Reversible Inactivation of the Tumor Suppressor PTEN by H2O2 *

By Seung-Rock Lee, Kap-Seok Yang, J. Kwon, Chunghee Lee, W. Jeong, S. Rhee. Journal of Biological Chemistry, 2002

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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 oxidized PTEN in vitro. Thioredoxin co-immunoprecipitated with PTEN from cell lysates; and incubation of cells with 2,4-dinitro-1-chlorobenzene (an inhibitor of thioredoxin reductase) delayed the reduction of oxidized PTEN, whereas incubation with buthioninesulfoximine (an inhibitor of glutathione biosynthesis) did not. These results suggest that the reversible inactivation of PTEN by H2O2might be important for the accumulation of 3′-phosphorylated phosphoinositides and that the uncontrolled generation of H2O2 associated with certain pathological conditions might contribute to cell proliferation by inhibiting PTEN function.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/667e78b4b39b11e8b1948902174dcb208e23f1dc

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Citations in the corpus

Cytokines in Radiobiological Responses: A Review (2012, neutral): “Other ROS-responsive molecules of importance in radiobiology would include the protein mutated in ataxia-telangiectasia (ATM) (40), redox-sensitive phosphatases that may be responsible for rapid phosphorylation of EGFR and PDGFR (41) after irradiation and that can lead to further ROS generation (42)”
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Reactive oxygen species in cancer (2010, background): “[93] Lee SR, et al. Reversible inactivation of the tumor suppressor PTEN by H2O2.”
ROS Function in Redox Signaling and Oxidative Stress (2014, background): “Purified human PTEN is inactivated by H2O2 through oxidation and disulfide bond formation between Cys121 and Cys71, a modification reversed by thioredoxin activity [27].”
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