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Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation.

ABSTRACT: Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcriptional activity is enhanced by the oxidative stress-induced SUMOylation of TP53INP1 at lysine 113. This SUMOylation is mediated by PIAS3 and CBX4, two SUMO ligases especially related to the p53 activation upon DNA damage. Importantly, this modification is reversed by three SUMO1-specific proteases SENP1, 2 and 6. Moreover, TP53INP1 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions. TP53INP1 mutation at lysine 113 prevents the pro-apoptotic, antiproliferative and antioxidant effects of TP53INP1 by impairing the p53 response on its target genes p21, Bax and PUMA. We conclude that TP53INP1 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress.

SUBMITTER: Peuget S

PROVIDER: S-EPMC4207477 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation.

Peuget S S Bonacci T T Soubeyran P P Iovanna J J Dusetti N J NJ

Cell death and differentiation 20140307 7

Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcript ...[more]

PMID: 24608790

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Project description:BackgroundAfrican Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress.ObjectiveTo test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs.MethodsProof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion.Main outcome measuresChanges in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha).ResultsA total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. - 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. - 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025).ConclusionsIn this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs.Trial registrationClinicalTrials.gov identifiers NCT02365285.

Project description:BackgroundCell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence.Methods and resultsBradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.ConclusionsBradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.

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Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation.

Publications

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation.

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