Related Experiment Video
Updated: May 21, 2026
Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
Distinct functions of JNK and c-Jun in oxidant-induced hepatocyte death
Muhammad Amir1, Kun Liu, Enpeng Zhao
1Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Abstract:
Overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling is a central mechanism of hepatocyte injury and death including that from oxidative stress. However, the functions of JNK and c-Jun are still unclear, and this pathway also inhibits hepatocyte death. Previous studies of menadione-induced oxidant stress demonstrated that toxicity resulted from sustained JNK/c-Jun activation as death was blocked by the c-Jun dominant negative TAM67. To further delineate the function of JNK/c-Jun signaling in hepatocyte injury from oxidant stress, the effects of direct JNK inhibition on menadione-induced death were examined. In contrast to the inhibitory effect of TAM67, pharmacological JNK inhibition by SP600125 sensitized the rat hepatocyte cell line RALA255-10G to death from menadione. SP600125 similarly sensitized mouse primary hepatocytes to menadione toxicity. Death from SP600125/menadione was c-Jun dependent as it was blocked by TAM67, but independent of c-Jun phosphorylation. Death occurred by apoptosis and necrosis and activation of the mitochondrial death pathway. Short hairpin RNA knockdowns of total JNK or JNK2 sensitized to death from menadione, whereas a jnk1 knockdown was protective. Jnk2 null mouse primary hepatocytes were also sensitized to menadione death. JNK inhibition magnified decreases in cellular ATP content and β-oxidation induced by menadione. This effect mediated cell death as chemical inhibition of β-oxidation also sensitized cells to death from menadione, and supplementation with the β-oxidation substrate oleate blocked death. Components of the JNK/c-Jun signaling pathway have opposing functions in hepatocyte oxidant stress with JNK2 mediating resistance to cell death and c-Jun promoting death.
Insights
The c-Jun N-terminal kinase (JNK)/c-Jun pathway has dual roles in liver cell injury from oxidative stress. JNK2 protects against cell death, while c-Jun promotes it, revealing complex signaling in hepatocyte damage.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Death Signaling
Background:
- c-Jun N-terminal kinase (JNK)/c-Jun signaling is implicated in hepatocyte injury and death, particularly from oxidative stress.
- Previous studies suggested sustained JNK/c-Jun activation contributes to menadione-induced oxidant stress toxicity.
- The precise roles of JNK and c-Jun in this pathway remain incompletely understood, with evidence suggesting both pro- and anti-death functions.
Purpose of the Study:
- To investigate the specific functions of JNK and c-Jun signaling in hepatocyte injury induced by menadione-mediated oxidative stress.
- To delineate the opposing roles of JNK isoforms and c-Jun in regulating cell death pathways during oxidative stress.
Main Methods:
- Utilized pharmacological JNK inhibition (SP600125) and dominant-negative c-Jun (TAM67) in rat and mouse primary hepatocytes.
- Employed short hairpin RNA (shRNA) knockdowns for total JNK, JNK1, and JNK2, as well as Jnk2 null primary hepatocytes.
- Assessed cell death mechanisms including apoptosis, necrosis, mitochondrial pathway activation, ATP content, and beta-oxidation.
Main Results:
- Pharmacological JNK inhibition sensitized hepatocytes to menadione-induced death, contrasting with the protective effect of c-Jun inhibition (TAM67).
- JNK inhibition-induced death was c-Jun dependent but independent of c-Jun phosphorylation, involving apoptosis, necrosis, and mitochondrial pathway activation.
- JNK2 knockdown or deficiency sensitized cells to menadione toxicity, while JNK1 knockdown was protective, indicating opposing roles for JNK isoforms.
Conclusions:
- Components of the JNK/c-Jun pathway exhibit opposing functions in hepatocyte response to oxidative stress.
- JNK2 acts as a mediator of resistance to cell death, whereas c-Jun promotes cell death.
- These findings highlight the complex, context-dependent roles of JNK/c-Jun signaling in liver injury and provide targets for therapeutic intervention.
Related Concept Videos
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
01:20The JAK-STAT Signaling Pathway
01:30Apoptosis