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
Open Access
- 28 January 2008
- journal article
- Published by Springer Science and Business Media LLC in BMC Cell Biology
- Vol. 9 (1), 6
- https://doi.org/10.1186/1471-2121-9-6
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.Keywords
This publication has 94 references indexed in Scilit:
- Immediate-Early and Delayed Primary Response Genes Are Distinct in Function and Genomic ArchitectureJournal of Biological Chemistry, 2007
- Resolution of the Nuclear Localization Mechanism of Glycogen Synthase Kinase-3Published by Elsevier BV ,2007
- Glycogen Synthase Kinase-3 Represses Cyclic AMP Response Element-binding Protein (CREB)-targeted Immediate Early Genes in Quiescent CellsPublished by Elsevier BV ,2007
- Rapid Turnover of Mcl-1 Couples Translation to Cell Survival and ApoptosisJournal of Biological Chemistry, 2007
- Integrating cell-signalling pathways with NF-κB and IKK functionNature Reviews Molecular Cell Biology, 2007
- The UCSC genome browser database: update 2007Nucleic Acids Research, 2006
- A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin SignalingCell, 2006
- Coordinated binding of NF-κB family members in the response of human cells to lipopolysaccharideProceedings of the National Academy of Sciences, 2006
- A New Description of Cellular QuiescencePLoS Biology, 2006
- Applied bioinformatics for the identification of regulatory elementsNature Reviews Genetics, 2004