Faculty Opinions recommendation of G-Quadruplex in the NRF2 mRNA 5' Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress.

2017 ◽  
Author(s):  
Mark Searcey
Keyword(s):  
Oxidative Stress ◽  
Untranslated Region ◽  
De Novo ◽  
Protein Translation ◽  
G Quadruplex ◽  
Nrf2 Protein

scholarly journals G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress

2016 ◽  
Vol 37 (1) ◽  
Author(s):  
Sang C. Lee ◽  
Jack Zhang ◽  
Josh Strom ◽  
Danzhou Yang ◽  
Thai Nho Dinh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Fate ◽  
Untranslated Region ◽  
De Novo ◽  
Tissue Injury ◽  
Elongation Factor ◽  
Protein Translation ◽  
General Measure ◽  
G Quadruplex ◽  
Nrf2 Protein

ABSTRACT Inhibition of protein synthesis serves as a general measure of cellular consequences of chemical stress. A few proteins are translated selectively and influence cell fate. How these proteins can bypass the general control of translation remains unknown. We found that low to mild doses of oxidants induce de novo translation of the NRF2 protein. Here we demonstrate the presence of a G-quadruplex structure in the 5′ untranslated region (UTR) of NRF2 mRNA, as measured by circular dichroism, nuclear magnetic resonance, and dimethylsulfate footprinting analyses. Such a structure is important for 5′-UTR activity, since its removal by sequence mutation eliminated H 2 O 2 -induced activation of the NRF2 5′ UTR. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics revealed elongation factor 1 alpha (EF1a) as a protein binding to the G-quadruplex sequence. Cells responded to H 2 O 2 treatment by increasing the EF1a protein association with NRF2 mRNA, as measured by RNA-protein interaction assays. The EF1a interaction with small and large subunits of ribosomes did not appear to change due to H 2 O 2 treatment, nor did posttranslational modifications, as measured by two-dimensional (2-D) Western blot analysis. Since NRF2 encodes a transcription factor essential for protection against tissue injury, our data have revealed a novel mechanism of cellular defense involving de novo NRF2 protein translation governed by the EF1a interaction with the G-quadruplex in the NRF2 5′ UTR during oxidative stress.

scholarly journals Nrf2 at the heart of oxidative stress and cardiac protection

2018 ◽  
Vol 50 (2) ◽  
pp. 77-97 ◽  
Author(s):  
Qin M. Chen ◽  
Anthony J. Maltagliati
Keyword(s):  
Cancer Biology ◽  
Wound Repair ◽  
De Novo ◽  
Gene Knockout ◽  
Ischemia Reperfusion ◽  
Protein Translation ◽  
Experimental Models ◽  
Matrix Remodeling ◽  
Cardiac Protection ◽  
Nrf2 Protein

The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.

scholarly journals Oxidative Stress in the Male Germline: A Review of Novel Strategies to Reduce 4-Hydroxynonenal Production

Antioxidants ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 132 ◽  
Author(s):  
Jessica Walters ◽  
Geoffry De Iuliis ◽  
Brett Nixon ◽  
Elizabeth Bromfield
Keyword(s):  
Oxidative Stress ◽  
Germ Cells ◽  
Cell Function ◽  
De Novo ◽  
Protein Translation ◽  
Egg Recognition ◽  
Male Germline ◽  
New Strategy ◽  
Artery Disease ◽  
The Stability

Germline oxidative stress is intimately linked to several reproductive pathologies including a failure of sperm-egg recognition. The lipid aldehyde 4-hydroxynonenal (4HNE) is particularly damaging to the process of sperm-egg recognition as it compromises the function and the stability of several germline proteins. Considering mature spermatozoa do not have the capacity for de novo protein translation, 4HNE modification of proteins in the mature gametes has uniquely severe consequences for protein homeostasis, cell function and cell survival. In somatic cells, 4HNE overproduction has been attributed to the action of lipoxygenase enzymes that facilitate the oxygenation and degradation of ω-6 polyunsaturated fatty acids (PUFAs). Accordingly, the arachidonate 15-lipoxygenase (ALOX15) enzyme has been intrinsically linked with 4HNE production, and resultant pathophysiology in various complex conditions such as coronary artery disease and multiple sclerosis. While ALOX15 has not been well characterized in germ cells, we postulate that ALOX15 inhibition may pose a new strategy to prevent 4HNE-induced protein modifications in the male germline. In this light, this review focuses on (i) 4HNE-induced protein damage in the male germline and its implications for fertility; and (ii) new methods for the prevention of lipid peroxidation in germ cells.

scholarly journals La Autoantigen Mediates Oxidant Induced De Novo Nrf2 Protein Translation

2011 ◽  
Vol 11 (6) ◽  
pp. M111.015032 ◽  
Author(s):  
Jack Zhang ◽  
Thai Nho Dinh ◽  
Kyle Kappeler ◽  
George Tsaprailis ◽  
Qin M. Chen
Keyword(s):  
De Novo ◽  
Protein Translation ◽  
Nrf2 Protein

scholarly journals Constitutive translation of human α-synuclein is mediated by the 5′-untranslated region

Open Biology ◽  
2016 ◽  
Vol 6 (4) ◽  
pp. 160022 ◽  
Author(s):  
Pelagia Koukouraki ◽  
Epaminondas Doxakis
Keyword(s):  
Untranslated Region ◽  
Mrna Translation ◽  
Protein Translation ◽  
Serum Starvation ◽  
Mrna Levels ◽  
Entry Site ◽  
Rna Motifs ◽  
Physiological Mechanisms ◽  
Internal Ribosome Entry ◽  
G Quadruplex

Genetic and biochemical studies have established a central role for α-synuclein (SNCA) accumulation in the pathogenesis of Parkinson's disease. Uncovering and subsequently interfering with physiological mechanisms that control SNCA expression is one approach to limit disease progression. To this end, the long and GC-rich 5′-untranslated region (UTR) of SNCA, which is predicted to fold into stable hairpin and G-quadruplex RNA motifs, was investigated for its role in mRNA translation. Inclusion of SNCA 5′-UTR significantly induced expression of both SNCA and luciferase ORF constructs. This effect was not associated with a change in mRNA levels or differential nucleocytoplasmic shuttling. Further, the presence of the 5′-UTR enhanced SNCA synthesis when cap-dependent translation was attenuated with rapamycin treatment. Analysis using multiple methodologies revealed that the 5′-UTR harbours an internal ribosome entry site (IRES) element that spans most of its nucleotide sequence. Signals such as plasma-membrane depolarization, serum starvation and oxidative stress stimulated SNCA protein translation via its 5′-UTR as well as enhanced its IRES activity. Taken together, these data support the idea that the 5′-UTR is an important positive regulator of SNCA synthesis under diverse physiological and pathological conditions, explaining in part the abundance of SNCA in healthy neurons and its accumulation in degenerative cells.

scholarly journals Myocardial ischemic reperfusion induces de novo Nrf2 protein translation

2014 ◽  
Vol 1842 (9) ◽  
pp. 1638-1647 ◽  
Author(s):  
Beibei Xu ◽  
Jack Zhang ◽  
Joshua Strom ◽  
Sang Lee ◽  
Qin M. Chen
Keyword(s):  
De Novo ◽  
Protein Translation ◽  
Ischemic Reperfusion ◽  
Nrf2 Protein

scholarly journals Curcumin activates Nrf2 through PKCδ-mediated p62 phosphorylation at Ser351

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jee-Yun Park ◽  
Hee-Young Sohn ◽  
Young Ho Koh ◽  
Chulman Jo
Keyword(s):  
Oxidative Stress ◽  
Crucial Role ◽  
Curcuma Longa ◽  
Expression Plasmid ◽  
Expression Of Genes ◽  
Nrf2 Activation ◽  
First Time ◽  
Nrf2 Protein ◽  
Endogenous Defense ◽  
In Cells

AbstractCurcumin, a phytochemical extracted from Curcuma longa rhizomes, is known to be protective in neurons via activation of Nrf2, a master regulator of endogenous defense against oxidative stress in cells. However, the exact mechanism by which curcumin activates Nrf2 remains controversial. Here, we observed that curcumin induced the expression of genes downstream of Nrf2 such as HO-1, NQO1, and GST-mu1 in neuronal cells, and increased the level of Nrf2 protein. Notably, the level of p62 phosphorylation at S351 (S349 in human) was significantly increased in cells treated with curcumin. Additionally, curcumin-induced Nrf2 activation was abrogated in p62 knockout (−/−) MEFs, indicating that p62 phosphorylation at S351 played a crucial role in curcumin-induced Nrf2 activation. Among the kinases involved in p62 phosphorylation at S351, PKCδ was activated in curcumin-treated cells. The phosphorylation of p62 at S351 was enhanced by transfection of PKCδ expression plasmid; in contrast, it was inhibited in cells treated with PKCδ-specific siRNA. Together, these results suggest that PKCδ is mainly involved in curcumin-induced p62 phosphorylation and Nrf2 activation. Accordingly, we demonstrate for the first time that curcumin activates Nrf2 through PKCδ-mediated p62 phosphorylation at S351.

scholarly journals Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter

2021 ◽  
Vol 22 (3) ◽  
pp. 1137
Author(s):  
Annalisa Ferino ◽  
Luigi E. Xodo
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Start Site ◽  
Dna Glycosylases ◽  
Repair Pathway ◽  
Transcription Start ◽  
G Quadruplex ◽  
Base Excision ◽  
Regulatory Functions

The promoter of the Kirsten ras (KRAS) proto-oncogene contains, upstream of the transcription start site, a quadruplex-forming motif called 32R with regulatory functions. As guanine under oxidative stress can be oxidized to 8-oxoguanine (8OG), we investigated the capacity of glycosylases 8-oxoguanine glycosylase (OGG1) and endonuclease VIII-like 1 (Neil1) to excise 8OG from 32R, either in duplex or G-quadruplex (G4) conformation. We found that OGG1 efficiently excised 8OG from oxidized 32R in duplex but not in G4 conformation. By contrast, glycosylase Neil1 showed more activity on the G4 than the duplex conformation. We also found that the excising activity of Neil1 on folded 32R depended on G4 topology. Our data suggest that Neil1, besides being involved in base excision repair pathway (BER), could play a role on KRAS transcription.

scholarly journals Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo

2021 ◽  
Vol 22 (4) ◽  
pp. 1707
Author(s):  
Sebastian Granitzer ◽  
Raimund Widhalm ◽  
Martin Forsthuber ◽  
Isabella Ellinger ◽  
Gernot Desoye ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acid ◽  
De Novo ◽  
Structural Similarity ◽  
Amino Acid Transporter ◽  
Cell Number ◽  
Mehg Exposure ◽  
Acid Transporter ◽  
And Oxidative Stress

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.

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