ArticleThe Journal of biological chemistry2015
Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Reactive Oxygen Species: A Double-Edged Sword in the Modulation of Cancer Signaling Pathway Dynamics.Cells · 2025Review
- Optimizing Divalent Cation Supplementation to Enhance the Production of the Kimchi Starter StrainJournal of microbiology and biotechnology · 2025Article
- High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension.Journal of translational medicine · 2025Article
- Thioredoxin h2 inhibits the MPKK5-MPK3 cascade to regulate the CBF-COR signaling pathway inHorticulture research · 2023Article
- Emerging Evidence of the Significance of Thioredoxin-1 in Hematopoietic Stem Cell Aging.Antioxidants (Basel, Switzerland) · 2022Review
- Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK-PGC1α Signaling and Limits Oxygen Toxicity.American journal of respiratory cell and molecular biology · 2022Article
- Chaperone-Mediated Autophagy of eNOS in Myocardial Ischemia-Reperfusion Injury.Circulation research · 2021Article
- Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis.Cardiovascular toxicology · 2021Article
- Short-duration hyperoxia causes genotoxicity in mouse lungs: protection by volatile anesthetic isoflurane.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response.International journal of molecular sciences · 2019Article
- Role of Thioredoxin in Age-Related Hypertension.Current hypertension reports · 2018Review
- S-Nitrosylation Regulates Cell Survival and Death in the Central Nervous System.Neurochemical research · 2018Review
- Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function.Science translational medicine · 2017Article
- Thioredoxin Uses a GSH-independent Route to Deglutathionylate Endothelial Nitric-oxide Synthase and Protect against Myocardial Infarction.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The mitogen-activated protein kinase kinase 4 (MKK4) is activated via phosphorylation of Ser-257 and Thr-261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress. We show that thioredoxin (Trx), a cellular redox protein, activates MKK4 via Cys-246 and Cys-266 residues as mutation of these residues renders MKK4 insensitive to phosphorylation by MAP3Ks, TNFα, or Trx. MKK4 is activated in vitro by reduced Trx but not oxidized Trx in the absence of an upstream kinase, suggesting that autophosphorylation of this protein occurs due to reduction of Cys-246 and Cys-266 by Trx. Additionally, mutation of Cys-246 and Cys-266 resulted in loss of kinase activity suggesting that the redox state of Cys-246 and Cys-266 is a critical determinant of MKK4 activation. Trx induces manganese superoxide dismutase (MnSOD) gene transcription by activating MKK4 via redox control of Cys-246 and Cys-266, as mutation of these residues abrogates MKK4 activation and MnSOD expression. We further show that MKK4 activates NFκB for its binding to the MnSOD promoter, which leads to AP-1 dissociation followed by MnSOD transcription. Taken together, our studies show that the redox status of Cys-246 and Cys-266 in MKK4 controls its activities independent of MAP3K, demonstrating integration of the endothelial redox environment to MAPK signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.