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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 performed RNA-seq analysisin MDA-MB-231 (R280K) upon silencing TP53 or the control siRNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68248 | GEO | 2016/04/27

SECONDARY ACCESSION(S): PRJNA282134

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 perform the analysis of transcriptomes,rRegardless of the cell background, of different mutant p53s.

2016-04-27 | GSE65458 | 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:This SuperSeries is composed of the SubSeries listed below.

2016-04-27 | GSE68249 | GEO

A gain-of-function p53 mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor Foxh1

Project description:Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype (CK) AML. Here, we identify a gain-of-function (GOF) p53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The p53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPCs) even prior to their transformation. We identify the Forkhead box H1 transcription factor (Foxh1) as a critical mediator of mutant p53 function that binds to and regulates stem cell-associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 gain-of-function in cancer.

2019-05-08 | GSE125097 | GEO

Mutant p53 interactome study with IP-MS

Project description:Inactivating TP53 mutations lead to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promote tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome with IP-MS.

2023-11-27 | PXD047094 | Pride

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

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

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [ERG and p53 ChIP-seq]

Project description:TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.

2023-06-27 | GSE184623 | GEO

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