Ero1-Lα plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia:: implication for cancer
Ero1-Lα plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia:: implication for cancer
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DOI：
10.1038/sj.onc.1208325
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发表时间：
2005-02-03
期刊：
影响因子：
8
通讯作者：
Keshet, E
中科院分区：
文献类型：
--
作者：
May, D;Itin, A;Keshet, E
氧是二硫键形成的最终氧化力来源，这表明在限制氧的情况下，蛋白质的正常折叠可能会受到影响。我们发现，血管内皮生长因子(一种具有多个二硫键的蛋白质)的分泌在低氧条件下确实受到阻碍，并通过人为增加二胺的氧化当量而部分恢复。生理上，氧化还原酶内质网氧化还原蛋白-1(Ero1)-Lpha，而不是其他二硫键形成的接力蛋白，在低氧和低血糖的作用下强烈上调，而低血糖是肿瘤的两个已知伴随因素。此外，我们提供了遗传证据表明，低氧和低血糖诱导的Ero1-Lpha是由转录因子低氧诱导因子1(HIF-1)介导的，但不依赖于P53。在天然人类肿瘤中，Ero1-Lpha mRNA是在低氧微环境中特异性诱导的，与上调的血管内皮生长因子表达一致。为了建立与Ero1-Lpha水平调节的生理学相关性，我们发现，即使通过siRNA适度地减少两到三倍的Ero1-Lpha的产生，也会导致显著抑制VEGF的分泌，损害增殖能力和促进细胞凋亡。综上所述，这些发现表明，低氧诱导Ero1-Lpha是先前未知的HIF-1介导的途径中的关键适应性反应，该途径在低氧条件下促进蛋白质分泌，并可能通过抑制VEGF驱动的血管生成来抑制肿瘤生长。
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)-Lalpha, 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-Lalpha 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-Lalpha mRNA was specifically induced in hypoxic microenvironments coinciding with that of upregulated VEGF expression. To establish a physiological relevance to modulations in Ero1-Lalpha levels, we showed that even a modest, two- to three-fold reduction in Ero1-Lalpha 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-Lalpha 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.