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Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

ABSTRACT: Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects from effects specific to different mutant variants and cell backgrounds. here we perform the analysis of transcriptomes,rRegardless of the cell background, of different mutant p53s.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65458 | GEO | 2016/04/27

SECONDARY ACCESSION(S): PRJNA274042

REPOSITORIES: GEO

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Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

Project description:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects from effects specific to different mutant variants and cell backgrounds. here we performed RNA-seq analysisin MDA-MB-231 (R280K) upon silencing TP53 or the control siRNA.

2016-04-27 | GSE68248 | GEO

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer

Project description:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. To complement our mutant p53 transcriptomic studies we have performed ChIP-seq analysis in MDA-MB-231 (R280K) using the mouse anti-p53 DO1 antibody or control mouse IgG versus the input material.

2016-04-28 | GSE66543 | GEO

26S proteasome is conserved, therapeutically relevant mediator of mutant p53 gain-of-function in cancer

Project description:Mutant p53 proteins, resulting form frequent TP53 tumor suppressor missense mutations, possess gain-of-function activities and are among the most widespread and robust oncoproteins in human tumors. They are potentially important but understudied therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects, from effects specific to different mutant variants and cell backgrounds. Here we identify 26S proteasome machinery as the common downstream effector controlled by mutant p53s in Triple Negative Breast Cancer (TNBC - aggressive carcinomas with TP53 as the most frequently mutated locus) and conserved in other human cancers. We have identified this pathway using a combination of single-model, multi-method vertical analysis (whole cell proteome, RNA sequencing an ChIP sequencing) and multi-cell line, horizontal analysis of transcriptiomes. We found that different missense mutant p53s regardless of the cell background transcriptionaly activate whole 26S proteasome machinery. Proteasome activity is significantly increased in p53 mutant versus wild-type or knockdown/null status - in cellular and mouse models as well as in human breast tumors. Increased proteasome activity leads to inhibition of tumor suppressive pathways. The control of mutant p53 over proteasome transcription and activity results in the increased resistance to proteasome inhibitors. By combining the mutant p53 targeting agents and proteasome inhibitor we were able to overcome the “bounce-back” proteasome inhibitor resistance mechanism in mutant p53 bearing TNBC cells and xenografts in vivo.

2016-05-03 | PXD001673 | Pride

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

Project description:Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

| PRJNA282133 | ENA

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-04-27 | GSE68249 | GEO

Differential gain-of-function activity of three p53 hotspot mutants in vivo

Project description:To identify mutant p53 gain-of-function, primary murine osteosarcomas expressing p53 heterozygous mutants were compared to p53 heterozygous tumors. Transcriptomes regulated by different p53 hotspots were used to identify their mechanisms of action. Validation was done in cell line expressing mutant p53, to confirm its binding to transcription factors Stat3 and Egr1.

2022-03-23 | GSE198802 | GEO

Systematic phenotypic characterization and integrated analysis show heterogeneous neomorphic activities of different missense mutant p53 proteins

Project description:The phenotypic and transcriptomic data on ten normal breast epithelial cell lines each expressing a distinct missense mutant p53 protein, and their systems-level analysis through ChIP-Seq and RNA-seq defines the molecular basis for phenotypic heterogeneity imparted by the different missense mutant p53 proteins. The focus of the study is to gain mechanistic insight on the neomorphic function of mutant p53 proteins and their manifestation into phenotypic heterogeneity in the context of a TNBC model.

2023-09-21 | GSE162341 | GEO

Proline 152 mutation in p53 abolishes cognate DNA binding, induces gain of function tumorigenesis

Project description:We have identified a relatively rare mutation in p53 in an Indian oral cancer patient sample at the fade end of its DNA binding domain [P152L]. Although P152L p53 DBD potentially binds to DNA, the full length protein is completely devoid of cognate site DNA binding ability. Also the mutant protein can efficiently tetramerize. Significantly, this mutant was found to induce cell mobility and proliferation with greater tumorigenic potential in nude mice, the mechanistic details of which is also investigated upon. These data establish P152L as a new gain of function p53 mutation

2019-08-02 | GSE119654 | GEO

Expression data from salivary tumor tissues derived from MMTV-ras transgenic mice with wild-type p53, no p53 or gain-of-function mutant p53

Project description:Salivary tumors isolated from MMTV-ras transgenic mice expressing wild-type p53, no p53 or p53R172H gain-of-funcion mutant were subjected to genome-wide gene expression profiling to assess the effect of the different p53 status on tumor gene expression.

2014-08-15 | GSE59452 | GEO

Genome-wide maps of H3K9me3 with tethered heterochromatin machinery

Project description:Purpose: The goal of this study is to characterize the domain(s) of H3K9me3 induced by artifical localization of heterochromatin factors in wild-type and mutant backgrounds.

2017-09-16 | GSE103926 | GEO

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