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Superoxide dismutase-3 downmodulates laminin α5 expression in endothelial cells via Nuclear Factor kappa B signaling inhibition

ABSTRACT: Superoxide dismutase-3 downmodulates laminin α5 expression in endothelial cells via Nuclear Factor kappa B signaling inhibition

PROVIDER: PRJNA782194 | ENA |

REPOSITORIES: ENA

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Superoxide dismutase-3 downmodulates laminin α5 expression in endothelial cells via Nuclear Factor kappa B signaling inhibition

Project description:The balance between laminins containing the α5 (LAMA5) or the α4 (LAMA4) subunits is determinant for the diapedesis of different leukocyte subtypes in inflammatory conditions. We have shown that the extracellular superoxide dismutase (SOD3) is a positive regulator of LAMA4, and this was associated with enhanced intratumor T cell infiltration in experimental and primary human cancers. Here we show that SOD3 overexpression in neoplastic or endothelial cells (ECs) downmodulates LAMA5 levels in implanted tumors. The inhibitory effect of SOD3 on LAMA5 expression occurs at the transcriptional level and is specific for SOD3, since LAMA5 levels are not changed by in SOD1-overexpressing cells. Global transcriptomic analyses revealed that SOD3 overexpression changes the transcription of 1,682 genes in ECs exposed to tumor secreted factors, being the canonical and non-canonical Nuclear Factor kappa B (NF-κB) pathways major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as the NF-κB-driven promoter activity in endothelial cells stimulated with tumor necrosis factor (TNF)-α, an inducer of NF-κB signaling

2022-03-02 | GSE189247 | GEO

Enterocyte Superoxide Dismutase 2 Deletion Drives Hyperinsulinemia and Obesity

Project description:Enterocyte Superoxide Dismutase 2 Deletion Drives Hyperinsulinemia and Obesity

| PRJNA664402 | ENA

Switch of mitochondrial superoxide dismutase into a prooxidant peroxidase in manganese-deficient cells

Project description:Superoxide radical anion and other Reactive Oxygen Species are constantly produced during respiration. In mitochondria, the dismutation of the superoxide radical anion is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. We show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H2O2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases.

2017-12-05 | GSE106206 | GEO

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling.

Project description:The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced intratumor T cell infiltration in primary human cancers. We show now that SOD3 overexpression in neoplastic and endothelial cells (ECs) reduces laminin α5 in tumor blood vessels. SOD3 represses the laminin α5 gene (LAMA5), but LAMA5 expression is not changed in SOD1-overexpressing cells. Transcriptomic analyses revealed SOD3 overexpression to change the transcription of 1682 genes in ECs, with the canonical and non-canonical NF-κB pathways as the major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as NF-κB-driven promoter activity in ECs stimulated with tumor necrosis factor (TNF)-α, an NF-κB signaling inducer. SOD3 inhibited the phosphorylation and degradation of IκBα (nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor alpha), an NF-κB inhibitor. Finally, TNF-α was found to be a transcriptional activator of LAMA5 but not of LAMA4; LAMA5 induction was prevented by SOD3. In conclusion, SOD3 is a major regulator of laminin balance in the basement membrane of tumor ECs, with potential implications for immune cell infiltration into tumors.

| S-EPMC8909228 | biostudies-literature

Enterocyte Superoxide Dismutase 2 Deletion Drives Hyperinsulinemia and Obesity

Project description:Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity, inflammation and insulin resistance via phospholipase A2 (PLA2) activation and increased synthesis of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese and hyperinsulinemic phenotype was rescued when fed an essential fatty acid deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal SOD2 mRNA levels and obesity features, such as body mass index and omega-6/omega-3 fatty acid ratio, appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal SOD2 levels, PLA2 activity and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.

2021-12-31 | GSE158237 | GEO

Switch of mitochondrial superoxide dismutase into a prooxidant peroxidase in manganese-deficient cells

Project description:Switch of mitochondrial superoxide dismutase into a prooxidant peroxidase in manganese-deficient cells

| PRJNA415919 | ENA

Neutrophils restrain sepsis associated coagulopathy via extracellular vesicles carrying superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis

Project description:Disseminated intravascular coagulation (DIC) is a deadly complication of sepsis lacking effective managements. Although excessive inflammatory responses are emerging as key triggers of coagulopathy in sepsis, the interplays between immune system and coagulation are not fully understood. In a murine model of sepsis induced by intraperitoneal lipopolysaccharide (LPS), we found neutrophils in circulation mitigate the occurrence of DIC, thereby preventing the subsequent septic death. We found circulating neutrophils constantly release extracellular vesicles (EVs) containing mitochondria, which carry substantial amount of Superoxide Dismutase 2 (Sod2) upon LPS exposure. The extracellular Sod2 is necessary to bring about neutrophils’ antithrombotic function by eliminating endothelial reactive oxygen species (ROS) accumulation and alleviating endothelial dysfunction. Intervening endothelial ROS accumulation by antioxidants significantly ameliorates DIC with correspondingly improved survival in sepsis. These findings revealed a novel interaction between neutrophils and vascular endothelium which critically regulates coagulation in sepsis and had potential implications for the management of septic DIC.

2022-07-26 | GSE206825 | GEO

Utilizing Ion Mobility-Mass Spectrometry to Investigate the Unfolding Pathway of Cu/Zn Superoxide Dismutase

Project description:IMS-MS data for Cu/Zn-Superoxide Dismutase (from bovine erythrocytes). Experiments were conducted on two different IMS platforms (DTIMS and TIMS) to compare the CCS values obtained under different types of IMS. Three separate solution conditions were used for the DTIMS data in order to obtain CCS values for the native, holo-dimeric protein, the holo-monomer, and the apo-monomer. Native conditions (30 mM ammonium acetate) were used to assess the native protein structure (holo-dimer). Holo-monomer formation was promoted by addition of 30% acetonitrile and 100 uM formic acid, while apo-monomer formation was promoted by addition of 30% acetonitrile and 0.1% formic acid.

| MSV000086204 | MassIVE

Combination scaffolds of salmon fibrin, hyaluronic acid, and laminin for human neural stem cell tissue engineering

Project description:A goal of this project is to evaluate the integrin mRNA expression in human neural stem/progenitor cells (hNSPC) using high-throughput sequencing technologies. We found high levels of mRNA expression for the β1, α7, α3, α6, β5, αV, α5, and α9 integrins. This suggests that hNSPCs may express integrin receptors that can bind fibrinogen and laminin proteins.

2016-12-14 | GSE76011 | GEO

Extracellular Superoxide Dismutase Regulates the Expression of GTPase Guanine Nucleotide Exchange Factors (GEFs), GTPase-activating proteins (GAPs), and Rho Guanine nucleotide disassociation inhibitors (GDI)

Project description:Extracellular superoxide dismutase (SOD3), which dismutases hydrogen peroxide to superoxide anion at cell membranes, mimics RAS oncogene action inducing primary cell immortalization at sustained low-level expression while high expression activates cancer barrier signaling through p53-p21 growth arrest pathway. We have previously demonstrated that the growth regulation of SOD3 occurs at the level of RAS and is mediated through non-transcriptional and transcriptional routes. Therefore, in the current work we assayed the growth suppressive mechanisms of SOD3 by characterizing the main signal transduction routes from the cell membrane into the nucleus. Based on our data robust over-expression of SOD3 in anaplastic thyroid cancer 8505c cells increased EGFR, RYK, ALK, FLT3, and EPHA10 tyrosine kinase receptor phosphorylation with consequent downstream SRC, FYN, YES, HCK, and LYN kinase activation. However, RAS pull-down experiment suggested lack of mitogen pathway stimulation that was confirmed by MEK1/2 and ERK1/2 Western blot. Interestingly, mRNA expression analysis indicated that SOD3 regulated in a dose dependent manner the expression of selected guanine nucleotide exchange factors (Rho GEF16, Ral GEF RGL1), GTPase activating proteins (ArfGAP ADAP2, Ras GAP RASAL1, RGS4), and Rho guanine nucleotide disassociation inhibitors (Rho GDI 2) therefore controlling the signal transduction through RAS GTPases to downstream signal transduction pathways. Our current data suggests a SOD3-induced activation of growth signal transduction is controlled in a dose dependent manner through GEF, GAP, and GDI.

2014-12-31 | GSE56546 | GEO

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