Methylglyoxal Down-Regulates the Expression of Cell Cycle Associated Genes and Activates the P53 Pathway in Human Endothelial Cells
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PROVIDER: PRJNA435977 | ENA |
REPOSITORIES: ENA
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Project description:Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. This study addressed 1) to what extent MGO changes the endothelial transcriptome when endothelial cells are exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this normalized by carnosine, a putative scavenger of MGO. Using gene expression profiling analysis, we demonstrated that MGO initiates distinct transcriptional changes in cell cycle/apoptosis gene, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation.
2019-02-13 | GSE111123 | GEO
Project description:Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-?B) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-? induced inflammation.
| S-EPMC6362029 | biostudies-literature
Project description:The p53 protein is encoded by TP53 gene and plays the key role in significant number of cellular processes including proliferation, apoptosis and regulation of many stress response pathways. P53 acts like a direct transcription activator of numerous genes regulating cell cycle arrest, DNA repair, growth inhibition and many others (Mollereau and Ma, 2014). The canonical biological function of p53 is maintaining genome integrity via elimination of damaged or exposed to genotoxic stress cells. Immortalized HaCaT cells are widely used for keratinocyte research, since they maintain stable keratinocyte phenotype, have nearly unlimited proliferative potential, do not require specific growth and differentiation factors (Colombo et al., 2017). Also, HaCaT cells produce typical differentiation markers such as cytokeratins K14 and K10, involucrin (Colombo et al., 2017) and respond to keratinocyte differentiation stimuli. Taking together, HaCaT cells have similar to normal human keratinocytes (NHK) properties, however, as many of spontaneously immortalized cell lines HaCaT cells bear two mutant p53 alleles - R282Q and H179Y (Lehman et al., 1993). Mutp53 in HaCaT has an increased affinity to other p53 family members (p63, p73), which significantly expands p53 properties. Moreover, mutp53 indirectly affects specific target genes via protein-protein interactions with other transcription factors (NF-Y, E2F1, NF-KB) or by tethering p63 to new promotor locations. For more detailed investigation of mutp53 impact on various processes in HaCaT cells we performed a shRNA mediated knockdown of mutp53. For generation of stable TP53 knockdown we employed plasmid vector pLKO-p53-shRNA-941 (Addgene # #25637) followed by puromycin selection of transduced cells. Here we present proteomic dataset obtained from wild type HaCaT cells and p53 knock down HaCaT keratinocytes.
2022-04-28 | PXD033538 | Pride
Project description:Cell cycle progression is linked to transcriptome dynamics and variations in the response of pluripotent cells to differentiation cues, mostly through unknown determinants. Here, we characterized the cell-cycleassociated transcriptome and proteome of mouse embryonic stem cells (mESCs) in naive ground state. We found that the thymine DNA glycosylase (TDG) is a cell-cycle-regulated co-factor of the tumor suppressor p53. Furthermore, TDG and p53 co-bind ESC-specific cis-regulatory elements and thereby control transcription of p53-dependent genes during self-renewal. We determined that the dynamic expression of TDG is required to promote the cell-cycle-associated transcriptional heterogeneity. Moreover, we demonstrated that transient depletion of TDG influences cell fate decisions during the early differentiation of mESCs. Our findings reveal an unanticipated role of TDG in promoting molecular heterogeneity during the cell cycle and highlight the central role of protein dynamics for the temporal control of cell fate during development.
2023-07-31 | GSE188636 | GEO
Project description:Cell cycle arrest in response to DNA damage is an important anti-tumorigenic mechanism. microRNAs (miRNAs) were shown recently to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G1 arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs, miR -192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest suggesting that multiple microRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression that includes a number of transcripts that regulate G1 and G2 checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215 and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results demonstrating a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are under-expressed in primary cancers support the idea that miR-192 and miR-215 function as tumor-suppressors.
2008-12-07 | GSE13105 | GEO
Project description:Cell cycle progression is linked to transcriptome dynamics and variations in the response of pluripotent cells to differentiation cues, through mostly unknown determinants. Here, we characterized the cell cycle–associated transcriptome and proteome of mouse embryonic stem cells (mESCs) in naïve ground state. We found that the thymine DNA glycosylase (TDG) is a cell cycle–regulated co-factor of the tumour suppressor p53. Further, TDG and p53 co-bind ESC-specific cis-regulatory elements and thereby control transcription of p53-dependent genes during self-renewal. We determined that the dynamic expression of TDG is required to promote the cell cycle–associated transcriptional heterogeneity. Moreover, we demonstrated that transient depletion of TDG influences cell fate decisions during the early differentiation of mESCs. Our findings reveal an unanticipated role of TDG in promoting molecular heterogeneity during the cell cycle, and highlight the central role of protein dynamics for the temporal control of cell fate during development.
2023-07-31 | PXD029596 | Pride
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks. RNA was isolated from human fetal lung fibroblasts, HCT116 p53+/+, or HCT116 p53-/- cells treated with doxorubicin or sham for 26 hours. Human fetal lung fibroblasts were transfected with siRNAs targeting DINO or non-targeting control and subsequently treated with doxorubicin for 26 hours.
2012-11-20 | E-GEOD-42368 | biostudies-arrayexpress
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks.
2012-11-20 | GSE42368 | GEO
Project description:Cell cycle arrest in response to DNA damage is an important anti-tumorigenic mechanism. microRNAs (miRNAs) were shown recently to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G1 arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs, miR -192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest suggesting that multiple microRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression that includes a number of transcripts that regulate G1 and G2 checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215 and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results demonstrating a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are under-expressed in primary cancers support the idea that miR-192 and miR-215 function as tumor-suppressors. Description: Transfection of siRNA luc, miR-192 or miR-215 into HCT116 Dicerex5, compared to mock-transfected cells, with mRNA expression profiled at 10h and 24h post-transfection. Species: Human Tissue: HCT116 Dicerex5 cell line (tissue of origin = human colorectal carcinoma); this cell line is hypomorphic for Dicer gene function. Dye-swap: no Negative control: siRNA luc Replicates per each timepoint: no
2010-06-24 | E-GEOD-13105 | biostudies-arrayexpress
Project description:Here, we show that the activity of the tumor suppressor p53 in the metazoan C. elegans switches organismal development between reproductive growth and dormancy by responding to nutrient availability signaled by the cytokine, ILC-17.1. ILC-17.1-dependent repression of the C. elegans p53 ortholog CEP-1 is required for larval growth and development; ILC-17.1 deficiency activates CEP-1/p53 in post-embryonically dividing progenitor blast cells, decreases glucose utilization and cytochrome C levels, upregulates cell cycle inhibitors, and causes larvae to arrest as stress-resistant, quiescent dauers.
2024-01-30 | GSE229132 | GEO