Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226407 | GEO | 2023/04/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Project description:Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein.SignificanceA mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.

| S-EPMC10287063 | biostudies-literature

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP2]

Project description:Mutations that occur within the oligomerization domain (OD) of the tumor suppressor p53 generally abolish p53 tetramerization and are associated with increased cancer susceptibility in Li-Fraumeni syndrome (LFS). Despite their prevalence, the impact of OD-mutant p53 proteins in cancer, especially beyond a loss of canonical p53 activity, has not been well elucidated. We sought to delineate the gain-of-function (GOF) vs. loss-of-function (LOF) activities of OD-mutant p53, specifically focusing on the LFS tumor-derived p53(A347D) variant. We obtained LFS patient-derived dermal fibroblasts heterozygous for the mutation and generated an allelic series of U2OS cancer cell lines expressing wild-type p53, heterozygous (p53+/AD) or homozygous (p53AD/AD) mutant p53 or no p53 (p53 KO). In contrast to wild-type p53, mutant p53(A347D) exclusively forms dimers in both fibroblasts and cancer cells and has lost the ability to bind and transactivate the majority of canonical p53 target genes, which yields comparable tumorigenic properties between mutant p53 and p53 KO cells. Mutant p53(A347D), however, displays neomorphic activities. Glycolysis and oxidative phosphorylation pathways are enriched in cells bearing p53(A347D) relative to both wild-type p53 and p53 KO cells. Furthermore, dimeric mutant p53 induces striking mitochondrial network aberration and preferentially associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Ultimately, we describe dimeric mutant p53 as wielding a double-edged sword: driving tumorigenesis through LOF while gaining enhanced apoptogenic activity, thereby providing a potential basis for select therapeutic approaches.

2023-04-20 | GSE226384 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA2]

2023-04-20 | GSE226406 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA1]

2023-04-20 | GSE226389 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP 1]

2023-04-20 | GSE226371 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death

Project description:Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death

| PRJNA940139 | ENA

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP2]

Project description:Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP2]

| PRJNA940109 | ENA

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA2]

Project description:Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA2]

| PRJNA940149 | ENA

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA1]

Project description:Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA1]

| PRJNA941287 | ENA

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP 1]

Project description:Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP 1]

| PRJNA940077 | ENA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data