Reversible Inactivation of the Tumor Suppressor PTEN by H2O2

These results suggest that the reversible inactivation of PTEN by H2O2 might 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

Seung-Rock Lee; Kap-Seok Yang; Jaeyul Kwon; Chunghee Lee; Woojin Jeong; Sue Goo Rhee


Scholarcy highlights

  • The generation of H2O2 appears to be required, for many normal cellular functions, including propagation of receptor signaling
  • We show that H2O2 induces reversible inactivation of PTEN through oxidation of the essential Cys124 and the formation by this residue of a disulfide with Cys71 and that the PTEN disulfide is reduced by thioredoxin
  • In Vitro Inactivation of PTEN by H2O2 Is Accompanied by the Formation of a Disulfide between the Active Site Cys124 and Cys71—Purified human PTEN was inactivated by H2O2 in a concentration-dependent manner
  • PTEN was inactivated on incubation with xanthine oxidase and xanthine, the combination of which results in the generation of superoxide anions that are subsequently converted to H2O2
  • The 3Ј-phosphorylated phosphoinositides bind and modulate numerous proteins that regulate a variety of cellular functions
  • This observation, together with the fact that PTEN, but not 5-phosphatases, contains an oxidizable cysteine residue at its active site, suggests that in cells exposed to H2O2, PIP3 synthesized by phosphoinositide 3-kinase activity is rapidly dephosphorylated by 5-phosphatases that are insensitive to H2O2, whereas dephosphorylation at the 3Ј position is markedly inhibited as a result of inactivation of PTEN by H2O2
  • Such a specific interaction is supported by the observation that a 14-kDa Trx-related protein was not able to reduce oxidized PTEN despite the fact that it contains a WCXXC motif, which is conserved among members of the thiol-disulfide oxidoreductase superfamily, and that TRP14 and Trx exhibit similar redox potentials and reactivity toward Thioredoxin reductase

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