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Inhibition of tyrosine phosphatases induces apoptosis independent from the CD95 system

S P Hehner1, T G Hofmann, W Dröge

  • 1Department of Immunochemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Germany.

Cell Death and Differentiation
|October 8, 1999
PubMed

Insights

Pervanadate induces apoptosis in lymphoid cells by inhibiting protein tyrosine phosphatases, activating caspases, and releasing cytochrome C. This cell death pathway is independent of CD95 and FADD but can be modulated by Bcl-2.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Protein tyrosine phosphatases (PTPs) regulate crucial cellular processes, including immune cell activation.
  • Pervanadate is a known inhibitor of PTPs and activator of B- and T-cells.
  • Apoptosis, or programmed cell death, is vital for immune system homeostasis.

Purpose of the Study:

  • To investigate the mechanism of pervanadate-induced apoptosis in lymphoid cells.
  • To determine the signaling pathways and molecular players involved in this apoptotic process.
  • To elucidate whether the CD95/FADD death receptor pathway mediates pervanadate-induced cell death.

Main Methods:

  • Treatment of lymphoid cell lines with pervanadate.
  • Inhibition of apoptosis using herbimycin A (tyrosine kinase inhibitor).
  • Analysis of caspase activation (caspases 3, 8, 9), mitochondrial permeability transition, cytochrome C release, and DNA fragmentation.
  • Assessment of apoptosis in T-cells with altered CD95, caspase-8, FADD, p56lck, CD45, or Bcl-2 expression.

Main Results:

  • Pervanadate efficiently induced apoptosis in lymphoid cells, characterized by caspase activation, mitochondrial dysfunction, cytochrome C release, and DNA fragmentation.
  • Pervanadate-induced apoptosis was blocked by herbimycin A, indicating a role for tyrosine kinases.
  • Cells deficient in CD95 or caspase-8, or overexpressing dominant-negative FADD, remained susceptible to pervanadate, ruling out CD95/FADD-dependent pathways.
  • The process did not require p56lck or CD45, but Bcl-2 overexpression conferred protection against pervanadate-induced apoptosis.

Conclusions:

  • Pervanadate induces apoptosis in lymphoid cells through a mechanism involving PTP inhibition, caspase activation, and mitochondrial pathways.
  • The CD95/FADD death receptor pathway is not involved in pervanadate-elicited apoptosis.
  • Bcl-2 plays a role in regulating this apoptotic process, likely by modulating mitochondrial events and caspase activation.

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