Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia
Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia
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DOI：
10.3109/10715762.2012.669041
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发表时间：
2012-06-01
影响因子：
3.3
通讯作者：
Berchner-Pfannschmidt, Utta
中科院分区：
文献类型：
--
作者：
Niecknig, Helene;Tug, Suzan;Berchner-Pfannschmidt, Utta
真核细胞的功能和生存依赖于持续和充足的氧气供应。细胞通过积累转录因子缺氧诱导因子1(HIF-1)来识别和响应低氧，HIF-1由氧敏感的HIF-1α和构成HIF-1β的亚基组成。除生理学外，HIF-1的诱导还参与心血管疾病、炎症和癌症等主要病理过程，这些过程与ROS的形成有关。ROS已被报道影响HIF-1的活性，但ROS在调节HIF-1中的作用尚未明确。为了阐明ROS对HIF-1的氧化还原调节作用，我们研究了外源性ROS处理(H_2O_2)对人骨肉瘤细胞株U2OS中HIF-1α和HIF-1调节蛋白Pro-羟基酶2(PHD2)的影响。在反应的早期阶段，H_2O_2诱导HIF-1α，但在较长的观察阶段则相反。在这里，PHD活性的调节似乎是关键因素，因为PHD2的敲除和抑制阻止了HIF-1α的减少。然而，H_2O_2处理在所有时间点持续抑制HIF-1的反式激活。我们的数据表明，ROS对HIF-1α蛋白含量的双重氧化还原调节与对HIF-1靶基因表达的持续抑制。
The function and survival of eukaryotic cells depends on a constant and sufficient oxygen supply. Cells recognize and respond to hypoxia by accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), composed of an oxygen-sensitive HIF-1 alpha and a constitutive HIF-1 beta subunit. Besides physiology, HIF-1 induction is involved in major pathological processes such as cardiovascular disease, inflammation and cancer, which are associated with the formation of reactive oxygen species (ROS). ROS have been reported to affect HIF-1 activity but the role for ROS in regulating HIF-1 has not been definitely settled. In order to shed light on the redox-regulation of HIF-1 by ROS, we studied the impact of exogenous ROS treatment (H2O2) on HIF-1 alpha and HIF-1 regulatory protein prolyl hydroxylase 2 (PHD2) in the human osteosarcoma cell line U2OS. At early reaction periods, H2O2 induced HIF-1 alpha but at prolonged observation phases the opposite occurred. Herein, modulation of PHD activity appeared to be the key element, because knockdown and inhibition of the PHD2 prevented reduction of HIF-1 alpha. However, H2O2 treatment constantly suppressed HIF-1 transactivation at all time-points. Our data indicate a dual redox regulation of HIF-1 alpha protein amount with a constant suppression of HIF-1 target gene expression by ROS.