Browse
Submit Data
Databases
API
Help

Dataset Information

4 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes.

ABSTRACT: A20 protects against pathologic vascular remodeling by inhibiting the inflammatory transcription factor NF-κB. A20's function has been attributed to ubiquitin editing of receptor-interacting protein 1 (RIP1) to influence activity/stability. The validity of this mechanism was tested using a murine model of transplant vasculopathy and human cells. Mouse C57BL/6 aortae transduced with adenoviruses containing A20 (or β-galactosidase as a control) were allografted into major histocompatibility complex-mismatched BALB/c mice. Primary endothelial cells, smooth muscle cells, or transformed epithelial cells (all human) were transfected with wild-type A20 or with catalytically inactive mutants as a control. NF-κB activity and intracellular localization of RIP1 was monitored by reporter gene assay, immunofluorescent staining, and Western blotting. Native and catalytically inactive versions of A20 had similar inhibitory effects on NF-κB activity (-70% vs. -76%; P > 0.05). A20 promoted localization of RIP1 to insoluble aggresomes in murine vascular allografts and in human cells (53% vs. 0%) without altering RIP1 expression, and this process was increased by the assembly of polyubiquitin chains (87% vs. 28%; P < 0.05). A20 captures polyubiquitinated signaling intermediaries in insoluble aggresomes, thus reducing their bioavailability for downstream NF-κB signaling. This novel mechanism contributes to protection from vasculopathy in transplanted organs treated with exogenous A20.

SUBMITTER: Enesa K

PROVIDER: S-EPMC4415009 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

YAP9/A20 complex suppresses proinflammatory responses and provides novel anti-inflammatory therapeutic potentials.

Project description:Innate anti-inflammatory mechanisms are essential for immune homeostasis and can present opportunities to intervene inflammatory diseases. In this report, we found that YAP isoform 9 (YAP9) is an essential negative regulator of the potent inflammatory stimuli such as TNFα, IL-1β, and LPS. YAP9 constitutively interacts with another anti-inflammatory regulator A20 (TNFAIP3) to suppress inflammatory responses, but A20 and YAP can function only in the presence of the other. YAP9 uses a short stretch of amino acids in the proline-rich domain (PRD) and transactivation domain (TAD) suppress the inflammatory signaling while A20 mainly uses the zinc finger domain 7 (ZF7). Cell-penetrating synthetic PRD, TAD, and ZF7 peptides act as YAP9 and A20 mimetics respectively to suppress the proinflammatory responses at the cellular level and in mice. Our data uncover a novel anti-inflammatory axis and anti-inflammatory agents that can be developed to treat acute or chronic conditions where TNFα, IL-1β, or LPS plays a key role in initiating and/or perpetuating inflammation.

| S-EPMC9420849 | biostudies-literature

YAP9/A20 Complex Suppresses Proinflammatory Responses and Provides Novel Anti-inflammatory Therapeutic Potentials

2022-06-22 | GSE203438 | GEO

A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis.

Project description:Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3), a ubiquitin-editing enzyme that restricts NF?B and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min)). While A20(FL/FL) villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL) villin-Cre APC(min/+) mice contain far greater numbers and larger colonic polyps than control APC(min) mice. We find that A20 binds to the ?-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of ?-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the ?-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting ?-catenin signaling and preventing colon tumorigenesis.

| S-EPMC3645994 | biostudies-literature

Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.

Project description:AimsThe nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs.Methods and resultsIn human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs.ConclusionOur data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.

| S-EPMC10411943 | biostudies-literature

Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation.

Project description:The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

| S-EPMC6645780 | biostudies-literature

Endothelial IGFBP6 Suppresses Vascular Inflammation and Atherosclerosis

Project description:It has previously been reported that expression levels of insulin-like growth factor binding protein 6 (IGFBP6) are reduced in unstable plaques compared to stable plaques in patients with coronary heart disease (CAD). However, the exact role and mechanism of IGFBP6 in endothelial homeostasis and inhibition of focal atherosclerotic plaque development in vivo remains unclear. Transcripome sequencing and bioinformatics analysis of IGFBP6-overexpressed human umbilical vein endothelial cells (HUVECs) suggest that pathway analysis and differentially expressed mRNA may help clarify the role and potential mechanism of IGFBP6 in the treatment of cardiovascular diseases.

2024-05-01 | GSE265787 | GEO

Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

Project description:Silymarin (SM) is a popular botanical medicine with purported liver protective effects. SM displays multiple effects in animal models and in cell culture including prevention of liver disease, reduction of inflammation, oxidative stress, and proliferation. Despite a plethora of data indicating that SM impinges on multiple cellular signaling pathways important in inflammation and disease, no unifying mechanisms have been forwarded. To define how SM elicits so many biological effects, the current study presents the first comprehensive transcriptional profiling study of human hepatoma cells treated with SM. The intention of the study was to focus on the early transcriptional events that are associated with SM-induced inhibition of proliferation and inflammation. Collectively, the data demonstrate that SM causes a rapid transcriptional reprogramming of cells that initially manifests as energy stress and slowing of cellular metabolism, leading to inhibition of cell growth and inflammation. The effects of silymarin on liver hepatoma Huh7.5.1 cells were detected using a time course approach.

2015-07-01 | E-GEOD-50994 | biostudies-arrayexpress

Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules.

Project description:Wnt signaling is essential for T cell development in the thymus, but the stages in which it occurs and the molecular mechanisms underlying Wnt responsiveness have remained elusive. Here we examined Wnt signaling activity in both human and murine thymocyte populations by determining beta-catenin levels, Tcf-reporter activation and expression of Wnt-target genes. We demonstrate that Wnt signaling occurs in all thymocyte subsets, including the more mature populations, but most prominently in the double negative (DN) subsets. This differential sensitivity to Wnt signaling was not caused by differences in the presence of Wnts or Wnt receptors, as these appeared to be expressed at comparable levels in all thymocyte subsets. Rather, it can be explained by high expression of activating signaling molecules in DN cells, e.g., beta-catenin, plakoglobin, and long forms of Tcf-1, and by low levels of inhibitory molecules. By blocking Wnt signaling from the earliest stage onwards using overexpression of Dickkopf, we show that inhibition of the canonical Wnt pathway blocks development at the most immature DN1 stage. Thus, responsiveness to developmental signals can be regulated by differential expression of intracellular mediators rather than by abundance of receptors or ligands.

| S-EPMC1413930 | biostudies-literature

A20: central gatekeeper in inflammation and immunity.

Project description:Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-kappaB, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-kappaB-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-kappaB signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity.

| S-EPMC2659177 | biostudies-literature

The downstream molecules of Notch signaling in vascular endothelial cell senescence

Project description:To further investigate the mechanism how the decline in Notch signaling induces premature senescence in endothelial cells, we performed microarray analysis and identified Id1 nd DUSP1 as the downstream molecules of Notch pathway. In quantitative PCR and western blot analyses, the expression level of Id1 and DUSP1 increased in Notch1 over-expressing endothelial cells and decreased in knockdown similar to the result of microarray. The gene expression of human unbilical endothelial vein cells (HUVEC) infected with retroviral vectors encoding Jagged1, Jagged1-shRNA, or Notch1-shRNA. HUVEC infected with empty vector was used as a control. In each genotypes, three independent lines at passage 8 were performed.

2012-08-28 | E-GEOD-40403 | biostudies-arrayexpress

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