Abstract
Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, FoxO1, FoxO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins
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Cell Differentiation / genetics
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Cell Lineage / genetics*
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Drosophila Proteins
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Endothelial Cells / metabolism*
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics*
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Gene Expression Regulation, Neoplastic / genetics*
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Hemangioma / genetics
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Hemangioma / metabolism
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Homeodomain Proteins / genetics
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Homeostasis / genetics
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Lymphoma / genetics
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Lymphoma / metabolism
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Mice
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Mice, Knockout
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Neovascularization, Physiologic / genetics
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Nerve Tissue Proteins / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Pre-B-Cell Leukemia Transcription Factor 1
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / genetics
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Transcription Factors / genetics
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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Drosophila Proteins
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FOXO protein, Drosophila
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FOXO4 protein, human
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Foxo1 protein, mouse
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Homeodomain Proteins
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Nerve Tissue Proteins
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Pbx1 protein, mouse
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Pre-B-Cell Leukemia Transcription Factor 1
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Spry2 protein, rat
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Transcription Factors
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Tumor Suppressor Proteins
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Proto-Oncogene Proteins c-akt