ArticleCell death & disease2017
The role of MAP2 kinases and p38 kinase in acute murine liver injury models.
Article in Cell death & disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
What it found
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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.
The trial behind it
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
39 citing papers in PubMed, 65 citations in OpenAlex.
- Mitogen-activated protein kinase kinase 4 (MKK4) as a promising therapeutic target in liver diseases: a review.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Off-Target MAP2K7 Inhibition Drives the Antileukemic Activity of the PD-1/PD-L1 inhibitor ACS-69 in Pediatric T-ALL.Research square · 2026Article
- Reactive oxygen species and peroxynitrite in acetaminophen-induced liver injury: Lipid peroxidation and ferroptosis-like cell death.Ferroptosis and oxidative stress · 2026Article
- AIBP protects drug-induced liver injury by inhibiting MAPK-mediated NR4A1 expression.iScience · 2024Article
- Regular Consumption of Green Tea as an Element of Diet Therapy in Drug-Induced Liver Injury (DILI).Nutrients · 2024Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.Annual review of pathology · 2024Review
- Mitochondrial P-JNK target, SAB (SH3BP5), in regulation of cell death.Frontiers in cell and developmental biology · 2024Review
- Components of the JNK-MAPK pathway play distinct roles in hepatocellular carcinoma.Journal of cancer research and clinical oncology · 2023Article
- Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection.iScience · 2023Article
- JNK Cascade-Induced Apoptosis-A Unique Role in GqPCR Signaling.International journal of molecular sciences · 2023Review
- Downregulation of hepatic METTL3 contributes to APAP-induced liver injury in mice.JHEP reports : innovation in hepatology · 2023Article
- c-Antioxidants & redox signaling · 2023Article
- The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets.Experimental biology and medicine (Maywood, N.J.) · 2023Review
- Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease.Biomedicines · 2022Review
- Review
- 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
- Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.Archives of toxicology · 2022Review
- MKK4 Knockdown Plays a Protective Role in Hemorrhagic Shock-Induced Liver Injury through the JNK Pathway.Oxidative medicine and cellular longevity · 2022Article
- Microtubule Organization Is Essential for Maintaining Cellular Morphology and Function.Oxidative medicine and cellular longevity · 2022Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
c-Jun N-terminal kinase (JNK) mediates hepatotoxicity through interaction of its phospho-activated form with a mitochondrial outer membrane protein, Sh3bp5 or Sab, leading to dephosphorylation of intermembrane Src and consequent impaired mitochondrial respiration and enhanced ROS release. ROS production from mitochondria activates MAP3 kinases, such as MLK3 and ASK1, which continue to activate a pathway to sustain JNK activation, and amplifies the toxic effect of acetaminophen (APAP) and TNF/galactosamine (TNF/GalN). Downstream of MAP3K, in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK. The relative role of MKK4 versus 7 in liver injury is largely unexplored, as is the potential role of p38 kinase, which might be a key mediator of toxicity in addition to JNK. Antisense oligonucleotides (ASO) to MKK4, MKK7 and p38 (versus scrambled control) were used for in vivo knockdown, and in some experiments PMH were used after in vivo knockdown. Mice were treated with APAP or TNF/GalN and injury assessed. MKK4 and MKK7 were expressed in liver and each was efficiently knocked down with two different ASOs. Massive liver injury and ALT elevation were abrogated by MKK4 but not MKK7 ASO pretreatment in both injury models. The protection was confirmed in PMH. Knockdown of MKK4 completely inhibited basal P-p38 in both cytoplasm and mitochondria. However, ALT levels and histologic injury in APAP-treated mice were not altered with p38 knockdown versus scrambled control. p38 knockdown significantly increased P-JNK levels in cytoplasm but not mitochondria after APAP treatment. In conclusion, MKK4 is the major MAP2K, which activates JNK in acute liver injury. p38, the other downstream target of MKK4, does not contribute to liver injury from APAP or TNF/galactosamine.
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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.