生物
分泌物
血管内皮生长因子
缺氧诱导因子
血管生成
缺氧(环境)
内质网
癌症研究
细胞生物学
HIF1A型
下调和上调
内分泌学
内科学
生物化学
血管内皮生长因子受体
化学
氧气
基因
医学
有机化学
作者
Dalit May,Ahuva Itin,Oded Gal,Hagar Kalinski,Elena Feinstein,Eli Keshet
出处
期刊:Oncogene
[Springer Nature]
日期:2004-12-13
卷期号:24 (6): 1011-1020
被引量:138
标识
DOI:10.1038/sj.onc.1208325
摘要
Oxygen is the ultimate source of oxidizing power for disulfide bond formation, suggesting that under limiting oxygen proper protein folding might be compromised. We show that secretion of vascular endothelial growth factor (VEGF), a protein with multiple disulfide bonds, was indeed impeded under hypoxia and was partially restored by artificial increase of oxidizing equivalents with diamide. Physiologically, the oxireductase endoplasmic reticulum oxidoreductin-1 (Ero1)-L alpha, but not other proteins in the relay of disulfide formation, was strongly upregulated by hypoxia and independently by hypoglycemia, two known accompaniments of tumors. Further, we provide genetic evidence that induction of Ero1-L alpha by hypoxia and hypoglycemia is mediated by the transcription factor hypoxia-inducible factor 1 (HIF-1) but is independent of p53. In natural human tumors, Ero1-L alpha mRNA was specifically induced in hypoxic microenvironments coinciding with that of upregulated VEGF expression. To establish a physiological relevance to modulations in Ero1-L alpha levels, we showed that even a modest, two- to three-fold reduction in Ero1-L alpha production via siRNA leads to significant inhibition of VEGF secretion, a compromised proliferation capacity and enhanced apoptosis. Together, these findings demonstrate that hypoxic induction of Ero1-L alpha is the key adaptive response in a previously unrecognized HIF-1-mediated pathway that operates to improve protein secretion under hypoxia and might be harnessed for inhibiting tumor growth via inhibiting VEGF-driven angiogenesis.
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