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dc.contributor.authorJones, David R
dc.contributor.authorFoulger, Rebecca
dc.contributor.authorKeune, Willem-Jan
dc.contributor.authorBultsma, Yvette
dc.contributor.authorDivecha, Nullin
dc.date.accessioned2013-03-11T14:40:21Z
dc.date.available2013-03-11T14:40:21Z
dc.date.issued2012-12-14
dc.identifier.citationPtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation. 2012: FASEB Jen_GB
dc.identifier.issn1530-6860
dc.identifier.pmid23241309
dc.identifier.doi10.1096/fj.12-218842
dc.identifier.urihttp://hdl.handle.net/10541/271665
dc.description.abstractOxidative 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 PtdIns5P is a redox-regulated second messenger. In response to hydrogen peroxide (H(2)O(2)), 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 H(2)O(2)-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 H(2)O(2)-induced PtdIns5P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H(2)O(2)-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H(2)O(2). 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. PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.
dc.languageENG
dc.language.isoenen
dc.rightsArchived with thanks to FASEB journal : official publication of the Federation of American Societies for Experimental Biologyen_GB
dc.titlePtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Inositide Laboratory, The Paterson Institute for Cancer Research, University of Manchester, Manchester UK.en_GB
dc.identifier.journalFASEB Journalen_GB
html.description.abstractOxidative 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 PtdIns5P is a redox-regulated second messenger. In response to hydrogen peroxide (H(2)O(2)), 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 H(2)O(2)-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 H(2)O(2)-induced PtdIns5P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H(2)O(2)-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H(2)O(2). 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. PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.


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