Distinct functions of JNK and c-Jun in oxidant-induced hepatocyte death

Muhammad Amir, Kun Liu, Enpeng Zhao, Mark J. Czaja

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3254-3265
Number of pages12
JournalJournal of Cellular Biochemistry
Volume113
Issue number10
DOIs
StatePublished - Oct 2012

Fingerprint

Vitamin K 3
JNK Mitogen-Activated Protein Kinases
Oxidants
Hepatocytes
Cell death
Oxidation
Cell Death
Toxicity
Chemical activation
Phosphorylation
Oxidative stress
Oleic Acid
Small Interfering RNA
Rats
Wounds and Injuries
Adenosine Triphosphate
Cells
Apoptosis
Oxidative Stress
Necrosis

Keywords

  • Apoptosis
  • ATP
  • fatty acid oxidation
  • menadione
  • necrosis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Distinct functions of JNK and c-Jun in oxidant-induced hepatocyte death. / Amir, Muhammad; Liu, Kun; Zhao, Enpeng; Czaja, Mark J.

In: Journal of Cellular Biochemistry, Vol. 113, No. 10, 10.2012, p. 3254-3265.

Research output: Contribution to journalArticle

Amir, Muhammad ; Liu, Kun ; Zhao, Enpeng ; Czaja, Mark J. / Distinct functions of JNK and c-Jun in oxidant-induced hepatocyte death. In: Journal of Cellular Biochemistry. 2012 ; Vol. 113, No. 10. pp. 3254-3265.
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