Kei Tobiume1, Atsushi Matsuzawa1, Takumi Takahashi1, Hideki Nishitoh1, Keiichi Morita1, Kohsuke Takeda1, Osamu Minowa2, Kohei Miyazono3, Tetsuo Noda2, Hidenori Ichijo1
1Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University 1‐5‐45 Yushima, Bunkyo‐ku Tokyo 113‐8549 Japan
2Department of Cell Biology, The Cancer Institute, Tokyo, Japanese Foundation for Cancer Research 1‐37‐1 Kami‐Ikebukuro, Toshima‐ku Tokyo 170‐8455 Japan
3Department of Biochemistry, The Cancer Institute, Tokyo, Japanese Foundation for Cancer Research 1‐37‐1 Kami‐Ikebukuro, Toshima‐ku Tokyo 170‐8455 Japan
Tóm tắt
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.
