Dataset Information

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets.

ABSTRACT: Mutations in the p53 tumor suppressor are frequent causes of cancer. Because p53 aggregates appear in some tumor cells, it has been suggested that p53 could also cause cancer by forming self-replicating protein aggregates (prions). Here, using yeast, we show that transient p53 overexpression induced the formation of p53 prion aggregates that were transmitted for >100 generations, found in lysate pellets, stained with Thioflavin T, and transmitted by cytoplasmic transfer, or transfection with lysates of cells carrying the prion or with p53 amyloid peptide. As predicted for a prion, transient interruption of p53 expression caused permanent p53 prion loss. Importantly, p53 transcription factor activity was reduced by prion formation suggesting that prion aggregation could cause cancer. p53 has also been found in liquid-like nuclear droplets in animal cell culture. In yeast, we found that liquid-like p53 foci appear in response to stress and disappear with stress removal.

SUBMITTER: Park SK

PROVIDER: S-EPMC7811139 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets.

Park Sei-Kyoung SK Park Sangeun S Pentek Christine C Liebman Susan W SW

iScience 20201229 1

Mutations in the p53 tumor suppressor are frequent causes of cancer. Because p53 aggregates appear in some tumor cells, it has been suggested that p53 could also cause cancer by forming self-replicating protein aggregates (prions). Here, using yeast, we show that transient p53 overexpression induced the formation of p53 prion aggregates that were transmitted for >100 generations, found in lysate pellets, stained with Thioflavin T, and transmitted by cytoplasmic transfer, or transfection with lys ...[more]

PMID: 33490908

Similar Datasets

Project description:Protein misfolding has been implicated in a large number of diseases termed protein- folding disorders (PFDs), which include Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathies, familial amyloid polyneuropathy, Huntington's disease, and type II diabetes. In these diseases, large quantities of incorrectly folded proteins undergo aggregation, destroying brain cells and other tissues. The interplay between ligand binding and hydration is an important component of the formation of misfolded protein species. Hydration drives various biological processes, including protein folding, ligand binding, macromolecular assembly, enzyme kinetics, and signal transduction. The changes in hydration and packing, both when proteins fold correctly or when folding goes wrong, leading to PFDs, are examined through several biochemical, biophysical, and structural approaches. Although in many cases the binding of a ligand such as a nucleic acid helps to prevent misfolding and aggregation, there are several examples in which ligands induce misfolding and assembly into amyloids. This occurs simply because the formation of structured aggregates (such as protofibrillar and fibrillar amyloids) involves decreases in hydration, formation of a hydrogen-bond network in the secondary structure, and burying of nonpolar amino acid residues, processes that also occur in the normal folding landscape. In this Account, we describe the present knowledge of the folding and misfolding of different proteins, with a detailed emphasis on mammalian prion protein (PrP) and tumoral suppressor protein p53; we also explore how ligand binding and hydration together influence the fate of the proteins. Anfinsen's paradigm that the structure of a protein is determined by its amino acid sequence is to some extent contradicted by the observation that there are two isoforms of the prion protein with the same sequence: the cellular and the misfolded isoform. The cellular isoform of PrP has a disordered N-terminal domain and a highly flexible, not-well-packed C-terminal domain, which might account for its significant hydration. When PrP binds to biological molecules, such as glycosaminoglycans and nucleic acids, the disordered segments appear to fold and become less hydrated. Formation of the PrP-nucleic acid complex seems to accelerate the conversion of the cellular form of the protein into the disease-causing isoform. For p53, binding to some ligands, including nucleic acids, would prevent misfolding of the protein. Recently, several groups have begun to analyze the folding-misfolding of the individual domains of p53, but several questions remain unanswered. We discuss the implications of these findings for understanding the productive and incorrect folding pathways of these proteins in normal physiological states and in human disease, such as prion disorders and cancer. These studies are shown to lay the groundwork for the development of new drugs.

Dataset Information

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets.

Publications

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets