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EMBO reports 2, 3, 222–228 (2001)
doi:10.1093/embo-reports/kve046
Published online: March 2001
ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis
Kei Tobiume1, 4, Atsushi Matsuzawa1, 4, Takumi Takahashi1, Hideki Nishitoh1, Kei-ichi Morita1, Kohsuke Takeda1, Osamu Minowa2, Kohei Miyazono3, Tetsuo Noda2 & Hidenori Ichijo1
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1 Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan
2 Department of Cell Biology, The Cancer Institute, Tokyo, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
3 Department of Biochemistry, The Cancer Institute, Tokyo, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
4 K. Tobiume and A. Matsuzawa contributed equally to this work
To whom correspondence should be addressed
Hidenori Ichijo Tel: +81-3-5803-5471; Fax: +81-3-5803-0192; ichijo.csi@tmd.ac.jp
Received 17 December 2000; Accepted 19 January 2001.
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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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