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Cancer Res DOI:10.1158/0008-5472.CAN-09-2877

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.

Publication TypeJournal Article
Year of Publication2010
AuthorsZimmer, M, Lamb, J, Ebert, BL, Lynch, M, Neil, C, Schmidt, E, Golub, TR, Iliopoulos, O
JournalCancer Res
Volume70
Issue8
Pages3071-9
Date Published2010 Apr 15
ISSN1538-7445
KeywordsAnti-Inflammatory Agents, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Tumor, Dimerization, Dose-Response Relationship, Drug, Epithelial Cells, Gene Expression Regulation, Humans, Intracellular Signaling Peptides and Proteins, Iron Regulatory Protein 1, Mutation, Prostaglandin D2, Protein Biosynthesis, Protein-Serine-Threonine Kinases, Response Elements, TOR Serine-Threonine Kinases, Transcription, Genetic
Abstract

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-Delta(12,14)-prostaglandin J(2) (PGJ(2)). As with our identified compounds, PGJ(2) inhibits translation of the HIF2a message in a mammalian target of rapamycin-independent manner by promoting the binding of iron regulatory protein-1 (IRP1) to a noncanonical iron responsive element (IRE) embedded within the 5'-untranslated region of the HIF2a message. The IRE is necessary and sufficient for mediating the effect. Mutation of the IRE sequence, or downregulation of IRP1 expression, blocks the effect of PGJ(2) 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 antineoplastic effects of PGJ(2) may be mediated through inhibition of HIF2a within tumor epithelial cells themselves and/or mesenchymal cells of the tumor microenvironment.

URLhttp://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=20354189
DOI10.1158/0008-5472.CAN-09-2877
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/20354189?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID20354189
PubMed Central IDPMC2861799
Grant ListUL1RR024924 / RR / NCRR NIH HHS / United States
R01 CA104574-04 / CA / NCI NIH HHS / United States
5R01CA104574 / CA / NCI NIH HHS / United States
R01 CA122591 / CA / NCI NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
UL1 RR024924 / RR / NCRR NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
R01 CA104574 / CA / NCI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States