Reversible Inactivation of the Tumor Suppressor PTEN by H2O2

The tumor suppressor PTEN regulates cell migration, growth, and survival by removing the 3′-phosphate of phosphoinositides. Exposure of purified PTEN or of cells to H2O2 resulted in inactivation of PTEN in a time- and H2O2concentration-dependent manner. Analysis of various cysteine mutants, including mass spectrometry of tryptic peptides, indicated that the essential Cys124 residue in the active site of PTEN specifically forms a disulfide with Cys71during oxidation by H2O2. The reduction of H2O2-oxidized PTEN in cells appears to be mediated predominantly by thioredoxin. Thus, thioredoxin was more efficient than glutaredoxin, glutathione, or a 14-kDa thioredoxin-like protein with regard to the reduction of…