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Sci. Signal., 27 November 2012
Vol. 5, Issue 252, p. ra86
[DOI: 10.1126/scisignal.2003223]


Regulation of Phosphatidylinositol-5-Phosphate Signaling by Pin1 Determines Sensitivity to Oxidative Stress

Willem-Jan Keune1, David R. Jones1, Yvette Bultsma1, Lilly Sommer1, Xiao Zhen Zhou2, Kun Ping Lu2, and Nullin Divecha1*

1 CRUK Inositide Laboratory, Paterson Institute for Cancer Research (PICR), The University of Manchester, Manchester M20 4BX, UK.
2 Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.

Abstract: 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.

* To whom correspondence should be addressed. E-mail: ndivecha{at}

Citation: W.-J. Keune, D. R. Jones, Y. Bultsma, L. Sommer, X. Z. Zhou, K. P. Lu, N. Divecha, Regulation of Phosphatidylinositol-5-Phosphate Signaling by Pin1 Determines Sensitivity to Oxidative Stress. Sci. Signal. 5, ra86 (2012).

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