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    Regulation of phosphatidylinositol-5-phosphate signaling by pin1 determines sensitivity to oxidative stress.

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    Authors
    Keune, Willem-Jan
    Jones, David R
    Bultsma, Yvette
    Sommer, Lilly
    Zhou, X
    Lu, K
    Divecha, Nullin
    Affiliation
    CRUK Inositide Laboratory, Paterson Institute for Cancer Research (PICR), The University of Manchester, Manchester M20 4BX, UK.
    Issue Date
    2012
    
    Metadata
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    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 (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 Signal
    Journal
    Science Signaling
    URI
    http://hdl.handle.net/10541/265195
    DOI
    10.1126/scisignal.2003223
    PubMed ID
    23193159
    Type
    Article
    Language
    en
    ISSN
    1937-9145
    ae974a485f413a2113503eed53cd6c53
    10.1126/scisignal.2003223
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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