scholarly journals H2O2 Activates the Nuclear Localization of Msn2 and Maf1 through Thioredoxins in Saccharomyces cerevisiae

2009 ◽  
Vol 8 (9) ◽  
pp. 1429-1438 ◽  
Author(s):  
Stéphanie Boisnard ◽  
Gilles Lagniel ◽  
Cecilia Garmendia-Torres ◽  
Mikael Molin ◽  
Emmanuelle Boy-Marcotte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cellular Response ◽  
Wide Spectrum ◽  
Stress Conditions ◽  
Negative Regulator ◽  
Nuclear Accumulation ◽  
Cell Defense ◽  
Expression Of Genes ◽  
Thioredoxin System ◽  
Enhanced Expression

ABSTRACT The cellular response to hydrogen peroxide (H2O2) is characterized by a repression of growth-related processes and an enhanced expression of genes important for cell defense. In budding yeast, this response requires the activation of a set of transcriptional effectors. Some of them, such as the transcriptional activator Yap1, are specific to oxidative stress, and others, such as the transcriptional activators Msn2/4 and the negative regulator Maf1, are activated by a wide spectrum of stress conditions. How these general effectors are activated in response to oxidative stress remains an open question. In this study, we demonstrate that the two cytoplasmic thioredoxins, Trx1 and Trx2, are essential to trigger the nuclear accumulation of Msn2/4 and Maf1, specifically under H2O2 treatment. Contrary to the case with many stress conditions previously described for yeast, the H2O2-induced nuclear accumulation of Msn2 and Maf1 does not correlate with the downregulation of PKA kinase activity. Nevertheless, we show that PP2A phosphatase activity is essential for driving Maf1 dephosphorylation and its subsequent nuclear accumulation in response to H2O2 treatment. Interestingly, under this condition, the lack of PP2A activity has no impact on the subcellular localization of Msn2, demonstrating that the H2O2 signaling pathways share a common route through the thioredoxin system and then diverge to activate Msn2 and Maf1, the final integrators of these pathways.

scholarly journals The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62

2019 ◽  
Vol 5 (4) ◽  
pp. eaav4570 ◽  
Author(s):  
Daqian Xu ◽  
Xinjian Li ◽  
Fei Shao ◽  
Guishuai Lv ◽  
Hongwei Lv ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Kinase Activity ◽  
Survival Rates ◽  
Adenosine Monophosphate ◽  
Nuclear Accumulation ◽  
Protein Kinase Activity ◽  
Reduction Cell ◽  
Expression Of Genes

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5′-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62’s aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

scholarly journals The Central Role of Redox-Regulated Switch Proteins in Bacteria

2021 ◽  
Vol 8 ◽  
Author(s):  
Rosi Fassler ◽  
Lisa Zuily ◽  
Nora Lahrach ◽  
Marianne Ilbert ◽  
Dana Reichmann
Keyword(s):  
Oxidative Stress ◽  
Defense Mechanisms ◽  
Stress Conditions ◽  
New Members ◽  
Post Translational Modifications ◽  
Metal Centers ◽  
Expression Of Genes ◽  
Future Challenges ◽  
Redox Switches

Bacteria possess the ability to adapt to changing environments. To enable this, cells use reversible post-translational modifications on key proteins to modulate their behavior, metabolism, defense mechanisms and adaptation of bacteria to stress. In this review, we focus on bacterial protein switches that are activated during exposure to oxidative stress. Such protein switches are triggered by either exogenous reactive oxygen species (ROS) or endogenous ROS generated as by-products of the aerobic lifestyle. Both thiol switches and metal centers have been shown to be the primary targets of ROS. Cells take advantage of such reactivity to use these reactive sites as redox sensors to detect and combat oxidative stress conditions. This in turn may induce expression of genes involved in antioxidant strategies and thus protect the proteome against stress conditions. We further describe the well-characterized mechanism of selected proteins that are regulated by redox switches. We highlight the diversity of mechanisms and functions (as well as common features) across different switches, while also presenting integrative methodologies used in discovering new members of this family. Finally, we point to future challenges in this field, both in uncovering new types of switches, as well as defining novel additional functions.

scholarly journals Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Innokenty M. Mokhosoev ◽  
Tatiana I. Mel’nikova ◽  
Yuri B. Porozov ◽  
Alexander A. Terentiev
Keyword(s):  
Oxidative Stress ◽  
Cell Signaling ◽  
Cellular Response ◽  
Protein Quality ◽  
Malonic Dialdehyde ◽  
Vascular Complications ◽  
Stress Conditions ◽  
Age Related ◽  
Glycation End Products ◽  
End Products

Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging. Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-κB, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivatives such as glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively). Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.

scholarly journals Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

2015 ◽  
Vol 112 (39) ◽  
pp. 12169-12174 ◽  
Author(s):  
Nadine Keleku-Lukwete ◽  
Mikiko Suzuki ◽  
Akihito Otsuki ◽  
Kouhei Tsuchida ◽  
Saori Katayama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell ◽  
Cell Model ◽  
Globin Gene ◽  
Organ Damage ◽  
Negative Regulator ◽  
Related Factor ◽  
Cell Defense ◽  
Sickle Cells ◽  
Nrf2 Activation

Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

Effects of heterologous expression of human cyclic nucleotide phosphodiesterase 3A (hPDE3A) on redox regulation in yeast

2016 ◽  
Vol 473 (22) ◽  
pp. 4205-4225 ◽  
Author(s):  
Dong Keun Rhee ◽  
Jung Chae Lim ◽  
Steven C. Hockman ◽  
Faiyaz Ahmad ◽  
Dong Ho Woo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Redox Regulation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Negative Regulator ◽  
Antioxidant Genes ◽  
Post Translational Modifications ◽  
Thioredoxin System ◽  
Antioxidant Gene Expression ◽  
Camp Levels

Oxidative stress plays a pivotal role in pathogenesis of cardiovascular diseases and diabetes; however, the roles of protein kinase A (PKA) and human phosphodiesterase 3A (hPDE3A) remain unknown. Here, we show that yeast expressing wild-type (WT) hPDE3A or K13R hPDE3A (putative ubiquitinylation site mutant) exhibited resistance or sensitivity to exogenous hydrogen peroxide (H2O2), respectively. H2O2-stimulated ROS production was markedly increased in yeast expressing K13R hPDE3A (Oxidative stress Sensitive 1, OxiS1), compared with yeast expressing WT hPDE3A (Oxidative stress Resistant 1, OxiR1). In OxiR1, YAP1 and YAP1-dependent antioxidant genes were up-regulated, accompanied by a reduction in thioredoxin peroxidase. In OxiS1, expression of YAP1 and YAP1-dependent genes was impaired, and the thioredoxin system malfunctioned. H2O2 increased cyclic adenosine monophosphate (cAMP)-hydrolyzing activity of WT hPDE3A, but not K13R hPDE3A, through PKA-dependent phosphorylation of hPDE3A, which was correlated with its ubiquitinylation. The changes in antioxidant gene expression did not directly correlate with differences in cAMP–PKA signaling. Despite differences in their capacities to hydrolyze cAMP, total cAMP levels among OxiR1, OxiS1, and mock were similar; PKA activity, however, was lower in OxiS1 than in OxiR1 or mock. During exposure to H2O2, however, Sch9p activity, a target of Rapamycin complex 1-regulated Rps6 kinase and negative-regulator of PKA, was rapidly reduced in OxiR1, and Tpk1p, a PKA catalytic subunit, was diffusely spread throughout the cytosol, with PKA activation. In OxiS1, Sch9p activity was unchanged during exposure to H2O2, consistent with reduced activation of PKA. These results suggest that, during oxidative stress, TOR-Sch9 signaling might regulate PKA activity, and that post-translational modifications of hPDE3A are critical in its regulation of cellular recovery from oxidative stress.

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases

2020 ◽  
pp. 1-18
Author(s):  
Amalia Merelli ◽  
Marisa Repetto ◽  
Alberto Lazarowski ◽  
Jerónimo Auzmendi
Keyword(s):  
Oxidative Stress ◽  
Intranasal Administration ◽  
Cellular Response ◽  
Wide Spectrum ◽  
Hypoxia Inducible Factor ◽  
Motor Deficits ◽  
Older Individuals ◽  
Hypoxic Area ◽  
Affected Tissue ◽  
Therapeutic Opportunity

The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.

scholarly journals The role of Trx/TBP-2 in oxidative stress induced autophagy in human lens epithelial cells

2019 ◽  
Author(s):  
Jianghua Hu ◽  
Lifang Shen ◽  
Chengshou Zhang ◽  
Ke Yao ◽  
Yibo Yu
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Cellular Response ◽  
Negative Regulator ◽  
Cell Counting ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Mrna Levels ◽  
Human Lens Epithelial Cells

Abstract Background: Oxidative stress plays an important role in age-related cataract development. The cellular antioxidant protein thioredoxin (Trx) and its negative regulator, thioredoxin binding protein-2 (TBP-2), maintain the intracellular redox balance upon oxidative stress. The aim of this study is to investigate role of Trx and TBP-2 in human lens epithelial cells (LECs) under oxidative stress. Methods: LECs were treated with 50 μM of H2O2 serum-free medium for different duration, and the mRNA and protein levels of Trx-1, Trx-2 and TBP-2 were measured by reverse transcription-polymerase chain reaction and Western blot. Trx-1 activity was evaluated by Thioredoxin Activity Fluorescent Assay. The subcellular localization of Trx-1, Trx-2 and TBP-2 was evaluated by cellular immunofluorescence. The cell viability was detected by Cell Counting Kit-8 (CCK-8) and the LC3-II protein level was detected to evaluate the autophagy level. The interaction between Trx-2 and TBP-2 was examined by Co-Immunoprecipitation (Co-IP). Results: The results showed that the mRNA levels of the Trx-1, Trx-2 and TBP-2 were kinetically changed after treatment with 50 μM of H2O2 for different duration. Exposure to H2O2 increased the expression of Trx-2 and TBP-2 but not Trx-1, while the exposure inhibited Trx-1 activity. TBP-2 was co-localized with Trx-1 and Trx-2, exposure to H2O2 enriched co-localization of TBP-2 to Trx-1 but not Trx-2, and increased the interaction between TBP-2 and Trx-1. Under normal circumstances, Trx-1 over-expression enhanced autophagic response and mainly regulates autophagy in the initiation. Conclusions: This study demonstrates differential roles of Trx-1 and Trx-2 in cellular response to oxidative stress, and oxidative stress increased Trx-1 interacting to TBP-2 and Trx-1 regulating autophagic response.

Down-regulation of EPHX2 gene transcription by Sp1 under high-glucose conditions

2015 ◽  
Vol 470 (3) ◽  
pp. 281-291 ◽  
Author(s):  
Ami Oguro ◽  
Shoko Oida ◽  
Susumu Imaoka
Keyword(s):  
Oxidative Stress ◽  
Gene Transcription ◽  
Transcriptional Activation ◽  
High Glucose ◽  
Binding Sites ◽  
Stress Conditions ◽  
Negative Regulator ◽  
General Function ◽  
Down Regulation

This study indicates a new aspect of Sp1 as a negative regulator of genes in addition to its general function of transcriptional activation. Under oxidative stress conditions, Sp1 negatively regulated EPHX2 gene transcription by competing for Sp1-binding sites with AP2α.

Anti-Diabetic Activity of a Mineraloid Isolate, in vitro and in Genetically Diabetic Mice

2011 ◽  
Vol 81 (1) ◽  
pp. 34-42 ◽  
Author(s):  
Joel Deneau ◽  
Taufeeq Ahmed ◽  
Roger Blotsky ◽  
Krzysztof Bojanowski
Keyword(s):  
Dna Microarrays ◽  
Human Fibroblasts ◽  
Diabetic Animal ◽  
In Vitro Tests ◽  
Diabetic Mice ◽  
Fossil Material ◽  
Expression Of Genes ◽  
Enhanced Expression ◽  
Genetically Diabetic Mice

Type II diabetes is a metabolic disease mediated through multiple molecular pathways. Here, we report anti-diabetic effect of a standardized isolate from a fossil material - a mineraloid leonardite - in in vitro tests and in genetically diabetic mice. The mineraloid isolate stimulated mitochondrial metabolism in human fibroblasts and this stimulation correlated with enhanced expression of genes coding for mitochondrial proteins such as ATP synthases and ribosomal protein precursors, as measured by DNA microarrays. In the diabetic animal model, consumption of the Totala isolate resulted in decreased weight gain, blood glucose, and glycated hemoglobin. To our best knowledge, this is the first description ever of a fossil material having anti-diabetic activity in pre-clinical models.

scholarly journals Thiol-based switching mechanisms of stress-sensing chaperones

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Kathrin Ulrich ◽  
Blanche Schwappach ◽  
Ursula Jakob
Keyword(s):  
Oxidative Stress ◽  
Environmental Changes ◽  
Stress Conditions ◽  
Stress Exposure ◽  
Atp Levels ◽  
Protein Functions ◽  
Activation Mechanisms ◽  
Client Proteins ◽  
Stress Sensing ◽  
Redox Switches

AbstractThiol-based redox switches evolved as efficient post-translational regulatory mechanisms that enable individual proteins to rapidly respond to sudden environmental changes. While some protein functions need to be switched off to save resources and avoid potentially error-prone processes, protective functions become essential and need to be switched on. In this review, we focus on thiol-based activation mechanisms of stress-sensing chaperones. Upon stress exposure, these chaperones convert into high affinity binding platforms for unfolding proteins and protect cells against the accumulation of potentially toxic protein aggregates. Their chaperone activity is independent of ATP, a feature that becomes especially important under oxidative stress conditions, where cellular ATP levels drop and canonical ATP-dependent chaperones no longer operate. Vice versa, reductive inactivation and substrate release require the restoration of ATP levels, which ensures refolding of client proteins by ATP-dependent foldases. We will give an overview over the different strategies that cells evolved to rapidly increase the pool of ATP-independent chaperones upon oxidative stress and provide mechanistic insights into how stress conditions are used to convert abundant cellular proteins into ATP-independent holding chaperones.

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