PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation
Autor: | Ivanova, Iglika G, Park, Catherine V, Yemm, Adrian I, Kenneth, Niall S |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
endocrine system
Protein Stability Gene regulation Chromatin and Epigenetics Eukaryotic Initiation Factor-2 Down-Regulation Gene Expression Endoplasmic Reticulum Stress Hypoxia-Inducible Factor 1 alpha Subunit eIF-2 Kinase Protein Biosynthesis PC-3 Cells Unfolded Protein Response Humans Thapsigargin Tumor Hypoxia RNA Messenger Y-Box-Binding Protein 1 5' Untranslated Regions Signal Transduction |
Zdroj: | Nucleic Acids Research |
ISSN: | 1362-4962 0305-1048 |
Popis: | HIF1α (hypoxia inducible factor 1α) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1α by preventing efficient HIF1α translation. Activation of PERK inhibits de novo HIF1α protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1α mRNA 5′UTR. Our data indicate that activation of the UPR can sensitise tumor cells to hypoxic stress, indicating that chemical activation of the UPR could be a strategy to target hypoxic malignant cancer cells. |
Databáze: | OpenAIRE |
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