expression assay. This revealed a profile of 11 significantly downregulated miRNAs in the proliferative DKO hearts (versus vehicle-injected control), that were enriched for mRNA targets involved in cell cycle regulation. In vitro studies have demonstrated that knockdown of these 11 miRNAs in neonatal rat cardiomyocytes can increase the occurrence of cytokinetic events. Ultimately, we aim to inject antagomirs targeting these miRNAs into animals post-myocardial infarction to determine the effect of p53/Mdm2-regulated miRNAs on heart function and CM proliferation in vivo.
2017-03-22 | E-MTAB-5531 | biostudies-arrayexpress
Project description:MDM2 inhibitor remarkably induced biomineralization in hDPSCs but it remained the problem that p53 activation is insufficient due to MDM2-p53 autoregulatory feedback loop. To overcome the limitation of the MDM2 inhibitors, we applied proteolysis targeting chimera (PROTAC), a technology that degrades a protein of interest (POI) by intracellular ubiquitin-proteasome system. Hence, we propose a strategy to induce hard tissue regeneration by MDM2-targeting PROTAC technology. We selected Nutlin-3 of POI ligand among various MDM2 inhibitors based on the screening process, and the selected CRBN of E3 ligase ligand. The MDM2-PROTAC synthesis platform was designed by each ligand combination. By performing the degradation test for selected compounds, we evaluated the characteristics of the developed MDM2 PROTAC such as the maximal degradation concentration (DCmax), the half of maximal degradation concentration (DC50), and half-lifetime. To investigate gene expression profiling of MDM2-targeting small molecules, we conducted RNA-sequencing under MDM2 PROTAC and Nutlin-3 (POI ligand) treated conditions. We not only confirmed a robust effect on biomineralization by MDM2-targeting small molecules but also demonstrated the potent osteogenic differentiation ability of MDM2 PROTAC when compared to an MDM2 inhibitor. MDM2-PROTAC significantly increased mRNA levels of osteogenic differentiation marker genes. Also, the significant bone generation effect of MDM2 PROTAC was validated in an ovariectomy (OVX)-induced osteoporosis animal model. Through these results, it is expected that a new therapeutic modality for hard tissue regeneration will be possible, and the application range of the PROTAC system can be expanded.
2024-06-11 | GSE255297 | GEO
Project description:The p53 transcription factor is a master regulator of cellular stress responses restrained by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces cell death in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2alpha -ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2alpha, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2alpha phosphorylation. Pharmacological induction of eIF2alpha phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2alpha, with clear therapeutic implications.
2022-11-01 | GSE191148 | GEO
Project description:The p53 transcription factor is a master regulator of cellular stress responses restrained by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces cell death in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2alpha -ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2alpha, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2alpha phosphorylation. Pharmacological induction of eIF2alpha phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2alpha, with clear therapeutic implications.
2022-09-01 | GSE191149 | GEO
Project description:Relapse after allo-HCT is a major cause of death of AML patients and results from immune evasion of AML blasts. Dysfunction of the p53 signaling pathway is frequent in AML and often caused by upregulation of the central p53 negative regulator Murine Double Minute 2 (MDM2). Besides its oncogenic effects p53 also regulates immune function and immune surveillance of solid cancer. We hypothesize that p53 also controls immune-related genes in AML cells and that p53 reactivation via MDM2-inhibition may enhance the immunogenicity of AML cells to allogeneic T cells.
2022-09-20 | GSE158103 | GEO