Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transactivation-deficient p53 Mutants in Ras-induced Cellular Senescence

ABSTRACT: As a critical cellular stress sensor, p53 mediates a variety of defensive processes including cell-cycle arrest, apoptosis, and senescence to prevent propagation of hyperproliferative cells or cells with a damaged genome, hence the formation of neoplasia. Transactivation of downstream genes plays an important while sometimes controversial role in regulating these cellular processes. To evaluate the dependence on transcriptional activation in p53’s activities, we generated genetically-modified mouse lines carrying mutations in the transactivation domains (TADs) of p53. These transactivatio-deficient mutants serve as unique reagents to probe the dependence on robust transactivation in p53-mediated cellular functions, as well as the underneath mechanisms. To identify genes differentially regulated by these p53 mutants, we performed gene expression profiling analysis on mouse embryonic fibroblast cells (MEFs) from these mice in the context of oncogenic Ras-induced premature cellular senescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE27901 | GEO | 2011/05/13

SECONDARY ACCESSION(S): PRJNA138211

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transactivation-deficient p53 Mutants in Ras-induced Cellular Senescence

Project description:As a critical cellular stress sensor, p53 mediates a variety of defensive processes including cell-cycle arrest, apoptosis, and senescence to prevent propagation of hyperproliferative cells or cells with a damaged genome, hence the formation of neoplasia. Transactivation of downstream genes plays an important while sometimes controversial role in regulating these cellular processes. To evaluate the dependence on transcriptional activation in p53’s activities, we generated genetically-modified mouse lines carrying mutations in the transactivation domains (TADs) of p53. These transactivatio-deficient mutants serve as unique reagents to probe the dependence on robust transactivation in p53-mediated cellular functions, as well as the underneath mechanisms. To identify genes differentially regulated by these p53 mutants, we performed gene expression profiling analysis on mouse embryonic fibroblast cells (MEFs) from these mice in the context of oncogenic Ras-induced premature cellular senescence. Mouse embryonic fibroblasts (MEFs) with different p53 genotypes were infected with retroviral H-Ras V12, which induces premature cellular senescence in p53 wild-type MEFs but not in p53 null MEFs. 5 genotypic groups of MEFs were used in the study: (i) p53L25Q/W26S, or "25,26", in which the first TAD (transactivation domain) of p53 is disrupted by the mutation, 5 biological samples; (ii) p53W53Q/F54S, or "53,54", in which the second TAD of p53 is disrupted by the mutation, 3 biological samples; (iii) p53L25Q/W26S/W53Q/F54S, or "QM", in which both TADs or p53 are disrupted, 3 biological samples; (iv) p53 wild-type, or "WT", 6 biological samples; (v) p53 null, or "Null", 6 biological samples.

2011-05-13 | E-GEOD-27901 | biostudies-arrayexpress

Mus musculus

Project description:Transactivation-deficient p53 Mutants in Ras-induced Cellular Senescence

| PRJNA138211 | ENA

Impact of transcriptional mutagenesis on p53 transactivation

Project description:The transcriptional error rate can be significantly increased by the presence of DNA lesions that instruct mis-insertion during transcription; a process referred to as transcriptional mutagenesis (TM). Herein, we determined the effect of O6-methylguanine (O6-meG) on transcription and subsequent transactivation activity of p53 in human lung H1299 cells. Levels of TM and effects on transactivation were determined by RNA-seq. Results showed that 47% of all p53 transcripts contained an uridine misincorporation opposite the lesion at 6 h post transfection, which was decreased to 18% at 24 h. TM at these levels reduced DNA binding activity of p53 to 21% and 80% compared to wild type p53, respectively. Gene expression data were analyzed to identify differentially expressed genes due to TM compared to the response of wild type p53. We show a temporal repression of transactivation of >100 high confidence p53 target genes including regulators of the cell cycle, DNA damage response and apoptosis. In addition, TM repressed the transcriptional downregulation by p53 of several negative regulators of proliferation and differentiation . Our work demonstrates that TM, even when restricting its effect to an individual transcription factor, has the potential to alter gene expression programs and diversify cellular phenotypes.

2019-10-16 | GSE138853 | GEO

Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73

Project description:The transcription factor p73, a member of the p53 tumor-suppressor family, regulates cell death and also supports tumorigenesis, though the mechanistic basis for the dichotomous functions is poorly understood. We report here the identification of an alternate transactivation domain (TAD) located at the extreme carboxyl (C)-terminus of TAp73β, a commonly expressed p73 isoform. Mutational disruption of this TAD significantly reduced TAp73β’s transactivation activity, to a level observed when the amino (N)-TAD that is similar to p53’s TAD is mutated. Mutation of both TADs almost completely abolished TAp73β’s transactivation activity. Expression profiling highlighted a unique set of targets involved in extracellular matrix-receptor interaction and focal adhesion to be regulated by the C-TAD, resulting in FAK phosphorylation, distinct from the N-TAD targets that are common to p53 and involved in growth inhibition. Interestingly, the C-TAD targets are also regulated by the oncogenic, amino-terminal deficient DNp73β isoform. Consistently, mutation of C-TAD reduces cellular migration and proliferation. Mechanistically, selective binding of TAp73β to DNAJA1 is required for the transactivation of C-TAD target genes, and silencing DNAJA1 expression abrogated all C-TAD-mediated effects. Taken together, our results provide a mechanistic basis for the dichotomous functions of TAp73 in the regulation cellular growth through its distinct TADs.

2024-05-07 | GSE262279 | GEO

Impact of transcriptional mutagenesis on p53 transactivation

Project description:Impact of transcriptional mutagenesis on p53 transactivation

| PRJNA577617 | ENA

The effect on p53-induced gene transactivation by LIMA1 knockdown.

Project description:To explore the effect of LIMA1 on gene transactivation induced by p53, we evaluated the changes in gene expression by RNA-seq in LIMA1 knockdown or control A549 cells.

2019-02-20 | GSE86347 | GEO

The effect on p53-induced gene transactivation by NEAT1 knockdown.

Project description:To explore the effect of NEAT1 on gene transactivation induced by p53, we evaluated the changes in gene expression by RNA-seq in NEAT1 knockdown or control U2OS cells.

2019-02-20 | GSE85831 | GEO

The effect on p53-induced gene transactivation by ARVCF knockdown.

Project description:To explore the effect of ARVCF on gene transactivation induced by p53, we evaluated the changes in gene expression by RNA-seq in ARVCF knockdown or control U2OS cells.

2022-02-01 | GSE126999 | GEO

Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells (Affymetrix)

Project description:The effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin or Nutlin-3 led to strikingly different p53 gene binding patterns based on ChIP-seq experiments. While two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was 6-times greater for Nutlin-3 than Doxorubicin, expression changes induced by Nutlin-3 were much less dramatic compared to Doxorubicin. Unexpectedly, the solvent DMSO alone induced p53 binding to many sites common to Doxorubicin; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification H3K4me3. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network. Gene expression analysis (using Affymetrix Human Genome U133 Plus 2.0 GeneChipÂ® arrays) of the p53 response in U2OS cells treated with either Doxorubicin or Nutlin-3, relative to their controls No Treatment and DMSO, respectively.

2013-07-01 | E-GEOD-46493 | biostudies-arrayexpress

Intricate coupling between the transactivation and basic-leucine zipper domains governs the CK2-dependent phosphorylation of ATF4

Project description:Most transcription factors possess at least one long intrinsically disordered transactivation domain that binds to a variety of co-activators and co-repressors and plays a key role in modulating the transcriptional activity. Despite the crucial importance of these mechanisms, the structural and functional basis of transactivation domain in yet poorly understood. Here, we focused on ATF4/CREB-2, an essential transcription factor for cellular stress adaptation. We found that the N-terminal region of the transactivation domain is involved in transient long-range interactions with the basic-leucine zipper domain. In vitro phosphorylation assays with the protein kinase CK2 show that the presence of the basic-leucine zipper domain is required for optimal phosphorylation of the transactivation domain. This study uncovers the intricate coupling existing between the transactivation and basic-leucine zipper domains of ATF4 and highlights its potential functional relevance.

2023-03-11 | PXD029704 | Pride

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