FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis
FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis
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DOI：
10.1016/j.cell.2006.12.029
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发表时间：
2007-01-26
期刊：
影响因子：
64.5
通讯作者：
DePinho, Ronald A.
中科院分区：
文献类型：
--
作者：
Paik, Ji-Hye;Kollipara, Ramya;DePinho, Ronald A.
活化的磷酸肌苷3-激酶（PI3K）AKT信号似乎是癌症发展中的一个专性事件。哺乳动物FoxO转录因子家族中高度相关的成员FoxO1、FoxO3和FoxO4是PI3K-AKT信号传导的几个效应臂之一，促进了FoxOs在与PI3K-AKT激活相关的肿瘤表型中的作用的遗传分析。虽然5个FoxO等位基因的种系或体细胞缺失会产生非常温和的肿瘤表型，但所有FoxO的广泛体细胞缺失会产生以胸腺淋巴瘤和血管瘤为特征的进行性癌症易感性，这表明哺乳动物FoxO确实是真正的肿瘤抑制因子。对受不同影响的内皮细胞的转录组和启动子分析确定了FoxO的直接靶点，并揭示了FoxO在体内对这些靶点的调控是高度上下文特异性的，即使在相同的细胞类型中也是如此。功能研究证实Sprouty2和PBX1等是foxo调节的内皮细胞形态发生和血管稳态的介质。
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 hemangionnas, 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.