PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.

Abstract

Oxidative stress initiates signaling pathways, which protect from stress-induced cellular damage, initiate apoptosis, or drive cells into senescence or into tumorigenesis. Oxidative stress regulates the activity of the cell survival factor PKB, through the regulation of PtdIns(3,4,5)P₃ synthesis. Whether oxidative stress regulates other phosphoinositides to control PKB activation is not clear. Here we show that PtdIns5P is a redox-regulated second messenger. In response to hydrogen peroxide (H₂O₂), we measured an increase in PtdIns5P in cells derived from human osteosarcoma, U2OS (5-fold); breast tumors, MDA-MB-468 (2-fold); and fibrosarcoma, HT1080 (3-fold); and in p53-null murine embryonic fibroblasts (8-fold). In U2OS cells, the increase in H₂O₂-dependent PtdIns5P did not require mTOR, PDK1, PKB, ERK, and p38 signaling or PIKfyve, a lipid kinase that increases PtdIns5P in response to osmotic and oncogenic signaling. A reduction in H₂O₂-induced PtdIns5P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H₂O₂-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H₂O₂. These data suggest that inhibition of PIP4K signaling might be useful as a novel strategy to increase the susceptibility of tumor cells to therapeutics that function through increased oxidative stress.

• Authors: David R Jones, Rebecca Foulger, Willem-Jan Keune, Yvette Bultsma, Nullin Divecha
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 4 Pg. 1644-56 (Apr 2013) ISSN: 1530-6860 [Electronic] United States
• PMID: 23241309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphatidylinositol Phosphates
• phosphatidylinositol 5-phosphate
• Hydrogen Peroxide
• 3-Phosphoinositide-Dependent Protein Kinases
• PDPK1 protein, human
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• 3-Phosphoinositide-Dependent Protein Kinases
• Cell Survival (drug effects)
• Cells, Cultured
• Enzyme Activation
• Humans
• Hydrogen Peroxide (pharmacology)
• Oxidation-Reduction
• Oxidative Stress (drug effects, physiology)
• Phosphatidylinositol Phosphates (metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Second Messenger Systems (physiology)
• p38 Mitogen-Activated Protein Kinases (metabolism)