Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress

Willem Jan Keune, David R. Jones, Yvette Bultsma, Lilly Sommer, Xiao Zhen Zhou, Kun Ping Lu, Nullin Divecha

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Oxidative signaling and oxidative stress contribute to aging, cancer, and diseases resulting from neurodegeneration. Pin1 is a proline isomerase that recognizes phosphorylated substrates and regulates the localization and conformation of its targets. Pin1-/- mice show phenotypes associated with premature aging, yet mouse embryonic fibroblasts (MEFs) from these mice are resistant to hydrogen peroxide (H2O2)-induced cell death. We found that the abundance of phosphatidylinositol-5-phosphate (PtdIns5P) was increased in response to H2O2, an effect that was enhanced in Pin1-/- MEFs. Reduction of H2O2-induced PtdIns5P compromised cell viability in response to oxidative stress, suggesting that PtdIns5P contributed to the enhanced cell viability of Pin1-/- MEFs exposed to oxidative stress. The increased PtdIns5P in the Pin1 -/- MEFs stimulated the expression of genes involved in defense against oxidative stress and reduced the accumulation of reactive oxygen species. Pin1 and PtdIns5P 4-kinases (PIP4Ks), enzymes that phosphorylate and thereby reduce the amount of PtdIns5P, interacted in a manner dependent on the phosphorylation of PIP4K. Although reintroduction of Pin1 into the Pin1 -/- MEFs reduced the amount of PtdIns5P produced in response to H2O2, in vitro assays indicated that the isomerase activity of Pin1 inhibited PIP4K activity. Whether this isomerise-mediated inhibition of PIP4K occurs in cells remains an open question, but the data suggest that the regulation of PIP4K by Pin1 may be complex.
Original languageEnglish
Article numberra86
JournalScience Signaling
Issue number252
Publication statusPublished - 27 Nov 2012

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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