Tuning the Transcriptional Response to Hypoxia by Inhibiting Hypoxia-inducible Factor (HIF) Prolyl and Asparaginyl Hydroxylases.
Tuning the Transcriptional Response to Hypoxia by Inhibiting Hypoxia-inducible Factor (HIF) Prolyl and Asparaginyl Hydroxylases.
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DOI：
10.1074/jbc.m116.749291
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发表时间：
2016-09-23
期刊：
影响因子：
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通讯作者：
Schofield CJ
中科院分区：
文献类型：
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作者：
Chan MC;Ilott NE;Schödel J;Sims D;Tumber A;Lippl K;Mole DR;Pugh CW;Ratcliffe PJ;Ponting CP;Schofield CJ
低氧诱导因子(HIF)系统在动物体内协调细胞对低氧的反应。缺氧诱导因子是一种α/β异源二聚体转录因子，以组织上下文依赖的方式调节成百上千个基因的表达。HIF系统的主要缺氧敏感成分涉及HIF羟基酶的氧依赖催化作用；在人类中，有三个HIF脯氨酸羟基酶(PhD1-3)和一个天冬酰胺基羟基酶(FIH)。PHD催化调节HIFα水平，FIH催化调节HIF活性。目前尚不清楚缺氧诱导因子α羟化状态的差异如何与诱导特定的缺氧诱导因子靶基因转录的变化有关。我们报道了使用小分子HIF羟基酶抑制剂的研究，这些研究调查了PHD或FIH抑制诱导HIF靶基因表达的程度。结果显示，在调节细胞中的缺氧反应基因方面，Pro和天冬酰胺羟化的作用有很大的不同。具有不同结构支架的PHD抑制剂的作用相似。在所测试的条件下，广谱的2-氧戊二酸双加氧酶抑制剂比选择性的PHD抑制剂更能模拟缺氧的整体转录反应，这与FIH在缺氧转录反应中的重要作用是一致的。事实上，选择性PHD和FIH抑制剂的联合应用导致了一组基因的转录诱导，而不是单独对PHD抑制完全反应。因此，对于HIF靶基因的治疗调节，考虑PHD和FIH活性是很重要的，在某些靶基因的情况下，同时抑制PHD和FIH催化可能是更可取的。
The hypoxia-inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an α/β-heterodimeric transcription factor that regulates the expression of hundreds of genes in a tissue context-dependent manner. The major hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1–3) and an asparaginyl hydroxylase (factor-inhibiting HIF (FIH)). PHD catalysis regulates HIFα levels, and FIH catalysis regulates HIF activity. How differences in HIFα hydroxylation status relate to variations in the induction of specific HIF target gene transcription is unknown. We report studies using small molecule HIF hydroxylase inhibitors that investigate the extent to which HIF target gene expression is induced by PHD or FIH inhibition. The results reveal substantial differences in the role of prolyl and asparaginyl hydroxylation in regulating hypoxia-responsive genes in cells. PHD inhibitors with different structural scaffolds behave similarly. Under the tested conditions, a broad-spectrum 2-oxoglutarate dioxygenase inhibitor is a better mimic of the overall transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in the transcriptional induction of a subset of genes not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.