Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

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

RESEARCH ARTICLES

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}picr.man.ac.uk

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).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Low PIP4K2B Expression in Human Breast Tumors Correlates with Reduced Patient Survival: A Role for PIP4K2B in the Regulation of E-Cadherin Expression.
W.-J. Keune, A. H. Sims, D. R. Jones, Y. Bultsma, J. T. Lynch, K. Jirstrom, G. Landberg, and N. Divecha (2013)
Cancer Res. 73, 6913-6925
   Abstract »    Full Text »    PDF »
PI5P migrates out of the PIP shadow.
K. Devereaux and G. Di Paolo (2013)
EMBO Rep. 14, 214-215
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882