Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2
Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2
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DOI：
10.1074/jbc.m607065200
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发表时间：
2007-01-19
影响因子：
4.8
通讯作者：
Fandrey, Joachim
中科院分区：
文献类型：
--
作者：
Berchner-Pfannschmidt, Utta;Yamac, Hatice;Fandrey, Joachim
转录因子复合体缺氧诱导因子1 （HIF-1）在细胞适应低氧可用性中起着至关重要的作用。o -2依赖性HIF脯氨酰羟化酶（PHDs）修饰HIF-1 α，在常氧条件下，HIF-1 α被送到蛋白酶体降解。缺氧条件下phd活性的降低可以稳定HIF-1 α并诱导HIF-1靶基因的表达。与缺氧一样，一氧化氮（NO）被发现抑制常氧ph活性，导致HIF-1 α积累。相反，在缺氧情况下，由于PHD活性增强，NO降低了HIF-1 α水平。在此，我们研究了NO在调节PHD表达中的作用及其对HIF-1 α降解的影响。我们报道了HIF-1 α和PHDs在常氧和缺氧条件下对NO治疗的双相反应。在早期阶段，NO抑制PHD活性，导致HIF-1 α积累，而在晚期，PHD水平升高会降低HIF-1 α。NO在常氧和缺氧条件下诱导PHD2和-3 mRNA和蛋白的表达，并以严格依赖hif -1的方式表达。no处理的PHD水平升高的细胞在再氧化时表现出HIF-1 α积累延迟和HIF-1 α降解加速。随后使用小干扰RNA抑制PHD2和-3的表达，表明PHD2专门负责调节NO处理下HIF-1 α的降解。总之，我们确定了PHD2的诱导是no诱导HIF-1 α降解的潜在机制。
The transcription factor complex hypoxia-inducible factor 1 (HIF-1) plays a crucial role in cellular adaptation to low oxygen availability. O-2-dependent HIF prolyl hydroxylases (PHDs) modify HIF-1 alpha, which is sent to proteasomal degradation under normoxia. Reduced activity of PHDs under hypoxia allows stabilization of HIF-1 alpha and induction of HIF-1 target gene expression. Like hypoxia, nitric oxide (NO) was found to inhibit normoxic PHD activity leading to HIF-1 alpha accumulation. In contrast under hypoxia, NO reduced HIF-1 alpha levels due to enhanced PHD activity. Herein, we studied the role of NO in regulating PHD expression and the consequences thereof for HIF-1 alpha degradation. We report a biphasic response of HIF-1 alpha and PHDs to NO treatment both under normoxia and hypoxia. In the early phase, NO inhibits PHD activity that leads to HIF-1 alpha accumulation, whereas in the late phase, increased PHD levels reduce HIF-1 alpha. NO induces expression of PHD2 and -3 mRNA and protein under normoxia and hypoxia in a strictly HIF-1-dependent manner. NO-treated cells with elevated PHD levels displayed delayed HIF-1 alpha accumulation and accelerated degradation of HIF-1 alpha upon reoxygenation. Subsequent suppression of PHD2 and -3 expression using small interfering RNA revealed that PHD2 was exclusively responsible for regulating HIF-1 alpha degradation under NO treatment. In conclusion, we identified the induction of PHD2 as an underlying mechanism of NO-induced degradation of HIF-1 alpha.