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Reversible inactivation of the tumor suppressor PTEN by H2O2

Seung-Rock Lee1, Kap-Seok Yang, Jaeyul Kwon

  • 1Laboratory of Cell Signaling, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-8015, USA. sgrhee@nih.gov

The Journal of Biological Chemistry
|March 28, 2002
PubMed

Insights

Hydrogen peroxide (H2O2) reversibly inactivates the tumor suppressor phosphatase and tensin homolog (PTEN) by forming a disulfide bond. Thioredoxin primarily reduces oxidized PTEN in cells, suggesting a role in regulating cell growth.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • The tumor suppressor PTEN is crucial for regulating cell migration, growth, and survival.
  • PTEN functions by dephosphorylating phosphoinositides at the 3' position.

Purpose of the Study:

  • To investigate the mechanism of PTEN inactivation by hydrogen peroxide (H2O2).
  • To identify the cellular reductant responsible for reactivating oxidized PTEN.

Main Methods:

  • Oxidation of purified PTEN and cell-based assays with H2O2.
  • Site-directed mutagenesis of PTEN cysteine residues.
  • Mass spectrometry to identify disulfide bond formation.
  • In vitro and in vivo assays using various reducing agents and inhibitors.

Main Results:

  • H2O2 inactivates PTEN in a time- and concentration-dependent manner.
  • Cys124 in PTEN's active site forms a disulfide bond with Cys71 upon oxidation by H2O2.
  • Thioredoxin, not glutaredoxin or glutathione, efficiently reduces oxidized PTEN in vitro and in cells.
  • Inhibition of thioredoxin reductase, but not glutathione biosynthesis, delays PTEN reactivation.

Conclusions:

  • Reversible PTEN inactivation by H2O2 may regulate 3'-phosphorylated phosphoinositides.
  • Uncontrolled H2O2 generation in pathological conditions could inhibit PTEN, promoting cell proliferation.

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