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.
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.
Zimmer
Michael
M
Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
Lamb
Justin
J
Ebert
Benjamin L
BL
Lynch
Mary
M
Neil
Christopher
C
Schmidt
Emmett
E
Golub
Todd R
TR
Iliopoulos
Othon
O
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D009154:Mutation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020218:Response Elements; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
D000893:Anti-Inflammatory Agents; D051792:Basic Helix-Loop-Helix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035941:Iron Regulatory Protein 1; D015230:Prostaglandin D2; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C546842:MTOR protein, human