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Transcription profiling of human 786-O clear cell renal carcinoma cells reveals small molecule inhibitors of HIF-2a translation link its 5 UTR Iron-Responsive Element (IRE) to oxygen sensing

ABSTRACT: 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 5â-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia de-represses 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. Experiment Overall Design: 3 replicate samples of 786-O human Clear Cell Renal Carcinoma cells untreated, mock treated with DMSO or treated with either of 4 HIF-2a inhibitor compounds identified by chemical genetic screening.

ORGANISM(S): Homo sapiens

SUBMITTER: Othon Iliopoulos

PROVIDER: E-GEOD-13818 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Small molecule inhibitors of HIF-2a translation link its 5’-UTR Iron-Responsive Element (IRE) to oxygen sensing

Project description: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 de-represses 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.

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