title: Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress.
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.
authors.affiliation: CRUK Inositide Laboratory, Paterson Institute for Cancer Research, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Keune
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Yvette
authors.initials: Y
authors.lastname: Bultsma
authors.forename: Lilly
authors.initials: L
authors.lastname: Sommer
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.forename: Nullin
authors.initials: N
authors.lastname: Divecha
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016877:Oxidants; D018129:Phosphatidylinositol Phosphates; C113567:phosphatidylinositol 5-phosphate; D006861:Hydrogen Peroxide; D017853:Phosphotransferases (Alcohol Group Acceptor); C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse