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Charting the impact of supraphysiologic MDM2 on gene regulatory circuits in sarcoma

ABSTRACT: Charting the impact of supraphysiologic MDM2 on gene regulatory circuits in sarcoma

PROVIDER: PRJNA880357 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21559344_1.fastq.gz	Fastqsanger.gz
	SRR21559344_2.fastq.gz	Fastqsanger.gz
	SRR22741744_1.fastq.gz	Fastqsanger.gz
	SRR22741744_2.fastq.gz	Fastqsanger.gz
	SRR22741745_1.fastq.gz	Fastqsanger.gz

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Charting the impact of supraphysiologic MDM2 on gene regulatory circuits in sarcoma

Project description:Amplification of the ubiquitin ligase MDM2 is a common mechanism of P53 inactivation across human tumors. Here we investigated the impact of supraphysiologic MDM2 expression on chromatin topology, gene expression and cellular phenotypes in liposarcoma tumors and models. We identified three independent gene regulatory circuits that predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind a shared set of enhancers associated with mesenchymal lineage genes that underlie the developmental state of these tumors. P53 and MDM2 co-occupy enhancers and promoters associated with P53 pathways. When highly expressed, MDM2 also binds an additional set of P53-independent promoters that engage in multi-way physical interactions and regulate genes involved in cell division, RNA splicing, translation and stress responses. We find that liposarcoma cells with low to moderate MDM2 levels are sensitive to P53 inhibitors and their combination with pro-apoptotic agents, but that cells with very high-level MDM2 amplification and expression resist treatment. Hence, heterogeneity of MDM2 expression between and within tumors may compromise therapeutic regimens. In conclusion, we distinguished P53-dependent and P53-independent circuits in MDM2 copy number amplified tumors whose interplay has implications for targeted therapy.

2023-04-10 | GSE213300 | GEO

Vanished MDM2 amplification in a poorly differentiated sarcoma with amplified TERT-TRIO fusion gene: a targeted effect of radiotherapy?

Project description:The identification of genetic alterations in sarcoma may give precious clues for the diagnosis. The detection of MDM2 amplification has an important impact since it may orientate towards a dedifferentiated liposarcoma (DDLPS) or more rarely towards an intimal sarcoma. Here we describe a poorly differentiated sarcoma initially diagnosed as a DDLPS, mainly on the basis of FISH analysis that detected MDM2 amplification. The patient was treated by adjuvant radiotherapy and, when the tumor recurred a few years later, MDM2 amplification was not observed anymore. We report the clinical, immunohistological, genomic and molecular description of the primary tumors and his recurrences.

2022-04-08 | GSE200434 | GEO

Analysis of gene expression in p53-null cell types following deletion of Mdm2

Project description:RNA-sequencing was performed to gain insight into the mechanism responsible for the apoptosis and cell cycle arrest induced by loss of Mdm2 in p53-null cells. Following CreERT2-mediated deletion of Mdm2 in three p53-null cell types (T cell lymphoma, sarcoma, and fibroblasts), RNA-sequencing was performed. This high-throughput data revealed Mdm2 deletion in p53-null cells upregulated p53/p73 transcriptional target genes known to induce apoptosis and cell cycle arrest.

2017-09-06 | GSE98705 | GEO

CDK4 inhibition diminishes p53 activation by Mdm2-antagonists

Project description:CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.

2018-09-20 | GSE113369 | GEO

MDM2 inhibition enhances immune checkpoint inhibitor therapy in melanoma

Project description:Immune checkpoint therapy has improved outcome of patients with advanced melanoma, however the tumor becomes refractory in a large number of patients. Therefore, novel combination therapies that enhance anti-melanoma immunity are highly desirable. We studied the impact of MDM2 (mouse double minute 2) inhibition, leading to p53 activation, on response to anti-PD-1 immunotherapy in melanoma. MDM2 treatment caused upregulation of MHC II and IL-15 in melanoma cells in a p53 dependent manner. Survival of melanoma bearing mice improved upon combining anti-PD1 and MDM2 inhibition in vivo. Lack of IL-15Rα in T cells abrogated the beneficial effect of the combined treatment. This gene expression study was performed to determine potential effects of MDM2 inhibition on genes in the melanoma microenvironment.

2024-08-22 | GSE184524 | GEO

MDM2 influences ACE2 stability and SARS-Cov2 uptake

Project description:The Angiotensin-converting enzyme 2 (ACE2) receptor is the central entry point for SARS-Cov2. Several SAR-Cov2 substrains have developed mutations in their spike protein to maximize their use of ACE2, e.g. to strengthen ACE2 binding for increased uptake or adapt to specific amino acid properties of ACE2 to cross the species barrier. But little is known about the effect of host regulators on ACE2 and subsequently their impact on SARS-Cov2 infection. Here we identify the E3 ligase MDM2 as a ACE2 modulator. The knockout of MDM2 induced a strong pro-viral effect specific for SARS-Cov2 and we could see the increase of ACE2 levels. This effect is likely dependent on the ubiquitination site Lysine 788, which MDM2 uses to induce proteasomal degradation of ACE2. Substituting this amino acid led to increased ACE2 levels and increased SARS-CoV2 infection facilitated by enhanced SARS-Cov2 uptake.

2023-09-08 | PXD040891 | Pride

Genome-wide maps of chromatin binding site for Mdm2.

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

Supraphysiologic MDM2 expression impacts P53-independent chromatin networks and therapeutic responses in sarcoma

Project description:Supraphysiologic MDM2 expression impacts P53-independent chromatin networks and therapeutic responses in sarcoma

| PRJNA956667 | ENA

Supraphysiologic MDM2 expression impacts P53-independent chromatin networks and therapeutic responses in sarcoma

Project description:Supraphysiologic MDM2 expression impacts P53-independent chromatin networks and therapeutic responses in sarcoma

| PRJNA956668 | ENA

1q gain clinical impact in Ewing's Sarcoma: role of DTL

Project description:This SuperSeries is composed of the following subset Series: GSE20355: BAC-microarrays aCGH data from 67 Ewing's Sarcoma tumor samples and 16 Ewing's Sarcoma cell lines GSE20356: Evaluation of copy number alterations in the Ewing's Sarcoma cell line SKES1 with Affymetrix 500k SNP microarray GSE20357: Expression data from DTL silenced-Ewing Sarcoma's cell lines along with their controls Refer to individual Series

2011-07-31 | E-GEOD-20368 | biostudies-arrayexpress

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