The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
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DOI：
10.1038/20459
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发表时间：
1999-05-20
期刊：
影响因子：
64.8
通讯作者：
Ratcliffe, PJ
中科院分区：
文献类型：
--
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
缺氧诱导因子-1（HIF-1）在细胞对缺氧的反应中起关键作用，包括调节参与能量代谢、血管生成和细胞凋亡的基因（1-4）。HIF的α亚基在正常条件下被蛋白酶体迅速降解，但在缺氧条件下稳定（5）。钴离子或铁螯合剂模拟缺氧，表明刺激可能通过对铁蛋白氧传感器的影响而相互作用（6，7）。在这里，我们证明了一个关键的作用，冯希佩尔-林道（VHL）肿瘤抑制基因产物pVHL在HIF-1的调节。在VHL缺陷细胞中，HIF α亚基组成性稳定，HIF-1被激活。pVHL的再表达恢复了氧依赖性不稳定性。pVHL和HIF α-亚基共免疫沉淀，并且pVHL存在于缺氧HIF-1 DNA结合复合物中。在暴露于铁螯合物或钴离子的细胞中，HIF-1从pVHL解离。这些发现表明HIF-1和pVHL之间的相互作用是铁依赖性的，并且对于HIF α-亚基的氧依赖性降解是必需的。因此，组成型HIF-1激活可能是VHL相关肿瘤血管生成表型的基础。pVHL/HIF-1相互作用为理解细胞氧感受提供了新的焦点。
Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis(1-4). The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia(5). Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor(6,7). Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.