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The codon 72 polymorphism of p53 regulates interactions with NF-κB and transactivation of genes involoved in immunity and inflamation

ABSTRACT: A common polymorphism at codon 72 in the p53 tumor suppressor gene encodes either proline(P72) or arginine(R72). These two variants might possess altered biological function which influences p53’s transcriptional, senescence and apoptotic functions. We found that P72 has increased apoptosis when compare to R72. To further identify unknown p53 target genes which might play a role in the increased apoptosis in P72 thymocytes, we have employed whole genome microarray expression profiling as a discovery platform. Mouse thymocytes were isolated from the thymuses of mice that were untreated (0 hour) or following 2 or 4 hours of exposure to 5 Gray of gamma radiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE26851 | GEO | 2011/01/25

SECONDARY ACCESSION(S): PRJNA135973

REPOSITORIES: GEO

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The codon 72 polymorphism of p53 regulates interactions with NF-κB and transactivation of genes involoved in immunity and inflamation

Project description:A common polymorphism at codon 72 in the p53 tumor suppressor gene encodes either proline(P72) or arginine(R72). These two variants might possess altered biological function which influences p53’s transcriptional, senescence and apoptotic functions. We found that P72 has increased apoptosis when compare to R72. To further identify unknown p53 target genes which might play a role in the increased apoptosis in P72 thymocytes, we have employed whole genome microarray expression profiling as a discovery platform. Mouse thymocytes were isolated from the thymuses of mice that were untreated (0 hour) or following 2 or 4 hours of exposure to 5 Gray of gamma radiation. Mouse thymocytes were isolated from the thymuses of mice that were untreated (0 hour) or following 2 or 4 hours of exposure to 5 Gray of gamma radiation. Four independent experiments were performed at each time point (P72 and R72) and at each timepoint 2 mice of each genotype were used, and their thymocytes were pooled together.

2011-01-25 | E-GEOD-26851 | biostudies-arrayexpress

Identification of TRIML2, a Novel p53 Target, that Enhances p53-SUMolylation and Regulates the Transactivation of Pro-apoptotic Genes

Project description:The tumor suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell cycle arrest, senescence and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell cycle arrest, while the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences a gene expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of pro-apoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3) and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress.

2014-12-01 | GSE61124 | GEO

Transcriptome analysis of polymorphic p53 codon 72 under genotoxic stress

Project description:We report the transcriptome data produced from isogenic polymorphic p53 codon 72 iPSCs under doxorubicin treatment. By inserting BAC DNA into one allele of the heterozygous polymorphic p53 codon 72, each clone expressed a p53 protein encoding P72 or R72 from another allele in which it was not inserted. The transcriptional regulation of p53 target genes was compared between the isogenic lines under doxorubicin treatment.

2021-09-10 | GSE183668 | GEO

Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α

Project description:Mutant forms of p53 protein often possess pro-tumorigenic function, conferring increased survival and migration to tumor cells via its “gain of function” activity. Whether and how a common polymorphism in TP53 at amino acid 72 (Pro72Arg, hereafter P72 and R72) impacts this gain of function has not been determined. We show that mutant p53 enhances migration and metastasis of tumors through the ability to bind and regulate PGC-1α, and that this regulation is markedly impacted by the codon 72 polymorphism. Tumor cells with the R72 variant of mutant p53 show increased PGC-1α function, along with greatly increased mitochondrial function and metastatic capability. Breast cancers containing mutant p53 and the R72 variant show poorer prognosis compared to P72. The combined results reveal PGC-1α as a novel “gain of function” partner of mutant p53, and indicate that the codon 72 polymorphism influences the impact of mutant p53 on metabolism and metastasis.

2018-01-19 | GSE109373 | GEO

TRAF6, a master activator of p53 transactivation, suppresses mitochondrial p53 and apoptosis

Project description:TRAF6 -/- thymi display defects in IR-induced p53 target gene expression and attenuate further enhancement of apoptosis upon IR treatment. TRAF6-mediated K63-linked ubiquitination of p53 at K24

2016-11-04 | GSE69730 | GEO

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

Transcription profiling of p68/72 deficient C2C12 cells cultured in either growth medium or differentiation medium to investigate the function of p68/p72 in muscle gene expression and skeletal C2C12 cell differentiation.

Project description:This project investigates the function of p68/p72 in muscle gene expression and skeletal C2C12 cell differentiation. p68/p72 in C2C12 cells cultured in either growth medium (GM) or differentiation medium (DM) was knocked down using shRNA p68/p72 retrovirus, and globle gene expression was profiled using Affymetrix MOE 430A and 430B GeneChip. Experiment Overall Design: The specific aim is to study muscle gene expression changes and skeletal muscle differenciation using RNA interference of p68/p72 in C2C12 cells.

2007-11-29 | E-GEOD-5305 | biostudies-arrayexpress

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

Transactivation-deficient p53 Mutants in Ras-induced Cellular Senescence

2011-05-13 | GSE27901 | GEO

Tri-KIX_DP_thymocytes

Project description:To determine the effect of mutation of the KIX domain of CBP and p300 on gene expression, thymuses dissected from four to seven week old wild type and CBP KIX/KIX;p300 +/KIX adult mice were dissociated into single cell suspesions, antibody stained for CD4 and CD8, sorted for CD4+ CD8+ double positive thymocytes, RNA was made from the sorted cells and transcriptional profiling by array was carried out. CD4+CD8+ double positive thymocytes were chosen because these cells express c-Myb.

2014-02-10 | E-MTAB-1974 | biostudies-arrayexpress

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