Phosphatidylinositol 3-Kinase Signaling in Proliferating Cells Maintains an Anti-Apoptotic Transcriptional Program Mediated by Inhibition of Foxo and Non-Canonical Activation of NFkB Transcription Factors

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dc.contributor.author Terragni, Jolyon en_US
dc.contributor.author Graham, Julie R en_US
dc.contributor.author Adams, Kenneth W en_US
dc.contributor.author Schaffer, Michael E en_US
dc.contributor.author Tullai, John W en_US
dc.contributor.author Cooper, Geoffrey M en_US
dc.date.accessioned 2012-01-11T16:42:55Z
dc.date.available 2012-01-11T16:42:55Z
dc.date.copyright 2008 en_US
dc.date.issued 2008-1-28 en_US
dc.identifier.citation Terragni, Jolyon, Julie R Graham, Kenneth W Adams, Michael E Schaffer, John W Tullai, Geoffrey M Cooper. "Phosphatidylinositol 3-kinase signaling in proliferating cells maintains an anti-apoptotic transcriptional program mediated by inhibition of FOXO and non-canonical activation of NFκB transcription factors" BMC Cell Biology 9:6. (2008) en_US
dc.identifier.issn 1471-2121 en_US
dc.identifier.uri http://hdl.handle.net/2144/3114
dc.description.abstract BACKGROUND. Phosphatidylinositol (PI) 3-kinase is activated by a variety of growth factor receptors and the PI 3-kinase/Akt signaling pathway is a key regulator of cell proliferation and survival. The downstream targets of PI 3-kinase/Akt signaling include direct regulators of cell cycle progression and apoptosis as well as a number of transcription factors. Growth factor stimulation of quiescent cells leads to robust activation of PI 3-kinase, induction of immediate-early genes, and re-entry into the cell cycle. A lower level of PI 3-kinase signaling is also required for the proliferation and survival of cells maintained in the presence of growth factors, but the gene expression program controlled by PI 3-kinase signaling in proliferating cells has not been elucidated. RESULTS. We used microarray analyses to characterize the changes in gene expression resulting from inhibition of PI 3-kinase in proliferating cells. The genes regulated by inhibition of PI 3-kinase in proliferating cells were distinct from genes induced by growth factor stimulation of quiescent cells and highly enriched in genes that regulate programmed cell death. Computational analyses followed by chromatin immunoprecipitations demonstrated FOXO binding to both previously known and novel sites in promoter regions of approximately one-third of the up-regulated genes, consistent with activation of FOXO1 and FOXO3a in response to inhibition of PI 3-kinase. NFκB binding sites were similarly identified in promoter regions of over one-third of the down-regulated genes. RelB was constitutively bound to promoter regions in cells maintained in serum, however binding decreased following PI 3-kinase inhibition, indicating that PI 3-kinase signaling activates NFκB via the non-canonical pathway in proliferating cells. Approximately 70% of the genes targeted by FOXO and NFκB regulate cell proliferation and apoptosis, including several regulators of apoptosis that were not previously known to be targeted by these transcription factors. CONCLUSION. PI 3-kinase signaling in proliferating cells regulates a novel transcriptional program that is highly enriched in genes that regulate apoptosis. At least one-third of these genes are regulated either by FOXO transcription factors, which are activated following PI 3-kinase inhibition, or by RelB, which is activated by PI 3-kinase via the non-canonical pathway in proliferating cells. en_US
dc.description.sponsorship National Institutes of Health (RO1 CA18689) en_US
dc.language.iso en en_US
dc.publisher BioMed Central en_US
dc.rights Copyright 2008 Terragni et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. en_US
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_US
dc.title Phosphatidylinositol 3-Kinase Signaling in Proliferating Cells Maintains an Anti-Apoptotic Transcriptional Program Mediated by Inhibition of Foxo and Non-Canonical Activation of NFkB Transcription Factors en_US
dc.type article en_US
dc.identifier.doi 10.1186/1471-2121-9-6 en_US
dc.identifier.pubmedid 18226221 en_US
dc.identifier.pmcid 2268685 en_US

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