Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing.
Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing.
复制标题
HIF-2A翻译的小分子抑制剂将其5'UTR铁响应元件与氧气传感联系起来。
DOI：
10.1016/j.molcel.2008.12.004
复制
发表时间：
2008-12-26
期刊：
影响因子：
16
通讯作者：
Iliopoulos, Othon
中科院分区：
文献类型：
--
作者：
Zimmer, Michael;Ebert, Benjamin L.;Neil, Christopher;Brenner, Keith;Papaioannou, Loannis;Melas, Antonia;Tolliday, Nicola;Lamb, Justin;Pantopoulos, Kostas;Golub, Todd;Iliopoulos, Othon
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 de-represses 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.
登录
查看更多内容
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
56.9
作者：
Golub, TR;Slonim, DK;Lander, ES
通讯作者：
Lander, ES
影响因子：
4.8
作者：
Arsham, AM;Howell, JJ;Simon, MC
通讯作者：
Simon, MC
影响因子：
4.8
作者：
Hanson, ES;Foot, LM;Leibold, EA
通讯作者：
Leibold, EA
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ