Interaction between PARP-1 and HIF-2α in the hypoxic response
Interaction between PARP-1 and HIF-2α in the hypoxic response
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DOI：
10.1038/onc.2013.9
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发表时间：
2014-02-13
期刊：
影响因子：
8
通讯作者：
Oliver, F. J.
中科院分区：
文献类型：
--
作者：
Gonzalez-Flores, A.;Aguilar-Quesada, R.;Oliver, F. J.
低氧诱导因子(HIF)介导低氧细胞的转录适应。HIFs调控的广泛转录程序涉及诱导控制血管生成、细胞代谢、细胞生长、转移、凋亡、细胞外基质重塑等基因。HIF是HIF-α和HIF-β亚基的异源二聚体。除了HIF-1α外，HIF-2α还进化为一种异构体，通过执行非冗余功能而对低氧适应做出不同的贡献。多聚(ADPribose)聚合酶-1(PARP-1)是一种核蛋白，通过调节染色质结构，作为基因特异性增强子/启动子结合复合体的一部分，参与DNA修复和基因转录的调控。先前的研究结果表明，PARP-1调节HIF-1的活性。在本研究中，我们重点研究了HIF-2α和PARP-1之间的相互作用。通过使用不同的方法抑制PARP-1，我们发现HIF-2α的mRNA表达、蛋白水平以及HIF-2依赖的基因表达，如ANGPTL4和EPO，都受到PARP-1的调控。这种调节发生在转录和转录后水平。我们还显示了HIF-2α与PARP-1之间的复杂形成。该复合体对PARP抑制敏感，似乎对von Hippel-Lindau依赖的HIF-2α降解具有保护作用。最后，我们发现，PALP-1(-/-)小鼠在循环缺氧诱导的EPO水平、红细胞数量和血红蛋白浓度方面表现出显著的降低。综上所述，这些结果揭示了PARP-1和HIF系统之间复杂的功能相互作用，并表明PARP-1参与了体内HIF介导的缺氧反应的微调。
Hypoxia-inducible factors (HIFs) mediate the transcriptional adaptation of hypoxic cells. The extensive transcriptional programm regulated by HIFs involves the induction of genes controlling angiogenesis, cellular metabolism, cell growth, metastasis, apoptosis, extracellular matrix remodeling and others. HIF is a heterodimer of HIF-alpha and HIF-beta subunits. In addition to HIF-1 alpha, HIF-2 alpha has evolved as an isoform that contributes differently to the hypoxic adaptation by performing non-redundant functions. Poly (ADPribose) polymerase-1 (PARP-1) is a nuclear protein involved in the control of DNA repair and gene transcription by modulating chromatin structure and acting as part of gene-specific enhancer/promoter-binding complexes. Previous results have shown that PARP-1 regulates HIF-1 activity. In this study, we focused on the cross-talk between HIF-2 alpha and PARP-1. By using different approaches to suppress PARP-1, we show that HIF-2 alpha mRNA expression, protein levels and HIF-2-dependent gene expression, such as ANGPTL4 and erythropoietin (EPO), are regulated by PARP-1. This regulation occurs at both the transcriptional and post-trancriptional level. We also show a complex formation between HIF-2 alpha with PARP-1. This complex is sensitive to PARP inhibition and seems to protect against the von Hippel-Lindau-dependent HIF-2 alpha degradation. Finally, we show that parp-1(-/-) mice display a significant reduction in the circulating hypoxia-induced EPO levels, number of red cells and hemoglobin concentration. Altogether, these results reveal a complex functional interaction between PARP-1 and the HIF system and suggest that PARP-1 is involved in the fine tuning of the HIF-mediated hypoxic response in vivo.