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Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell death

M D Jacobsen1, M Weil, M C Raff

  • 1MRC Laboratory for Molecular Cell Biology, University College London, United Kingdom.

The Journal of Cell Biology
|June 1, 1996
PubMed

Insights

Staurosporine (STS) induces programmed cell death (PCD) in mammalian cells. A protease inhibitor, zVAD-fmk, blocks STS-induced PCD, confirming it as a genuine cell death pathway and implicating CPP32-family proteases in the process.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Biochemistry

Background:

  • Staurosporine (STS) induces apoptotic cell death in mammalian cells, suggesting constitutive expression of programmed cell death (PCD) machinery.
  • The Ced-3/Interleukin-1 beta converting enzyme (ICE) family of cysteine proteases are implicated in PCD.
  • Reliable evidence is needed to confirm STS-induced cell death as bona fide PCD.

Purpose of the Study:

  • To confirm that STS-induced cell death is a genuine example of PCD.
  • To investigate the role of Ced-3/ICE family proteases in STS-induced PCD.
  • To explore the utility of protease inhibitors in studying PCD during development.

Main Methods:

  • Treatment of mammalian cells and anucleate cytoplasts with staurosporine (STS) and cycloheximide (CHX).
  • Inhibition of STS-induced cell death using Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a cysteine protease inhibitor.
  • Analysis of CPP32 activation and its inhibition by Bcl-2.
  • Assessment of zVAD-fmk effects on PCD in developing mouse interdigital webs.

Main Results:

  • zVAD-fmk suppressed STS-induced and (STS + CHX)-induced cell death in various mammalian cell types, including anucleate cytoplasts, validating them as PCD.
  • CPP32, a Ced-3/ICE family member, was activated during STS-induced PCD, and Bcl-2 inhibited this activation.
  • CPP32-family members, but not ICE, were required for STS-induced PCD in some cells.
  • zVAD-fmk inhibited PCD in developing mouse paws, preventing web tissue removal during digit development.

Conclusions:

  • STS-induced cell death in mammalian cells is a bona fide example of PCD.
  • CPP32-family proteases play a crucial role in STS-induced PCD.
  • Protease inhibitors like zVAD-fmk are valuable tools for studying PCD in developmental processes.

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