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PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation

Lookup NU author(s): Dr Iglika Ivanova, Dr Catherine Park, Dr Adrian Yemm, Dr Niall Kenneth

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

HIF1a (hypoxia inducible factor 1a) 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 HIF1a 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 HIF1a by preventing efficient HIF1a translation. Activation of PERK inhibits de novo HIF1a protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1a 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.

Publication metadata

Author(s): Ivanova IG, Park CV, Yemm AI, Kenneth NS

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2018

Volume: 46

Issue: 8

Pages: 3878-3890

Print publication date: 04/05/2018

Online publication date: 26/02/2018

Acceptance date: 14/02/2018

Date deposited: 19/04/2018

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: https://doi.org/10.1093/nar/gky127

DOI: 10.1093/nar/gky127

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