Activation of C-Jun N-terminal kinase is required for glutathione transferase A4 induction during oxidative stress, not during cell proliferation, in mouse hepatocytes.
Expression of the mouse glutathione transferase Alpha 4 (mGSTA4) has been studied during hepatocyte isolation and in cultured hepatocytes. Transient mGSTA4 induction during liver disruption correlated to strong oxidative stress and induction of the Jun N-terminal kinase (JNK) pathway. Similarly, tumor necrosis factor alpha induced both JNK phosphorylation and mGSTA4 expression while specific JNK inhibitor JNKI1 prevented these two events and JNK activator anisomycin strongly induced mGSTA4 expression. We also found that endogenous JNK and mGSTA4 co-immunoprecipitate. A second mGSTA4 induction occurred 2 days after cell seeding concomitantly to DNA replication and was prevented by treatment with mitogen-activated protein kinase (MEK) inhibitor U0126. Our data demonstrate that mGSTA4 is strongly increased during oxidative stress possibly via JNK pathway and during proliferation via MEK/extracellular signal-regulated kinase pathway, and suggest that mGSTA4 might be an endogenous regulator of JNK activity by direct binding.
Desmots
Fabienne
F
INSERM U620, Université de Rennes I, IFR140, France.
Loyer
Pascal
P
Rissel
Maryvonne
M
Guillouzo
André
A
Morel
Fabrice
F
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004261:DNA Replication; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000201:enzymology*; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D002070:Butadienes; D009570:Nitriles; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; C041116:leukotriene-C4 synthase