缺氧诱导因子-2α（HIF-2α）翻译的小分子抑制剂将其5'非翻译区铁反应元件与氧感应联系起来。
Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing.
作者信息
Zimmer Michael, Ebert Benjamin L, Neil Christopher, Brenner Keith, Papaioannou Ioannis, Melas Antonia, Tolliday Nicola, Lamb Justin, Pantopoulos Kostas, Golub Todd, Iliopoulos Othon
机构信息
Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
出版信息
Mol Cell. 2008 Dec 26;32(6):838-48. doi: 10.1016/j.molcel.2008.12.004.
Cells transiently adapt to hypoxia by globally decreasing protein translation. However, specific proteins needed to respond to hypoxia evade this translational repression. The mechanisms of this phenomenon remain unclear. We screened for and identified small molecules that selectively decrease HIF-2a translation in an mTOR-independent manner, by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to a recently reported iron-responsive element (IRE) within the 5'-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia derepresses HIF-2a translation by disrupting the IRP1-HIF-2a IRE interaction. Thus, this chemical genetic analysis describes a molecular mechanism by which translation of the HIF-2a message is maintained during conditions of cellular hypoxia through inhibition of IRP-1-dependent repression. It also provides the chemical tools for studying this phenomenon.
细胞通过全面降低蛋白质翻译来短暂适应缺氧环境。然而，应对缺氧所需的特定蛋白质却能逃避这种翻译抑制。这种现象的机制仍不清楚。我们筛选并鉴定出了一些小分子，它们通过增强铁调节蛋白1（IRP1）与低氧诱导因子-2α（HIF-2α）信使核糖核酸5'非翻译区（UTR）内最近报道的铁反应元件（IRE）的结合，以一种不依赖雷帕霉素靶蛋白（mTOR）的方式选择性降低HIF-2α的翻译。用短发夹RNA（shRNA）敲低IRP1的表达消除了这些化合物的作用。缺氧通过破坏IRP1-HIF-2α IRE相互作用来解除对HIF-2α翻译的抑制。因此，这种化学遗传学分析描述了一种分子机制，通过该机制，在细胞缺氧条件下，通过抑制IRP-1依赖性抑制来维持HIF-2α信使核糖核酸的翻译。它还为研究这一现象提供了化学工具。
Zotero 插件