P53 amyloid formation induced cellular transformation and tumor formation in xenograft model
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA632633 | ENA |
REPOSITORIES: ENA
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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
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
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. 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)
2016-01-04 | E-GEOD-74550 | biostudies-arrayexpress
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
Project description:Aggregation of islet amyloid polypeptide (IAPP) into islet amyloid results in β-cell toxicity in human type 2 diabetes. To determine the effect of islet amyloid formation on gene expression, we performed RNA-seq analysis using cultured islets from either wild-type mice (mIAPP), which are not amyloid prone, or mice that express human IAPP (hIAPP), which develop amyloid. Comparing mIAPP and hIAPP islets, 5025 genes were differentially regulated (2439 upregulated and 2586 downregulated). When considering gene sets (reactomes), 248 and 52 pathways were up- and downregulated, respectively. Of the top 100 genes upregulated under two conditions of amyloid formation, seven were common. Of these seven genes, only steroidogenic acute regulatory protein AQ2 (Star) demonstrated no effect of glucose per se to modify its expression. We confirmed this differential gene expression using quantitative reverse transcription polymerase chain reaction and also demonstrated the presence of StAR protein in islets containing amyloid. Furthermore, Star is a part of reactomes representing metabolism, metabolism of lipids, metabolism of steroid hormones, metabolism of steroids and pregnenolone biosynthesis. Thus, examining gene expression that is differentially regulated by islet amyloid has the ability to identify new molecules involved in islet physiology and pathology applicable to type 2 diabetes.
2019-08-29 | GSE135276 | GEO
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
Project description:p16INK4A inhibits the CDK4/6 kinases and is therefore an important cell cycle regulator. Accumulation of p16INK4A in response to oncogenic transformation leads to cellular senescence and it is therefore frequently lost in cancer. p16INK4A is also known to accumulate under conditions of cellular oxidative stress and therefore could potentially be regulated by redox signaling, which is a form of signal transduction that is mediated by the reversible oxidation of cysteine-thiol side chains in proteins. We found that oxidation of the single cysteine residue in p16INK4A in human cells occurs under relatively mild oxidizing conditions and that this leads to disulfide dependent dimerization. p16INK4A is a well-characterized all alpha-helical protein, but we find that upon cysteine-dependent dimerization, p16INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. We find that p16INK4A amyloid formation abolishes its function as a CDK4/6 inhibitor in human cells. Taken together, these observations mechanistically link the cellular redox state to the inactivation of p16INK4A through the formation of amyloid fibrils.
2019-09-04 | PXD012353 | Pride
Project description:p53 is a transcriptional activator that induces myriad target genes. However, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we identify Neat1, a ncRNA constituent of paraspeckles, as a p53 target gene induced by mouse and human p53 in different cell types and by diverse stress signals. Using fibroblasts derived from Neat1-/- mice, we examine the functional role of Neat1 in the p53 pathway. We find that Neat1 is dispensable for cell-cycle arrest and apoptosis in response to genotoxic stress, but plays a crucial role in suppressing transformation in response to oncogenic signals. To determine the effects of Neat1 deficiency on cells, we used E1A;HRasV12-expressing wild-type and Neat1-/- mouse embryonic fibroblasts (MEFs) for RNA-sequencing analysis. This analysis revealed that Neat1 deficiency impacts the regulatory networks involved in nervous system development and axon guidance programs, as well as genes of the SWI/SNF complex and components of the pancreas development network. These findings suggest that the ability of Neat1 to globally regulate gene expression, with effects on diverse transcriptional programs, provides a potential mechanism for how Neat1 acts to suppress transformation and tumor initiation.
2017-07-27 | GSE100098 | GEO
Project description:Crespo2012 - Kinetics of Amyloid Fibril
Formation
This model is described in the article:
A generic
crystallization-like model that describes the kinetics of
amyloid fibril formation.
Crespo R, Rocha FA, Damas AM,
Martins PM.
J. Biol. Chem. 2012 Aug; 287(36):
30585-30594
Abstract:
Associated with neurodegenerative disorders such as
Alzheimer, Parkinson, or prion diseases, the conversion of
soluble proteins into amyloid fibrils remains poorly
understood. Extensive "in vitro" measurements of protein
aggregation kinetics have been reported, but no consensus
mechanism has emerged until now. This contribution aims at
overcoming this gap by proposing a theoretically consistent
crystallization-like model (CLM) that is able to describe the
classic types of amyloid fibrillization kinetics identified in
our literature survey. Amyloid conversion represented as a
function of time is shown to follow different curve shapes,
ranging from sigmoidal to hyperbolic, according to the relative
importance of the nucleation and growth steps. Using the CLM,
apparently unrelated data are deconvoluted into generic
mechanistic information integrating the combined influence of
seeding, nucleation, growth, and fibril breakage events. It is
notable that this complex assembly of interdependent events is
ultimately reduced to a mathematically simple model, whose two
parameters can be determined by little more than visual
inspection. The good fitting results obtained for all cases
confirm the CLM as a good approximation to the generalized
underlying principle governing amyloid fibrillization. A
perspective is presented on possible applications of the CLM
during the development of new targets for amyloid disease
therapeutics.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000531.
To cite BioModels Database, please use:
BioModels Database:
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To the extent possible under law, all copyright and related or
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2014-07-17 | BIOMD0000000531 | BioModels
Project description:RNA-seq-based identification of StAR upregulation by islet amyloid formation
| PRJNA558147 | ENA