FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis

Ji Hye Paik, Ramya Kollipara, Gerald Chu, Hongkai Ji, Yonghong Xiao, Zhihu Ding, Lili Miao, Zuzana Tothova, James W. Horner, Daniel R. Carrasco, Shan Jiang, D. Gary Gilliland, Lynda Chin, Wing H. Wong, Diego H. Castrillon, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)309-323
Number of pages15
JournalCell
Volume128
Issue number2
DOIs
StatePublished - Jan 26 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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