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ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis

K Tobiume1, A Matsuzawa, T Takahashi

  • 1Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.

EMBO Reports
|March 27, 2001
PubMed

Insights

Apoptosis signal-regulating kinase 1 (ASK1) is crucial for TNF and oxidative stress-induced apoptosis by activating JNK and p38 pathways. ASK1 deletion confers resistance to these apoptotic stimuli.

Area of Science:

  • Cellular biology
  • Molecular signaling pathways
  • Apoptosis research

Background:

  • Apoptosis signal-regulating kinase 1 (ASK1) is activated by cytotoxic stresses like TNF and ROS.
  • The roles of downstream JNK and p38 signaling in apoptosis remain debated.
  • ASK1 links stress signals to cell death pathways.

Purpose of the Study:

  • To investigate the specific role of ASK1 in TNF- and oxidative stress-induced apoptosis.
  • To elucidate the involvement of ASK1-mediated JNK/p38 activation in these processes.
  • To determine if ASK1 is essential for sustained JNK/p38 activation during apoptosis.

Main Methods:

  • Gene deletion of ASK1 in mice (ASK1-/-).
  • Analysis of embryonic fibroblasts (ASK1-/- cells).
  • Assessment of JNK and p38 activation in response to TNF and H2O2.
  • Evaluation of apoptosis induction.

Main Results:

  • ASK1-/- embryonic fibroblasts showed abolished sustained JNK and p38 activation upon TNF or H2O2 treatment.
  • ASK1-/- cells exhibited resistance to TNF- and H2O2-induced apoptosis.
  • TNF-induced apoptosis, but not Fas-induced apoptosis, was dependent on ROS-mediated ASK1-JNK/p38 activation.

Conclusions:

  • ASK1 is selectively required for sustained JNK/p38 activation and apoptosis induced by TNF and oxidative stress.
  • The ASK1-JNK/p38 pathway is a critical mediator of specific stress-induced cell death.
  • ASK1 plays a non-redundant role in TNF and ROS signaling pathways leading to apoptosis.

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