PtdIns5P is an oxidative stress‐induced second messenger that regulates PKB activation. Issue 4 (14th December 2012)

• Record Type: Journal Article
• Authors: Jones, David R.; Foulger, Rebecca; Keune, Willem‐Jan; Bultsma, Yvette; Divecha, Nullin
• Is Part Of: FASEB journal. Volume 27:Issue 4(2013)
• Page Start: 1644
• Page End: 1656
• Publication Date: 2012-12-14
• Subjects: phosphoinositide -- phosphatidylinositol‐5‐phosphate kinase -- lipid kinase; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.12-218842
• Languages: English
• ISSNs: 0892-6638

Abstract

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) P 3 synthesis. Whether oxidative stress regulates other phosphoinositides to control PKB activation is not clear. Here we show that PtdIns5 P is a redox‐regulated second messenger. In response to hydrogen peroxide (H2 O2 ), we measured an increase in PtdIns5 P 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 H2 O2 ‐dependent PtdIns5 P did not require mTOR, PDK1, PKB, ERK, and p38 signaling or PIKfyve, a lipid kinase that increases PtdIns5 P in response to osmotic and oncogenic signaling. A reduction in H2 O2 ‐in‐duced PtdIns5 P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H2 O2 ‐induced PtdIns5 P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H2 O2 . 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.—Jones, D. R., Foulger, R., Keune, W.‐J., Bultsma, Y., Divecha, N. PtdIns5 P is an oxidative stress‐induced second messenger that regulates PKB activation. FASEB J. 27, 1644–1656 (2013). www.fasebj.org