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

J Cell Biochem. 2012 Oct;113(10):3254-65. doi: 10.1002/jcb.24203.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenoviridae / genetics
  • Adenoviridae / metabolism
  • Animals
  • Anthracenes / pharmacology
  • Cell Death
  • Cell Line, Transformed
  • Drug Resistance
  • Gene Knockdown Techniques
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology*
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 9 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 9 / genetics
  • Mitogen-Activated Protein Kinase 9 / metabolism*
  • Oleic Acid / pharmacology
  • Oxidation-Reduction
  • Oxidative Stress
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Vitamin K 3 / toxicity*


  • Anthracenes
  • Peptide Fragments
  • Proto-Oncogene Proteins c-jun
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • TAM67 peptide
  • pyrazolanthrone
  • Oleic Acid
  • Vitamin K 3
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase 9