title: PtdIns5P and Pin1 in oxidative stress signaling.
abstract: Oxidative signaling is important in cellular health, involved in aging and contributes to the development of several diseases such as cancer, neurodegeneration and diabetes. Correct management of reactive oxygen species (ROS) prevents oxidative stress within cells and is imperative for cellular wellbeing. A key pathway that is regulated by oxidative stress is the activation of proline-directed stress kinases (p38, JNK). Phosphorylation induced by these kinases is often translated into cellular outcome through the recruitment of the prolyl-isomerase Pin1. Pin1 binds to phosphorylated substrates using its WW-domain and can induce conformational changes in the target protein through its prolyl-isomerase activity. We show that exposure of cells to UV irradiation or hydrogen peroxide (H₂O₂), induces the synthesis of the phosphoinositide second messenger PtdIns5P in part by inducing the interaction between phosphatidylinositol-5-phosphate 4-kinase (PIP4K) enzymes that remove PtdIns5P, with Pin1. In response to H₂O₂ exposure, Murine Embryonic Fibroblasts (MEFs) derived from Pin1⁻/⁻ mice showed increased cell viability and an increased abundance of PtdIns5P compared to wild-type MEFs. Decreasing the levels of PtdIns5P in Pin1⁻/⁻ MEFs decreased both their viability in response to H₂O₂ exposure and the expression of genes required for cellular ROS management. The decrease in the expression of these genes manifested itself in the increased accumulation of cellular ROS. These data strongly argue that PtdIns5P acts as a stress-induced second messenger that can calibrate how cells manage ROS.
authors.affiliation: Inositide Laboratory CRUK, The Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom. wjkeune@hotmail.com
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Keune
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Nullin
authors.initials: N
authors.lastname: Divecha
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018384:Oxidative Stress / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018129:Phosphatidylinositol Phosphates; D017382:Reactive Oxygen Species; C113567:phosphatidylinositol 5-phosphate; D006861:Hydrogen Peroxide; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse