Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia
Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia
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DOI：
10.1074/jbc.m112.373365
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发表时间：
2012-08-17
影响因子：
4.8
通讯作者：
Marsden, Philip A.
中科院分区：
文献类型：
--
作者：
Ho, J. J. David;Metcalf, Julie L.;Marsden, Philip A.
细胞感知和响应环境氧浓度的过程是细胞生存和功能的基础，它们通常针对基因调控事件。然而，到目前为止，人们对microRNA通路和缺氧信号之间的联系知之甚少。在这里，我们在体外和体内表明，慢性缺氧损害Dicer（DICER 1）的表达和活性，导致microRNA生物合成的全球后果。我们发现，von Hippel-Lindau依赖的Dicer下调是低氧诱导因子α（HIF-α）亚基表达和功能的关键。具体来说，我们发现EPAS 1/HIF-2 α受Dicer依赖性microRNA miR-185的调节，而miR-185在缺氧时下调。缺氧反应/HIF靶基因在慢性缺氧中的完全表达（例如，G. VEGFA、FLT 1/VEGFR 1、KDR/VEGFR 2、BNIP 3L和SLC 2A 1/GLUT 1），其功能是调节对受损氧可用性的各种适应性反应，也依赖于低氧介导的Dicer功能的下调和转录后基因调控的变化。因此，慢性缺氧中Dicer的功能缺陷与HIF-α亚型和缺氧反应/HIF靶基因有关，特别是在血管内皮中。这些发现与新兴疗法有关，因为我们表明，在慢性缺氧下RNA干扰的疗效，而不是正常的氧气供应，是Dicer依赖性的。总的来说，这些发现表明，在慢性缺氧下Dicer的下调是一种适应性机制，其通过HIF-α和microRNA依赖性机制来维持细胞缺氧反应，从而为氧依赖性microRNA调控途径提供了必要的机制见解。
The processes by which cells sense and respond to ambient oxygen concentration are fundamental to cell survival and function, and they commonly target gene regulatory events. To date, however, little is known about the link between the microRNA pathway and hypoxia signaling. Here, we show in vitro and in vivo that chronic hypoxia impairs Dicer (DICER1) expression and activity, resulting in global consequences on microRNA biogenesis. We show that von Hippel-Lindau-dependent down-regulation of Dicer is key to the expression and function of hypoxia-inducible factor alpha (HIF-alpha) subunits. Specifically, we show that EPAS1/HIF-2 alpha is regulated by the Dicer-dependent microRNA miR-185, which is down-regulated by hypoxia. Full expression of hypoxia-responsive/HIF target genes in chronic hypoxia (e. g. VEGFA, FLT1/VEGFR1, KDR/VEGFR2, BNIP3L, and SLC2A1/GLUT1), the function of which is to regulate various adaptive responses to compromised oxygen availability, is also dependent on hypoxia-mediated down-regulation of Dicer function and changes in post-transcriptional gene regulation. Therefore, functional deficiency of Dicer in chronic hypoxia is relevant to both HIF-alpha isoforms and hypoxia-responsive/HIF target genes, especially in the vascular endothelium. These findings have relevance to emerging therapies given that we show that the efficacy of RNA interference under chronic hypoxia, but not normal oxygen availability, is Dicer-dependent. Collectively, these findings show that the down-regulation of Dicer under chronic hypoxia is an adaptive mechanism that serves to maintain the cellular hypoxic response through HIF-alpha- and microRNA-dependent mechanisms, thereby providing an essential mechanistic insight into the oxygen-dependent microRNA regulatory pathway.