Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation.
Oxidative stress is known to induce apoptosis in a wide variety of cell types, apparently by modulating intracellular signaling pathways. High concentrations of H2O2 have been found to induce apoptosis in L929 mouse fibroblast cells. To elucidate the mechanisms of H2O2-mediated apoptosis, ERK1/2, p38-MAPK, and JNK1/2 phosphorylation was examined, and ERK1/2 and JNK1/2 were found to be activated by H2O2. Inhibition of ERK1/2 activation by treatment of L929 cells with PD98059 or dominant-negative ERK2 transfection blocked H2O2-induced apoptosis, while inhibition of JNK1/2 by dominant-negative JNK1 or JNK2 or MKK4 or MKK7 transfection did not affect H2O2-mediated apoptosis. H2O2-mediated ERK1/2 activation was not only Ras-Raf dependent, but also both tyrosine kinase (PDGFbeta receptor and Src) and PKCdelta dependent. H2O2-mediated PKCdelta-dependent and tyrosine kinase-dependent ERK1/2 activations were independent from each other. Based on the above results, we suggest for the first time that oxidative damage-induced apoptosis is mediated by ERK1/2 phosphorylation which is not only Ras-Raf dependent, but also both tyrosine kinase and PKCdelta dependent.
Lee
Yoon-Jin
YJ
Division of Molecular Life Sciences, Ewha Woman's University, College of Natural Science, Seoul 120-750, Korea.
Cho
Hae-Nyun
HN
Soh
Jae-Won
JW
Jhon
Gil Ja
GJ
Cho
Chul-Koo
CK
Chung
Hee-Yong
HY
Bae
Sangwoo
S
Lee
Su-Jae
SJ
Lee
Yun-Sil
YS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D011518:Proto-Oncogene Proteins; D006861:Hydrogen Peroxide; D010770:Phosphotransferases; C497259:Prkcd protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one