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Homo sapiens

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

PROVIDER: PRJNA282134 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR1995321_1.fastq.gz	Fastqsanger.gz
	SRR1995321_2.fastq.gz	Fastqsanger.gz
	SRR1995322_1.fastq.gz	Fastqsanger.gz
	SRR1995322_2.fastq.gz	Fastqsanger.gz
	SRR1995323_1.fastq.gz	Fastqsanger.gz

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Homo sapiens

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

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Homo sapiens

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

| PRJNA277233 | ENA

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

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

Transcriptional consequences of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). In mice, DNE of p53 missense variants confer a selective advantage on hematopoietic cells upon DNA damage in vivo. Clinical outcomes in acute myeloid leukemia patients showed no evidence of GOF for TP53 missense mutations. These findings establish dominant-negativity as the primary unit of selection for TP53 missense mutations in myeloid malignancies.

2019-08-30 | GSE131592 | GEO

Genome-wide binding of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

2019-08-30 | GSE131484 | 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. 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. 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.

2016-04-27 | GSE65458 | GEO

Genome-wide binding of wild-type p53 and R248Q missense mutant variants in isogenic human acute myeloid leukemia (AML) cell lines

Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). The precise functional and molecular mechanisms of the DNE have remained elusive. Using a variety of novel model systems including CRISPR-edited human isogenic cell lines, transcriptional reporter cell lines, and targeted protein degradation assays combined with functional and molecular analyses we functionally characterize the DNE and demonstrate that formation of heterotetramers between R248Q and WT p53 impairs proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation.

2025-03-14 | GSE284299 | GEO

Distinct gain of function mechanism for the hot-spot mutant p53R175H

Project description:TP53 (p53) is the most commonly mutated gene in human cancers, and p53 missense mutations are present in more than 40% of all human tumors. Most p53 mutations are located within the DNA binding domain, including hotspot mutations R175H, R248W, and R273H. To elucidate the precise mechanism by which p53 missense mutants execute their gain-of-functions (GOFs) in vivo, we used a proteomic screen to identify any protein that recognizes the p53 DNA-binding domain (DBD) in a manner dependent on its mutation status. To do so, we first purified the potential binding proteins associated with the p53 DBD through multi-step affinity chromatography from a SFB-p53 H1299 stable cell line. The affinity-purified SFB-p53 interacting proteins were detected by liquid chromatography mass spectrometry/mass spectrometry (LC–MS/MS) and revealed a few cellular proteins that have been reported to interact with the DNA binding domain of p53, such as TP53BP1, USP28, and Sirt1. Interestingly, we also identified many new interacting proteins from the same complex.

2023-02-17 | PXD039886 | Pride

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