Small-Molecule Inhibitors of HIF-2a Translation Link Its 5′UTR Iron-Responsive Element to Oxygen Sensing

被引：146

作者：

Zimmer, Michael ^{[1
,2
]}

Ebert, Benjamin L. ^{[3
]}

Neil, Christopher ^{[1
,2
]}

Brenner, Keith ^{[1
,2
]}

Papaioannou, Loannis ^{[1
,2
]}

Melas, Antonia ^{[1
,2
]}

Tolliday, Nicola ^{[4
]}

Lamb, Justin ^{[3
]}

Pantopoulos, Kostas ^{[5
,6
]}

Golub, Todd ^{[3
]}

Iliopoulos, Othon ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[3] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA

[4] Harvard Univ, Sch Med, ICCB, Boston, MA 02115 USA

[5] McGill Univ, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada

[6] McGill Univ, Dept Med, Montreal, PQ H3T 1E2, Canada

来源：

MOLECULAR CELL | 2008年 / 32卷 / 06期

关键词：

D O I：

10.1016/j.molcel.2008.12.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：838 / 848

页数：11

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