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Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase

T Hatai1, A Matsuzawa, S Inoshita

  • 1Laboratory of Cell Signaling, Department of Hard Tissue Engineering, Division of Bio-Matrix, the Maxillofacial Orthognathics, Tokyo Medical and Dental University, Tokyo, Japan.

The Journal of Biological Chemistry
|June 13, 2000
PubMed

Insights

Apoptosis Signal-regulating Kinase 1 (ASK1) triggers cell death via mitochondria and caspases. ASK1 activates caspase-9 and caspase-3, leading to apoptosis, independent of caspase-8.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Apoptosis Signal-regulating Kinase 1 (ASK1) is a key signaling molecule in stress- and cytokine-induced apoptosis.
  • The precise mechanisms by which ASK1 induces apoptosis, particularly the roles of caspases and mitochondria, remain incompletely understood.

Purpose of the Study:

  • To elucidate the roles of caspases and mitochondria in ASK1-mediated apoptosis.
  • To determine the specific caspase activation pathways involved in ASK1-induced cell death.

Main Methods:

  • Investigated ASK1-induced apoptosis using a constitutively active mutant (ASK1DeltaN).
  • Utilized caspase inhibitors (zVAD-fmk) and gene-deficient cells (caspase-8 and caspase-9 knockout).
  • Monitored cytochrome c release from mitochondria and caspase activation (caspase-3, -8, -9).

Main Results:

  • Caspase inhibition (zVAD-fmk) largely prevented ASK1-induced cell death, indicating caspase dependence.
  • ASK1DeltaN overexpression induced mitochondrial cytochrome c release and activated caspase-9 and caspase-3.
  • Caspase-8-deficient cells remained sensitive to ASK1, while caspase-9-deficient cells did not activate caspase-3.
  • Mitochondrial cytochrome c release preceded caspase-3 activation and cell death.

Conclusions:

  • ASK1 executes apoptosis primarily through the mitochondria-dependent activation of caspases.
  • The intrinsic caspase pathway, involving caspase-9 and caspase-3, is crucial for ASK1-induced apoptosis.
  • Caspase-8 is not essential for ASK1-mediated cell death.

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