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P53 amyloid formation induced cellular transformation and tumor formation in xenograft model

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150522 | GEO | 2020/05/14

REPOSITORIES: GEO

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Project description:Martins2013 - True and apparent inhibition of amyloid fribril formation This model is described in the article: True and apparent inhibition of amyloid fibril formation. Martins PM. Prion 2013 Mar-Apr; 7(2): 136-139 Abstract: A possible therapeutic strategy for amyloid diseases involves the use of small molecule compounds to inhibit protein assembly into insoluble aggregates. According to the recently proposed Crystallization-Like Model, the kinetics of amyloid fibrillization can be retarded by decreasing the frequency of new fibril formation or by decreasing the elongation rate of existing fibrils. To the compounds that affect the nucleation and/or the growth steps we call true inhibitors. An apparent inhibition mechanism may however result from the alteration of thermodynamic properties such as the solubility of the amyloidogenic protein. Apparent inhibitors markedly influence protein aggregation kinetics measured in vitro, yet they are likely to lead to disappointing results when tested in vivo. This is because cells and tissues media are in general much more buffered against small variations in composition than the solutions prepared in lab. Here we show how to discriminate between true and apparent inhibition mechanisms from experimental data on protein aggregation kinetics. The goal is to be able to identify false positives much earlier during the drug development process. This model is hosted on BioModels Database and identified by: BIOMD0000000561. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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P53 amyloid formation induced cellular transformation and tumor formation in xenograft model

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