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A designed inhibitor of p53 aggregation rescues p53 tumor-suppression in ovarian carcinomas

ABSTRACT: Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated, amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs. Vehicle vs. ReACp53 treatment in 4 different samples: 2 cell lines (MCF7 w/ WT p53 as negative control and OVCAR3 w/ R248Q p53) and 2 clinical specimens (primary cells from patient #8 w/ WT p53 as negative control and primary cells from patient #1 w/ R248Q p53)

ORGANISM(S): Homo sapiens

SUBMITTER: Sanaz Memarzadeh

PROVIDER: E-GEOD-74550 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A designed inhibitor of p53 aggregation rescues p53 tumor-suppression in ovarian carcinomas

Project description:Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated, amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.

2016-01-04 | GSE74550 | GEO

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Project description:Transcriptome analysis of protein mimetic amyloid inhibitor that potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

2020-11-23 | GSE161952 | GEO

p53 amyloid formation induced cellular transformation and tumor formation in xenograft model

Project description:p53 mutation and its subsequent loss of function along with gain of oncogenic functions is associated with cancer. However, the exact mechanism of how altered p53 acts as an oncogene is not clear yet. Recently, it was suggested that p53 aggregation and amyloid formation leads to both loss of tumor suppressive function and gain of oncogenic functions in cells. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloid aggregates show enhanced survival, apoptotic resistance with increased proliferation and migration rate. We further establish the tumorigenic potential of p53 amyloid containing cells in a mice xenograft model. Furthermore, these tumors tested positive for p53 amyloid aggregates. Comprehensive gene-expression analysis suggests that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor suppressor associated genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to initiation of tumor development.

2020-05-14 | GSE150522 | GEO

p53 amyloid induced cellular transformation and tumor formation in the mouse xenograft model

Project description:p53 amyloid formation is predicted to be involved in cancer initiation, but the direct evidence of how altered p53 acts as an oncogene is lacking. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. Proteomic profiling of cells containing p53 aggregates suggests that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor-suppressive genes. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.

2022-07-16 | PXD019498 | Pride

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Project description:It is a TMT10Plex proteomics dataset used for relative protein and phosphoprotein quantification in the manuscript entitled "Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function". It contains both non-phosphorylated (used for identification and quantification of total proteomes) and phospho enriched (used for identification and quantification of phosphoproteins) dataset.

2020-12-05 | MSV000086563 | MassIVE

Genome Wide Profiling of p53 Response to Differentiation or DNA Damage of Human Embryonic Stem Cells

Project description:Tumor suppressor p53 promotes differentiation of human embryonic stem cells (hESCs), but an in-depth understanding of mechanism is lacking. Here, we define p53 functions in hESCs by genome wide profiling of p53 chromatin interactions and intersection with gene expression during early differentiation and in response to DNA damage. During differentiation, p53 targets and regulates a unique collection of genes, many of which encode transcription factors and developmental regulators with chromatin structure poised by OCT4 and NANOG and marked by repressive H3K27me3 in pluripotent hESCs. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in regulation of cell death and cell cycle genes are conserved during both DNA damage and differentiation. Our findings expand the registry of p53 -regulated genes in hESCs and define specific functions of p53 in opposing pluripotency, which are highly distinct from stress-induced p53 response in stem cells. Identification of p53 binding sites in hESC under three conditions: Pluripotent, DNA damaged, Differentiating

2013-10-18 | E-GEOD-39762 | biostudies-arrayexpress

Genome Wide Profiling of p53 Response to Differentiation or DNA Damage of Human Embryonic Stem Cells

2013-10-18 | E-GEOD-39912 | biostudies-arrayexpress

Evaluation of the p53 isoform Δ133p53β aggregation capacity

Project description:p53 isoforms and particularly Δ133p53β play a critical role in cancer progression. We demonstrate that WT Δ133p53β activity is regulated through an aggregation-dependent mechanism. Creation of WT Δ133p53β aggregates depends on associations with specific interacting partners and was observed both in cancer cell lines and in human tumour biopsies.

2021-06-04 | PXD022998 | Pride

Readout of histone methylation by Trim24 locally restricts chromatin opening by p53

Project description:The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually diverse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dependence for p53 regulation. Here, we show that the ability of p53 to open chromatin and activate its target genes is indeed locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated lysine 4 of histone H3, thereby preferentially locating to those p53 sites that reside in closed chromatin, while it is deterred from accessible chromatin by lysine 4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to impact gene expression as a function of the local chromatin state. These findings link histone methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors which locally modulate TF function.

2023-05-05 | PXD039553 | Pride

p53-SLP vaccine in combination with Imiquimod or IFNα

Project description:Primary objectives: The primary objective of the study is to assess whether the administration of p53-SLP together with the local application of imiquimod or the injection of interferon-alfa is safe and able to induce an immune response specific to p53. Primary endpoints: Safety will be assessed during the whole study by collecting all adverse events (with a focus on administration site reactions), vital signs, blood-chemistry and haematological parameters. Immunogenicity will be assessed by an array of complementary immunological assays which focus on p53-specific T-cell proliferation, enumeration of circulating IFNγ-producing T-cells, Th1/Th2 cytokine production, and p53 protein recognition by circulating and vaccine-site-homing T-cells.

| 2524913 | ecrin-mdr-crc

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