@article{7f9ff274a41349a2821e42d2712c12e5,
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.",
author = "Paik, {Ji Hye} and Ramya Kollipara and Gerald Chu and Hongkai Ji and Yonghong Xiao and Zhihu Ding and Lili Miao and Zuzana Tothova and Horner, {James W.} and Carrasco, {Daniel R.} and Shan Jiang and Gilliland, {D. Gary} and Lynda Chin and Wong, {Wing H.} and Castrillon, {Diego H.} and DePinho, {Ronald A.}",
note = "Funding Information: We are grateful to Sarah Weiler and Mychelle Neptune for the generation of the conditional FoxO knockout mouse strains. We are also grateful to Karen Marmon, Alice Yu, and Yan Zhang for their assistance in the animal facility. We thank Nabeel El-Bardeesy, Susan Dymecki, Klaus Rajewsky, A.F. Parlow, the NCI BRB Preclinical Repository for reagents, and the DFCI-Broad RNAi Consortium for lentiviral shRNA vectors. We also thank Dong-In Yuk for assistance with RISH. D.G.G. is an Investigator of the Howard Hughes Medical Institute. J-H.P. and Z.D. are Damon Runyon Fellows supported by the Damon Runyon Cancer Research Foundation. D.H.C. is a Sidney Kimmel Foundation Scholar and supported by the Mary Kay Ash and Lance Armstrong Foundations. This work was supported by grants to D.H.C., D.G.G., L.C., W.H.W., and R.A.D. from the NIH. R.A.D. is an American Cancer Society Research Professor and an Ellison Medical Foundation Scholar and supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. ",
year = "2007",
month = jan,
day = "26",
doi = "10.1016/j.cell.2006.12.029",
language = "English (US)",
volume = "128",
pages = "309--323",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "2",
}