Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation.
Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation.
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DOI：
10.1038/ncb2954
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发表时间：
2014-05
影响因子：
21.3
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中科院分区：
文献类型：
--
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The tumor vascular microenvironment supports tumorigenesis by supplying not only oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feed-forward mechanism in which endothelial cells (EC), in response to tumor-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of profilin-1 (Pfn-1) at Tyr129 in EC induces binding to tumor suppressor protein von Hippel-Lindau (VHL), prevents VHL-mediated degradation of prolyl-hydroxylated HIF-1α, culminating in HIF-1α accumulation even in normoxia. Elevated HIF-1α induces expression of multiple angiogenic factors, leading to vascular abnormality and tumor progression. In a genetic model of GBM, mice with an EC-specific defect in Pfn-1 phosphorylation exhibit reduced tumor angiogenesis, normalized vasculature, and improved survival. Moreover, EC-specific Pfn-1 phosphorylation is associated with tumor aggressiveness in human glioma. These findings suggest that targeting Pfn-1 phosphorylation may offer a selective strategy for therapeutic intervention of malignant solid tumors.
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影响因子：
3.7
作者：
Galbán S;Lemasson B;Williams TM;Li F;Heist KA;Johnson TD;Leopold JS;Chenevert TL;Lawrence TS;Rehemtulla A;Mikkelsen T;Holland EC;Galbán CJ;Ross BD
通讯作者：
Ross BD
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
64.8
作者：
KIM, KJ;LI, B;FERRARA, N
通讯作者：
FERRARA, N
影响因子：
23.9
作者：
Charles N;Ozawa T;Squatrito M;Bleau AM;Brennan CW;Hambardzumyan D;Holland EC
通讯作者：
Holland EC
影响因子：
50.3
作者：
Batchelor, Tracy T.;Sorensen, A. Gregory;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.