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한빛사논문, 상위피인용논문

조회8,222

Harvard Medical School

Cell, Vol 128, 309-323, 26 January 2007 FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis

Abstract

Ji-Hye Paik,^1,2,11 Ramya Kollipara,^1,2,11 Gerald Chu,^1,2,4,5 Hongkai Ji,⁶ Yonghong Xiao,⁵ Zhihu Ding,^1,2 Lili Miao,^1,2,5 Zuzana Tothova,⁷ James W. Horner,^1,2,3 Daniel R. Carrasco,^1,2,3,4,5 Shan Jiang,^1,2 D. Gary Gilliland,⁷ Lynda Chin,^1,2,5,8 Wing H. Wong,⁹ Diego H. Castrillon,^1,4,10,* and Ronald A. DePinho^{1,2,3,5, *}

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
² Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
³ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
⁴ Department of Pathology, Brigham and Women''s Hospital, Harvard Medical School, Boston, MA 02115, USA
⁵ Center for Applied Cancer Science, Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
⁶ Department of Statistics, Harvard University, Cambridge, MA 02138, USA
⁷ Division of Hematology, Department of Medicine, Brigham and Women''s Hospital, Boston, MA 02115, USA
⁸ Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA
⁹ Department of Statistics, Stanford University, Stanford, CA 94305, USA
¹⁰ Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical School, Dallas, TX 75390, USA

*Corresponding author
Diego H. Castrillon

*Corresponding author
Ronald A. DePinho

Summary

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.

Footnotes

¹¹ These authors contributed equally to this work.

논문정보

형식Research article
게재일2007년 01월 (BRIC 등록일 )
연구진국외 연구진
분야 의약학 > 분자세포의학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2009-06-04)

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