scholarly journals ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo

2008 ◽  
Vol 205 (5) ◽  
pp. 1227-1242 ◽  
Author(s):  
Philipp S. Lange ◽  
Juan C. Chavez ◽  
John T. Pinto ◽  
Giovanni Coppola ◽  
Chiao-Wang Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Neurological Diseases ◽  
Glutathione Depletion ◽  
Bzip Transcription Factor ◽  
Behavioral Recovery ◽  
Activating Transcription Factor 4 ◽  
Death And Loss

Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress–inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress–induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4−/− neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4−/− mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.

scholarly journals Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance

2019 ◽  
Vol 116 (19) ◽  
pp. 9433-9442 ◽  
Author(s):  
Jonathan K. M. Lim ◽  
Alberto Delaidelli ◽  
Sean W. Minaker ◽  
Hai-Feng Zhang ◽  
Milena Colovic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Redox Balance ◽  
Gene Encoding ◽  
Oncogenic Ras ◽  
Opposing Effects ◽  
Whole Transcriptome ◽  
Intracellular Redox

The RAS family of proto-oncogenes are among the most commonly mutated genes in human cancers and predict poor clinical outcome. Several mechanisms underlying oncogenic RAS transformation are well documented, including constitutive signaling through the RAF-MEK-ERK proproliferative pathway as well as the PI3K-AKT prosurvival pathway. Notably, control of redox balance has also been proposed to contribute to RAS transformation. However, how homeostasis between reactive oxygen species (ROS) and antioxidants, which have opposing effects in the cell, ultimately influence RAS-mediated transformation and tumor progression is still a matter of debate and the mechanisms involved have not been fully elucidated. Here, we show that oncogenic KRAS protects fibroblasts from oxidative stress by enhancing intracellular GSH levels. Using a whole transcriptome approach, we discovered that this is attributable to transcriptional up-regulation of xCT, the gene encoding the cystine/glutamate antiporter. This is in line with the function of xCT, which mediates the uptake of cystine, a precursor for GSH biosynthesis. Moreover, our results reveal that the ETS-1 transcription factor downstream of the RAS-RAF-MEK-ERK signaling cascade directly transactivates the xCT promoter in synergy with the ATF4 endoplasmic reticulum stress-associated transcription factor. Strikingly, xCT was found to be essential for oncogenic KRAS-mediated transformation in vitro and in vivo by mitigating oxidative stress, as knockdown of xCT strongly impaired growth of tumor xenografts established from KRAS-transformed cells. Overall, this study uncovers a mechanism by which oncogenic RAS preserves intracellular redox balance and identifies an unexpected role for xCT in supporting RAS-induced transformation and tumorigenicity.

scholarly journals MAPK-directed activation of the whitefly transcription factor CREB leads to P450-mediated imidacloprid resistance

2020 ◽  
Vol 117 (19) ◽  
pp. 10246-10253 ◽  
Author(s):  
Xin Yang ◽  
Shun Deng ◽  
Xuegao Wei ◽  
Jing Yang ◽  
Qiannan Zhao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathway ◽  
Gene Families ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Bzip Transcription Factor ◽  
Camp Response Element ◽  
Response Element

The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-acting factors such as signal-regulated transcription factors. Here we resolve in fine detail the trans-regulation of CYP6CM1, a cytochrome P450 that confers resistance to neonicotinoid insecticides in the whitefly Bemisia tabaci, by the mitogen-activated protein kinase (MAPK)-directed activation of the transcription factor cAMP-response element binding protein (CREB). Reporter gene assays were used to identify the putative promoter of CYP6CM1, but no consistent polymorphisms were observed in the promoter of a resistant strain of B. tabaci (imidacloprid-resistant, IMR), which overexpresses this gene, compared to a susceptible strain (imidacloprid-susceptible, IMS). Investigation of potential trans-acting factors using in vitro and in vivo assays demonstrated that the bZIP transcription factor CREB directly regulates CYP6CM1 expression by binding to a cAMP-response element (CRE)-like site in the promoter of this gene. CREB is overexpressed in the IMR strain, and inhibitor, luciferase, and RNA interference assays revealed that a signaling pathway of MAPKs mediates the activation of CREB, and thus the increased expression of CYP6CM1, by phosphorylation-mediated signal transduction. Collectively, these results provide mechanistic insights into the regulation of xenobiotic responses in insects and implicate both the MAPK-signaling pathway and a transcription factor in the development of pesticide resistance.

scholarly journals Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Aruna Marchetto ◽  
Shunya Ohmura ◽  
Martin F. Orth ◽  
Maximilian M. L. Knott ◽  
Maria V. Colombo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Ewing Sarcoma ◽  
Target Genes ◽  
Transcriptome Profiling ◽  
In Vivo Experiments ◽  
Ets Family ◽  
Pdx Models

AbstractEwing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 – a physiological driver of proliferation of osteo-chondrogenic progenitors – by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.

scholarly journals TFIIA Plays a Role in the Response to Oxidative Stress

2006 ◽  
Vol 5 (7) ◽  
pp. 1081-1090 ◽  
Author(s):  
Susan M. Kraemer ◽  
David A. Goldstrohm ◽  
Ann Berger ◽  
Susan Hankey ◽  
Sherry A. Rovinsky ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Expression Profiles ◽  
Intracellular Localization ◽  
Regulation Of Gene Expression ◽  
Wild Type ◽  
Mutant Strains

ABSTRACT To characterize the role of the general transcription factor TFIIA in the regulation of gene expression by RNA polymerase II, we examined the transcriptional profiles of TFIIA mutants of Saccharomyces cerevisiae using DNA microarrays. Whole-genome expression profiles were determined for three different mutants with mutations in the gene coding for the small subunit of TFIIA, TOA2. Depending on the particular mutant strain, approximately 11 to 27% of the expressed genes exhibit altered message levels. A search for common motifs in the upstream regions of the pool of genes decreased in all three mutants yielded the binding site for Yap1, the transcription factor that regulates the response to oxidative stress. Consistent with a TFIIA-Yap1 connection, the TFIIA mutants are unable to grow under conditions that require the oxidative stress response. Underexpression of Yap1-regulated genes in the TFIIA mutant strains is not the result of decreased expression of Yap1 protein, since immunoblot analysis indicates similar amounts of Yap1 in the wild-type and mutant strains. In addition, intracellular localization studies indicate that both the wild-type and mutant strains localize Yap1 indistinguishably in response to oxidative stress. As such, the decrease in transcription of Yap1-dependent genes in the TFIIA mutant strains appears to reflect a compromised interaction between Yap1 and TFIIA. This hypothesis is supported by the observations that Yap1 and TFIIA interact both in vivo and in vitro. Taken together, these studies demonstrate a dependence of Yap1 on TFIIA function and highlight a new role for TFIIA in the cellular mechanism of defense against reactive oxygen species.

scholarly journals ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo

2008 ◽  
Vol 181 (4) ◽  
pp. i13-i13
Author(s):  
Philipp S. Lange ◽  
Juan C. Chavez ◽  
John T. Pinto ◽  
Giovanni Coppola ◽  
Chiao-Wang Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor

Abstract 1371: Overexpression Of Mitochondrial Transcription Factor A Protects Failing Myocardium From Oxidative Stress

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masayoshi Yoshida ◽  
Tomomi Ide ◽  
Mayumi Yamato ◽  
Masaki Ikeuchi ◽  
Takaki Tsutsumi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Transcription Factor ◽  
Hela Cells ◽  
Nuclear Dna ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A

Background: Reactive oxygen species (ROS) from mitochondria play a pivotal role in the pathogenesis and progression of heart failure. Mitochondrial transcription factor A (TFAM), a nucleus-encoded protein, in mitochondria promotes transcription of mitochondrial DNA (mtDNA), maintains mtDNA, and increases mtDNA copy number. We previously reported that overexpression of human TFAM ameliorated cardiac remodeling and improved survival by maintaining mitochondrial function. We investigated whether those beneficial effects result from the increase of antioxidative properties both in vivo and in vitro. Methods and Results: [in vivo study] We created myocardial infarction (MI) in wild type (WT) mice and human TFAM transgenic (TG) mice as a model of heart failure. We evaluated free radical generation by in vivo ESR on 28th day after the operation. MI size did not different between WT and MI. Overexpression of TFAM ameliorated MI-induced cardiac hypertrophy (histology) and LV dysfunction (2D echo and cath). Furthermore, the rate of signal decay in in vivo ESR, indicative of oxidative stress, was accelerated in WT-MI (0.10 ± 0.01 vs 0.19 ± 0.02/min, n=4–5, P<0.01) whereas decelerated in TG-MI (0.12 ± 0.02/min; n=4, P<0.01). DNA microarrays analysis of myocardium (8 weeks old, male) indicated that TG overexpressed (double or more) antioxidant relevant genes mostly encoded in nuclear DNA, such as Mthfd2 and Adh1 without affecting mitochondrial respiratory enzyme activities. [in vitro study] We measured superoxide in Hela cells using Dihydroethidium in the presence of rotenone, a complex I inhibitor. Overexpression of TFAM in Hela cells significantly reduced superoxide production (72.8 %). Conclusion: Overexpression of TFAM suppresses ROS. Such an antioxidative property of TFAM may contribute to its powerful anti-remodeling effect in failing heart.

scholarly journals Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes

2020 ◽  
Vol 21 (10) ◽  
pp. 3579 ◽  
Author(s):  
Rebecca M. Haley ◽  
Sean T. Zuckerman ◽  
Hassan Dakhlallah ◽  
Jeffery R. Capadona ◽  
Horst A. von Recum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurological Diseases ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
The Novel ◽  
Systemic Delivery ◽  
Neuroprotective Effects

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.

The role of oxidative stress in the toxicity of pyridoxal isonicotinoyl hydrazone (PIH) analogues

2002 ◽  
Vol 30 (4) ◽  
pp. 755-758 ◽  
Author(s):  
J. L. Buss ◽  
J. Neuzil ◽  
P. Ponka
Keyword(s):  
Oxidative Stress ◽  
K562 Cells ◽  
Redox Status ◽  
Jurkat Cells ◽  
Glutathione Depletion ◽  
Pyridoxal Isonicotinoyl Hydrazone ◽  
Fe Complexes

Pyridoxal isonicotinoyl hydrazone (PIH) analogues are effective iron chelators in vivo and in vitro, and may be of value for the treatment of secondary iron overload. The sensitivity of Jurkat cells to Fe-chelator complexes was enhanced several-fold by the depletion of the antioxidant glutathione, indicating the role of oxidative stress in their toxicity. K562 cells loaded with eicosapentaenoic acid, a fatty acid particularly susceptible to oxidation, were also more sensitive to the toxic effects of the Fe complexes, and toxicity was proportional to lipid peroxidation. Thus Fechelator complexes cause oxidative stress, which may be a major component of their toxicity. As was the case for their Fe complexes, the toxicity of PIH analogues was enhanced by glutathione depletion of Jurkat cells and eicosapentaenoic acidloading of K562 cells. Thus the toxicity of the chelators themselves is also enhanced by compromised cellular redox status. In addition, the toxicity of the chelators was diminished by culturing Jurkat cells under hypoxic conditions, which may limit the production of the reactive oxygen species that initiate oxidative stress. A significant part of the toxicity of the chelators may be due to intracellular formation of Fe-chelator complexes, which oxidatively destroy the cell.

scholarly journals Neuroprotective Effects of Quercetin in Pediatric Neurological Diseases

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5597
Author(s):  
Lourdes Alvarez-Arellano ◽  
Marcela Salazar-García ◽  
Juan Carlos Corona
Keyword(s):  
Oxidative Stress ◽  
Neurological Diseases ◽  
Natural Compounds ◽  
Autism Spectrum ◽  
Cns Tumors ◽  
Neuroprotective Effects ◽  
Neuroprotective Therapy ◽  
Ameliorative Effect

Oxidative stress is a crucial event underlying several pediatric neurological diseases, such as the central nervous system (CNS) tumors, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Neuroprotective therapy with natural compounds used as antioxidants has the potential to delay, ameliorate or prevent several pediatric neurological diseases. The present review provides an overview of the most recent research outcomes following quercetin treatment for CNS tumors, ASD and ADHD as well as describes the potential in vitro and in vivo ameliorative effect on oxidative stress of bioactive natural compounds, which seems like a promising future therapy for these diseases. The neuroprotective effects of quercetin against oxidative stress can also be applied in the management of several neurodegenerative disorders with effects such as anti-cancer, anti-inflammatory, anti-viral, anti-obesity and anti-microbial. Therefore, quercetin appears to be a suitable adjuvant for therapy against pediatric neurological diseases.

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