The connectivity map links iron regulatory protein-1-mediated inhibition of hypoxia-inducible factor-2a translation to the anti-inflammatory 15-deoxy-delta12,14-prostaglandin J2.
The connectivity map links iron regulatory protein-1-mediated inhibition of hypoxia-inducible factor-2a translation to the anti-inflammatory 15-deoxy-delta12,14-prostaglandin J2.
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DOI：
10.1158/0008-5472.can-09-2877
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Iliopoulos O
中科院分区：
文献类型：
--
作者：
Zimmer M;Lamb J;Ebert BL;Lynch M;Neil C;Schmidt E;Golub TR;Iliopoulos O
Hypoxia Inducible Factors 1 and 2 (HIF1 and HIF2) are heterodimeric transcription factors consisting of alpha regulatory subunits and a constitutively expressed beta subunit. The expression of alpha regulatory subunits is promoted by hypoxia, cancer-associated mutations and inflammatory cytokines. Thus, HIF1 and HIF2 provide a molecular link between cancer and inflammation. We have recently identified novel small molecules that selectively inhibit translation of the HIF2a message and thereby powerfully inhibit the expression of HIF2a target genes. We report here that Connectivity Map analysis links three of these compounds to the anti-inflammatory cytokine 15-deoxy-Δ12,14-Prostaglandin J2 (PGJ2). As with our identified compounds, PGJ2 inhibits translation of the HIF2a message in an mTOR independent manner by promoting the binding of Iron Regulatory Protein-1 (IRP1) to a non-canonical Iron Responsive Element (IRE) embedded within the 5′-UTR of the HIF2a message. The IRE is necessary and sufficient for mediating the effect. Mutation of the IRE sequence, or down regulation of IRP1 expression, blocks the effect of PGJ2 on HIF2a translation. This is the first report of an endogenous natural molecule regulating HIF2a translation and it suggests that part of the anti-inflammatory and putative anti-neoplastic effects of PGJ2 may be mediated through inhibition of HIF2a within tumor epithelial cells themselves and/or mesenchymal cells of the tumor microenvironment.
