Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing.
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.
Zimmer
Michael
M
Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Ebert
Benjamin L
BL
Neil
Christopher
C
Brenner
Keith
K
Papaioannou
Ioannis
I
Melas
Antonia
A
Tolliday
Nicola
N
Lamb
Justin
J
Pantopoulos
Kostas
K
Golub
Todd
T
Iliopoulos
Othon
O
D020121:5' Untranslated Regions / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D054852:Small Molecule Libraries / Q000032:analysis / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1
D020121:5' Untranslated Regions; D051792:Basic Helix-Loop-Helix Proteins; D017077:Culture Media, Conditioned; D007501:Iron; D007502:Iron Chelating Agents; D035925:Iron-Regulatory Proteins; D010100:Oxygen; D011494:Protein Kinases; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D054852:Small Molecule Libraries; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C546842:MTOR protein, human