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p38 mitogen-activated protein kinase mediates bid cleavage, mitochondrial dysfunction, and caspase-3 activation

S Zhuang1, J T Demirs, I E Kochevar

  • 1Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

The Journal of Biological Chemistry
|June 6, 2000
PubMed

Insights

p38 mitogen-activated protein kinase and caspase-8 mediate apoptosis differently. p38 and caspase-8 act upstream of Bid in singlet oxygen-induced apoptosis, while only caspase-8 mediates H(2)O(2)-induced apoptosis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • p38 mitogen-activated protein kinase (MAPK) activation is implicated in apoptosis.
  • Signaling pathways linking p38 to caspase-3 activation remain unclear.
  • Reactive oxygen species (ROS) like singlet oxygen and hydrogen peroxide (H(2)O(2)) can induce apoptosis.

Purpose of the Study:

  • To elucidate the signaling events downstream of p38 that lead to caspase-3 activation.
  • To differentiate the roles of p38 and caspase-8 in apoptosis induced by singlet oxygen and H(2)O(2).

Main Methods:

  • Human leukemia cells were treated with singlet oxygen or H(2)O(2).
  • p38 phosphorylation was assessed.
  • Apoptosis was evaluated using DNA fragmentation assays.
  • Inhibitors of p38 (SB203580) and caspase-8 (Ile-Glu-Thr-Asp-fluoromethyl ketone) were used.
  • Mitochondrial events (Bid cleavage, mitochondrial membrane potential, cytochrome c release) were analyzed.

Main Results:

  • Singlet oxygen and H(2)O(2) stimulated p38 phosphorylation.
  • SB203580 inhibited DNA fragmentation and caspase-3 activation induced by singlet oxygen but not H(2)O(2).
  • SB203580 affected Bid cleavage, mitochondrial membrane potential, and cytochrome c release, but not caspase-8 cleavage.
  • Caspase-8 blockade prevented DNA fragmentation and downstream events (except p38 phosphorylation) in both singlet oxygen- and H(2)O(2)-treated cells.

Conclusions:

  • Caspase-3 activation in singlet oxygen-induced apoptosis involves parallel pathways regulated by p38 and caspase-8 acting upstream of Bid.
  • Hydrogen peroxide-induced apoptosis relies solely on a caspase-8-mediated pathway for caspase-3 activation.

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