Regulation of phosphatidylinositol-5-phosphate signaling by pin1 determines sensitivity to oxidative stress.
Affiliation
CRUK Inositide Laboratory, Paterson Institute for Cancer Research (PICR), The University of Manchester, Manchester M20 4BX, UK.Issue Date
2012
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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 (H(2)O(2))-induced cell death. We found that the abundance of phosphatidylinositol-5-phosphate (PtdIns5P) was increased in response to H(2)O(2), an effect that was enhanced in Pin1(-/-) MEFs. Reduction of H(2)O(2)-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 H(2)O(2), 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.Citation
Regulation of phosphatidylinositol-5-phosphate signaling by pin1 determines sensitivity to oxidative stress. 2012, 5 (252):ra86 Sci SignalJournal
Science SignalingDOI
10.1126/scisignal.2003223PubMed ID
23193159Type
ArticleLanguage
enISSN
1937-9145ae974a485f413a2113503eed53cd6c53
10.1126/scisignal.2003223
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