Mutant TP53 hijacks RNA-splicing factor RBM28 to suppress double-strand RNA triggered antitumor immunity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303217 | GEO | 2026/04/23
REPOSITORIES: GEO
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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
Project description:Missense mutations in the TP53 gene are frequent genetic alterations in human tumor tissue and cell lines. In contrast to wild-type p53, the mutant p53 (mutp53) protein has lost the transcriptional activity towards pro-apoptotic and growth arrest genes, but retained the property to interact with DNA in a structure-specific fashion. Expression of mutp53 is advantageous for tumor cells, however the molecular mechanism of mutp53 action is still not known. We used the glioblastoma-derived U-251 MG human cell line to analyze DNA binding of mutant p53 (R273H mutation) on a Nimblegen custom 135k tiling array and to correlate mutp53 binding regions with the epigenetic state and occupation by other transcription factors (ETS1 and SP1). We found that mutp53-binding regions are G/C-rich and are located around transcriptional start sites (TSS) of many protein-coding genes, which in most cases are active, but are not always regulated upon transient mutp53 depletion. We propose a model which does not only rely on interactions of mutp53 with diverse transcriptional regulators at active promoters, but primarily is based on a DNA binding activity of mutp53.
2012-12-10 | GSE35453 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal cancers, with limited therapeutic options and a dismal prognosis. A critical driver of its progression is mutant p53 (mutp53), which reshapes the tumor microenvironment (TME) by modulating the secretion of key signaling molecules. Given the potential of secretome profiling to reveal novel biomarkers and druggable targets, we investigated the role of the mutp53-driven secretome in PDAC cells and its implications for disease progression. Through mass-spectrometry (MS) analysis, we identified a set of secreted proteins modulated by mutp53, with the nuclear high mobility group A1 (HMGA1) serving as a central regulator. HMGA1 is a transcription factor involved in several cellular processes and found to be upregulated in different tumors, but its extracellular role in cancer remains largely unexplored. We demonstrate that mutp53-driven HMGA1 secretion promotes PDAC cell hyperproliferation, where HMGA1 deficiency significantly impairs tumor growth highlighting a critical role of this protein in tumor aggressiveness. Notably, we discovered that chemotherapy enhances HMGA1 secretion specifically in TP53-mutant PDAC cells through a mechanism dependent on Casein Kinase 2 (CK2) activity. To unravel the downstream oncogenic signaling triggered by secreted HMGA1, we conducted phosphoproteomic analysis, identifying hyperphosphorylation of Nucleophosmin 1 (NPM1), as a pivotal event that further amplifies tumor cell proliferation. Collectively, our findings reveal that a panel of chemotherapeutic agents stimulate a novel mutp53-dependent CK2-HMGA1-NPM1 axis that fuels PDAC aggressiveness in an autocrine/paracrine manner. Targeting this pathway at multiple levels emerges as a promising therapeutic strategy to counteract mutp53-driven tumor progression andimprove patient outcomes.
2025-11-10 | PXD062127 | Pride
Project description:The human TP53 gene is frequently mutated in tumors and cell lines. Unlike other tumor suppressors that are commonly inactivated by deletions or nonsense mutations, the majority of p53-mutations are missense point mutations that result in the expression of a full-length protein with an altered amino acid that has lost sequence specific DNA-binding. Expression of mutant p53 (mutp53) confers advantages to tumor cells and transcriptional regulation of several genes mediating the beneficial effects has been shown to play a role. However, molecular mechanisms of transcriptional regulation by mutp53 are still poorly understood. We used the glioblastoma-derived U-251 MG human cell line endogenously expressing mutp53 protein (R273H mutation) to analyze gene expression profiles on Agilent Whole Human Genome Microarray after transient and stable depletion of mutp53 expression. Gene expression data was correlated with a ChIP study on a custom tiling array to understand the contribution of endogenously expressed mutp53 to transcriptional regulation.
2012-12-10 | GSE35454 | GEO
Project description:Missense point mutations in the TP53 gene are frequent genetic alterations in human tumor tissue and cell lines derived thereof. Mutant p53 (mutp53) proteins have lost sequence-specific DNA binding, but have retained the ability to interact in a structure-selective manner with non-B DNA and to act as regulators of transcription. To identify functional binding sites of mutp53, we established a small library of genomic sequences bound by p53R273H in U251 human glioblastoma cells using chromatin immunoprecipitation (ChIP). Mutp53 binding to isolated DNA fragments confirmed the specificity of the ChIP. The mutp53 bound DNA sequences are rich in repetitive DNA elements, which are dispersed over non-coding DNA regions. Stable down-regulation of mutp53 expression strongly suggested that mutp53 binding to genomic DNA is functional. We identified the PPARGC1A and FRMD5 genes as p53R273H targets regulated by binding to intronic and intra-genic sequences. We propose a model that attributes the oncogenic functions of mutp53 to its ability to interact with intronic and intergenic non-B DNA sequences and modulate gene transcription via re-organization of chromatin.
2008-12-18 | GSE13991 | GEO
Project description:The human TP53 gene is frequently mutated in tumors and cell lines. Unlike other tumor suppressors that are commonly inactivated by deletions or nonsense mutations, the majority of p53-mutations are missense point mutations that result in the expression of a full-length protein with an altered amino acid that has lost sequence specific DNA-binding. Expression of mutant p53 (mutp53) confers advantages to tumor cells and transcriptional regulation of several genes mediating the beneficial effects has been shown to play a role. However, molecular mechanisms of transcriptional regulation by mutp53 are still poorly understood. We used the glioblastoma-derived U-251 MG human cell line endogenously expressing mutp53 protein (R273H mutation) to analyze gene expression profiles on Agilent Whole Human Genome Microarray after transient and stable depletion of mutp53 expression. Gene expression data was correlated with a ChIP study on a custom tiling array to understand the contribution of endogenously expressed mutp53 to transcriptional regulation. This series of microarray experiments contains the gene expression profiles of glioblastoma-derived U-251 MG human cell lines engineered to constitutively express a p53-specific shRNA or scrambled control shRNA. To reverse the effect of mutp53 depletion, stable clones were modified by stable integration of a mutp53-R273H expression construct or empty pCDNA3 vector as a control. In addition, we performed gene expression analysis of U-251 MG cells transiently transfected with p53-specific siRNA or control siRNA (3 biological replicates each).
2012-12-10 | E-GEOD-35454 | biostudies-arrayexpress
Project description:A disappointingly small proportion (10-30%) of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy, and prevents ICB responsiveness by repressing immunogenic double-stranded (ds)RNAs, such as those arising from the dysregulated expression of endogenous retroelements (EREs). These dsRNAs trigger an interferon (IFN)-dependent antitumor response by activating the A-form dsRNA (A-RNA) sensing proteins MDA-5, PKR, and OAS1. Here, we show that ADAR1 also prevents accrual of endogenous Z-form dsRNA elements (Z-RNAs) which were enriched in the 3’UTRs of IFN-stimulated mRNAs. Depleting ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, culminating in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and strongly reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumor immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily-translatable avenue for rekindling immune responsiveness of ICB-resistant human cancers.
2022-03-03 | GSE184962 | GEO
Project description:A disappointingly small proportion (10-30%) of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy, and prevents ICB responsiveness by repressing immunogenic double-stranded (ds)RNAs, such as those arising from the dysregulated expression of endogenous retroelements (EREs). These dsRNAs trigger an interferon (IFN)-dependent antitumor response by activating the A-form dsRNA (A-RNA) sensing proteins MDA-5, PKR, and OAS1. Here, we show that ADAR1 also prevents accrual of endogenous Z-form dsRNA elements (Z-RNAs) which were enriched in the 3’UTRs of IFN-stimulated mRNAs. Depleting ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, culminating in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and strongly reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumor immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily-translatable avenue for rekindling immune responsiveness of ICB-resistant human cancers.
2022-03-03 | GSE184960 | GEO
Project description:A disappointingly small proportion (10-30%) of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy, and prevents ICB responsiveness by repressing immunogenic double-stranded (ds)RNAs, such as those arising from the dysregulated expression of endogenous retroelements (EREs). These dsRNAs trigger an interferon (IFN)-dependent antitumor response by activating the A-form dsRNA (A-RNA) sensing proteins MDA-5, PKR, and OAS1. Here, we show that ADAR1 also prevents accrual of endogenous Z-form dsRNA elements (Z-RNAs) which were enriched in the 3’UTRs of IFN-stimulated mRNAs. Depleting ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, culminating in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and strongly reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumor immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily-translatable avenue for rekindling immune responsiveness of ICB-resistant human cancers.
2022-03-03 | GSE184964 | GEO
Project description:Missense point mutations in the TP53 gene are frequent genetic alterations in human tumor tissue and cell lines derived thereof. Mutant p53 (mutp53) proteins have lost sequence-specific DNA binding, but have retained the ability to interact in a structure-selective manner with non-B DNA and to act as regulators of transcription. To identify functional binding sites of mutp53, we established a small library of genomic sequences bound by p53R273H in U251 human glioblastoma cells using chromatin immunoprecipitation (ChIP). Mutp53 binding to isolated DNA fragments confirmed the specificity of the ChIP. The mutp53 bound DNA sequences are rich in repetitive DNA elements, which are dispersed over non-coding DNA regions. Stable down-regulation of mutp53 expression strongly suggested that mutp53 binding to genomic DNA is functional. We identified the PPARGC1A and FRMD5 genes as p53R273H targets regulated by binding to intronic and intra-genic sequences. We propose a model that attributes the oncogenic functions of mutp53 to its ability to interact with intronic and intergenic non-B DNA sequences and modulate gene transcription via re-organization of chromatin. For the study of the consequences of mutant p53 (R273H) knockdown on gene expression, total RNA from parental U251 glioblastoma cells and UsiA12 clone was prepared from two independent cell culture experiments (biological replicates) and processed for microarray-based profiling of gene expression. UsiA12 clone was derived from the U251 cells transfected with the pSuper-p53 and pCI-neo vectors.
2010-06-24 | E-GEOD-13991 | biostudies-arrayexpress