PERK/eIF2 alpha signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1 alpha translation

Ivanova, Iglika G, Park, Catherine V, Yemm, Adrian I and Kenneth, Niall S ORCID: 0000-0001-8528-1021 (2018) PERK/eIF2 alpha signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1 alpha translation. Nucleic Acids Research, 46 (8). pp. 3878-3890.

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Official URL: https://academic.oup.com/nar/article/46/8/3878/490...

Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Thapsigargin, eIF-2 Kinase, Eukaryotic Initiation Factor-2, RNA, Messenger, 5' Untranslated Regions, Signal Transduction, Gene Expression, Protein Biosynthesis, Down-Regulation, Hypoxia-Inducible Factor 1, alpha Subunit, Y-Box-Binding Protein 1, Protein Stability, Unfolded Protein Response, Endoplasmic Reticulum Stress, Tumor Hypoxia, PC-3 Cells
Depositing User:	Symplectic Admin
Date Deposited:	21 Jul 2020 08:20
Last Modified:	18 Jan 2023 23:40
DOI:	10.1093/nar/gky127
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3094660