title: FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Ramya
authors.initials: R
authors.lastname: Kollipara
authors.forename: Gerald
authors.initials: G
authors.lastname: Chu
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.forename: Lili
authors.initials: L
authors.lastname: Miao
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.forename: James W
authors.initials: JW
authors.lastname: Horner
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carrasco
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Wing H
authors.initials: WH
authors.lastname: Wong
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins; D042783:Endothelial Cells / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006391:Hemangioma / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C477334:FOXO protein, Drosophila; C108803:FOXO4 protein, human; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; C481797:Pbx1 protein, mouse; C404992:Spry2 protein, rat