ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis |
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Authors: | Tobiume K Matsuzawa A Takahashi T Nishitoh H Morita K Takeda K Minowa O Miyazono K Noda T Ichijo H |
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Institution: | Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. |
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Abstract: | Apoptosis signal-regulating kinase (ASK) 1 is activated in response to various cytotoxic stresses including TNF, Fas and reactive oxygen species (ROS) such as H2O2, and activates c-Jun NH2-terminal kinase (JNK) and p38. However, the roles of JNK and p38 signaling pathways during apoptosis have been controversial. Here we show that by deleting ASK1 in mice, TNF- and H2O2-induced sustained activations of JNK and p38 are lost in ASK1–/– embryonic fibroblasts, and that ASK1–/– cells are resistant to TNF- and H2O2-induced apoptosis. TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1–JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis. |
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