Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

ABSTRACT: Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from patient samples that contain a wild-type p53 gene. We found that the MDM2 W329G mutant was resistant to the inhibitory effect of ribosomal protein L11 (RPL11) on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous mdm2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267150 | GEO | 2024/05/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Partial loss of Rpl11 in adult mice recapitulates Diamond-Blackfan anemia (DBA) and promotes lymphomagenesis

Project description:Diamond-Blackfan anemia (DBA) is characterized by anemia and cancer susceptibility, and is caused by mutations in ribosomal genes, including Rpl11. Here, we report that Rpl11-heterozygous embryos are not viable, and homozygous deletion of Rpl11 in adult mice results in death within a few weeks, accompanied by bone marrow aplasia and intestinal atrophy. Importantly, deletion of a single Rpl11 allele in adult mice results in anemia associated to decreased erythroid progenitors and defective erythroid maturation. These phenotypes are also present in mice transplanted with inducible heterozygous Rpl11 bone marrow, indicating a cell-autonomous role of RPL11 in erythropoiesis. Additionally, fibroblasts lacking one or both Rpl11 alleles show defective p53 activation upon ribosomal stress or DNA damage. Furthermore, fibroblasts and hematopoietic tissues from heterozygous Rpl11 mice present higher basal cMYC levels. Accordingly, heterozygous Rpl11 mice are highly susceptible to radiation-induced lymphomagenesis. We conclude that Rpl11-deficient mice recapitulate DBA disorder, including cancer predisposition. RNAseq profiles of bone marrow hematopoietic progenitors cells from WT (Rpl11+/+:: Tg.UbC-CreERT2) and LOX (Rpl11+/lox::Tb.Ub-CreERT2) mice, n=4 independent animals per genotype

2015-09-01 | E-GEOD-72537 | biostudies-arrayexpress

Partial loss of Rpl11 in adult mice recapitulates Diamond-Blackfan anemia (DBA) and promotes lymphomagenesis

2015-09-01 | GSE72537 | GEO

Pereira2020 - NRF2–p53 integrated-systems model of oxidative stress

Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2. The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).

2021-10-29 | MODEL2110270001 | BioModels

p53 activity results in DNA replication fork processivity

Project description:p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This was observed in tumor-derived U2OS cells, but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion, and in freshly isolated thymocytes from mice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supported DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53’s tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity, i.e. the prevention of DNA damage during replication.

2016-10-06 | GSE87668 | GEO

XL-MS of 5S RNP preribosomal complexes

Project description:The 5S RNP is assembled from its three components (5S rRNA, Rpl5/uL18, and Rpl11/uL5) before being incorporated into the pre-60S subunit. However, when ribosome synthesis is disturbed, a free 5S RNP can enter the MDM2–p53 pathway to regulate cell cycle and apoptotic signaling. Here we reconstitute and determine the cryo-EM structure of the conserved hexameric 5S RNP with fungal or human factors. This reveals how the nascent 5S rRNA associates with the initial nuclear import complex Syo1–uL18–uL5, and upon further recruitment of two nucleolar factors Rpf2–Rrs1 develops into the 5S RNP precursor that can assemble into the pre-ribosome. In addition, we elucidate the structure of another 5S RNP intermediate, carrying the human ubiquitin ligase Mdm2, which unraveled how this enzyme can be sequestered from its target substrate p53. Our data provide molecular insight into how the 5S RNP can mediate between ribosome biogenesis and cell proliferation.

2023-06-13 | PXD040087 | Pride

A recurrently amplified long noncoding RNA in colorectal cancer regulates p53 protein stability through GRWD1/RPL11/MDM2 axis [RNA-seq]

Project description:By integrating genome-wide copy number alteration, RNA-seq and proteomics data from 589 colorectal cancer (CRC) patients, we revealed that chromosome 8q24.21 amplification is negatively correlated with p53 protein stability. Using siRNA and CRISPR activation screening, we pinpointed a novel long noncoding gene (PiHL, P53 inHibiting LncRNA) from 8q24.21 as a p53 negative regulator. PiHL is drastically upregulated in CRC and is an independent predictor of CRC poor prognosis. Further In vitro and In vivo models demonstrate that PiHL is crucial in maintaining cell proliferation and inhibiting cell apoptosis through a p53-depedent manner. Mechanistically, PiHL acts to promote p53 ubiquitination by sequestering RPL11 from MDM2, through enhancing GRWD1 and RPL11 complex formation. We further show that p53 can form a feedback loop with PiHL by directly binding to PiHL promoter and regulating its expression. Our study successfully illustrates how cancer cells hijack the PiHL-p53 axis to promote CRC progression and suggests PiHL as a potential therapeutic target in human CRCs.

2019-12-31 | GSE124526 | GEO

5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq)

Project description:The tumor suppressor gene TP53 is mutated in approximately half of all human tumors. Of those, around 10% are nonsense mutations that produce truncated and inactive p53 protein. Induction of translational readthrough is a promising approach for rescuing full-length p53 and thereby eliminate tumor cells with nonsense mutant TP53. To find novel nonsense mutant TP53 readthrough-inducing compounds with a tolerable toxicity profile, we performed an in silico screening of data at the National Cancer Institute database and identified 5-Fluorouracil (5-FU). We show here that 5-FU induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53 and that this activity is mediated by its metabolite 5-Fluorouridine (FUr). Ribo-seq analysis validated induction of translational readthrough by FUr. We also show that FUr is incorporated into RNA where it potentially allows base pairing of Arg tRNA at the R213X UGA premature termination codon. Full-length p53 rescued by FUr is transcriptionally active and triggers p53-dependent cell death. Moreover, treatment with 5-FU or FUr restores full-length p53 expression in TP53 R213X mutant human tumor xenografts in vivo. Our results suggest that induction of readthrough by 5-FU/FUr could contribute to therapeutic efficacy in patients with TP53 nonsense mutant tumors.

2022-12-01 | GSE196709 | GEO

5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (RNA-Seq)

2022-12-01 | GSE196710 | GEO

Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type

Project description:Recent preclinical studies suggest that combining MEK and MDM2 inhibition synergize to induce apoptosis in RAS/BRAF-mutant and TP53 wild-type CRC models. In vitro, in RKO cell lines (poorly differentiated colon carcinoma cell line resistant to single agent targeting MDM2 and MEK and BRAF inhibition), the MDM2 plus MEK inhibitor combination generated a synergistic increase in apoptotic index. In vivo, in mice harboring human RKO colon tumor xenografts the combination of MDM2 plus MEK inhibition elicited 93% decreases in tumor volume. This trial is to conduct a single-center, Phase 1 dose escalation study of trametinib combined with HDM201 (a HDM2 inhibitor) in patients with advanced/metastatic RAS/RAF mutant and TP53 wt CRC.

| 2287507 | ecrin-mdr-crc

Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [HCT116 microarray]

Project description:The Mdm2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that Mdm2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, Mdm2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the Mdm2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. Mdm2 physically associated with EZH2 on chromatin, enhancing the trimethylation of Histone 3 at lysine 27 and the ubiquitination of Histone 2A at lysine 119 (H2AK119) at its target genes. Removing Mdm2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, Mdm2 supports the Polycomb-mediated repression of lineage specific genes independent of p53. microarray analysis in HCT116 p53-/-cells

2015-12-31 | E-GEOD-73294 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data