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Prevalent p53 gain-of-function mutants co-opt epigenetic pathways to drive cancer growth

ABSTRACT: We investigated the genomewide binding pattern of prevalent p53 gain-of-function (GOF) mutants by ChIP-seq, in a panel of breast cancer cell lines. We assessed the genomewide changes of H3K4me3 upon GOF p53 knockdown in MDA-MB-468 breast cancer cells bearing the p53 R273H mutation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE59176 | GEO | 2015/07/31

SECONDARY ACCESSION(S): PRJNA254538

REPOSITORIES: GEO

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Prevalent p53 gain-of-function mutants co-opt epigenetic pathways to drive cancer growth

Project description:We investigated the genomewide binding pattern of prevalent p53 gain-of-function (GOF) mutants by ChIP-seq, in a panel of breast cancer cell lines. We assessed the genomewide changes of H3K4me3 upon GOF p53 knockdown in MDA-MB-468 breast cancer cells bearing the p53 R273H mutation. This study uses ChIP-seq of H3K4me3 and histone H3 in wild-type or p53 R172H knock-in MEFs. Additionally, this study examines the transcriptome of wild-type or p53 R172H knock-in MEFs using polyA+ RNA-seq.

2015-07-31 | E-GEOD-59176 | biostudies-arrayexpress

Prevalent p53 gain-of-function mutants co-opt epigenetic pathways to drive cancer growth

Project description:Prevalent p53 gain-of-function mutants co-opt epigenetic pathways to drive cancer growth

| PRJNA254538 | ENA

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

ChIP-chip data for identifying target genes and consensus binding sequences of mutant p53 in MDA-MB-468 breast cancer cells

Project description:The tumor suppressor p53 exerts its role mainly as a transcription factor. The TP53 gene, which encodes the p53 protein, is the most commonly mutated gene in human cancers, particularly triple negative breast cancer (TNBC). Variations in the TP53 gene occur mainly in exons 5–8 and result in missense mutations in the DNA-binding domain of the p53 protein that alter DNA binding specificity. To identify the target genes of mutant p53, we performed chromatin immunoprecipitation followed by DNA microarray (ChIP-chip). Briefly, the TNBC cell line MDA-MB-468 containing the endogenous p53-R273H mutation (the arginine residue at position 273 is mutated to a histidine) was cross-linked with 1% formaldehyde and ultrasonically sheared to generate chromatin fragments in a range of 200∼1000 bp. An aliquot of the sheared chromatin was kept as input, and the other chromatin was precipitated with a p53 monoclonal antibody. DNA was purified from the precipitated chromatin and the unprecipitated chromatin (i.e., input), amplified, and labeled with Cy5 (ChIP DNA) or Cy3 (input DNA). Cy5- and Cy3-labeled DNA samples were cohybridized with the NimbleGen Human ChIP-chip 2.1 M Deluxe Promoter Array. The raw and analyzed data are described in this article. They are useful for identifying target genes and consensus binding motifs of the p53 R273H mutant and for further clarifying the molecular mechanism underlying the oncogenic activity of the p53 mutant.

2019-12-08 | GSE128304 | GEO

Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth.

Project description:TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.

| S-EPMC4568559 | biostudies-literature

Gene expression profiling of MDA-MB-468 cells following p53-R273H mutant knock-down

Project description:A total of 58 genes were up-regulated (> 1.5 fold-change) while 117 genes were down-regulated Microarray experiments were performed in duplicate as follows: MDA-MB-468 cells were transduced with lentiviral shRNA targeting endogenous p53-R273H mutant (p53si-1)or a non-targeting shRNA (NS). Total RNA from cells was extracted using Qiagen RNA isolation kit (Qiagen, Valencia, CA, USA) according to the manufacturersâ protocol. RNA purity was examined by spectrophotometric determination at 260/280 nm. The microarray hybridizations were carried out using the Affymetrix Human Gene 1.0 ST arrays.

2016-06-30 | E-GEOD-65967 | biostudies-arrayexpress

Gain-of-Function p53 Protein Transferred via Small Extracellular Vesicles Promotes Conversion of Fibroblasts to a Cancer-Associated Phenotype

Project description:Crosstalk between tumor and stromal cells is essential for tumor pathogenesis. Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs), among others. Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrated that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to stromal cells. In this study, we performed RNA sequencing to explore the gene signature alterations in small EVs after knockdown GOF p53 expression.

2020-11-18 | GSE148698 | GEO

Homo sapiens

Project description:Gene expression profiling of MDA-MB-468 cells following p53-R273H mutant knock-down

| PRJNA275589 | ENA

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

The lung-enriched p53 mutants V157F and R158L/P regulate a novel transcriptome in lung cancer

Project description:Lung cancer is the leading cause of cancer-related deaths in the US, and alterations in the tumor suppressor gene TP53 are the most frequent somatic mutation among all histologic subtypes of lung cancer. Mutations in TP53 frequently result in a protein that exhibits not only loss of tumor suppressor capability but also gain of oncogenic function (GOF). The canonical p53 hotspot mutants R175H and R273H, for example, confer upon tumors a metastatic phenotype in murine models of mutant p53. To our knowledge, GOF phenotypes of the less often studied V157, R158, and A159 mutants – which occur with higher frequency in lung cancer compared with other solid tumors – have not been defined. In this study, we aimed to define whether the lung mutants are simply equivalent to full loss of the p53 locus, or whether they additionally acquire the ability to drive new downstream effector pathways. Using a publicly available human lung cancer dataset, we characterized patients with V157, R158, and A159 p53 mutations. Additionally, we show here that cell lines with mutant p53-V157F, p53-R158L, and p53-R158P exhibit a loss of expression of canonical wildtype p53 target genes. Furthermore, these lung-enriched p53 mutants regulate genes not previously linked to p53 function including PLAU. Paradoxically, mutant p53 represses genes associated with increased cell viability, migration, and invasion. These findings collectively represent the first demonstration that lung-enriched p53 mutations at V157 and R158 regulate a novel transcriptome in human lung cancer cells and may confer de novo function.

2019-09-26 | GSE120534 | GEO

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