Hydrogen peroxide-induced liver cell necrosis is dependent on AP-1 activation.
To determine whether intracellular signaling events involved in apoptosis may also mediate necrosis, the role of the transcription factor AP-1 was investigated in a hepatoma cell model of cellular necrosis induced by oxidant stress. Treatment of the human hepatoma cell line HuH-7 with H2O2 caused dose-dependent necrosis as determined by light microscopy, fluorescent staining, and an absence of DNA fragmentation. H2O2 treatment led to increases in c-fos and c-jun mRNA levels, Jun nuclear kinase activity, and AP-1 DNA binding. AP-1 transcriptional activity measured with an AP-1-driven luciferase reporter gene was also increased. To determine whether this AP-1 activation contributed to H2O2-induced cell necrosis, HuH-7 cells were stably transfected with an antisense c-jun expression vector. Cells expressing antisense c-jun had decreased levels of AP-1 activation and significantly increased survival after H2O2 exposure. These data indicate that AP-1 activation occurs during oxidant-induced cell necrosis and contributes to cell death. Necrosis is therefore not always a passive process but may involve the activation of intracellular signaling pathways similar to those that mediate apoptosis.
Xu
Y
Y
Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Bradham
C
C
Brenner
D A
DA
Czaja
M J
MJ
D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D053938:DNA Fragmentation; D017930:Genes, Reporter; D016758:Genes, jun; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000096:biosynthesis; D009336:Necrosis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D008156:Luciferases; D005978:Glutathione