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Lookup NU author(s): Dr Catherine Park, Dr Iglika Ivanova, Dr Niall Kenneth
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. The cellular response to hypoxia is characterised by a switch in the transcriptional program, mediated predominantly by the hypoxia inducible factor family of transcription factors (HIF). Regulation of HIF1 is primarily controlled by post-translational modification of the HIF1α subunit, which can alter its stability and/or activity. This study identifies an unanticipated role for the X-linked inhibitor of apoptosis (XIAP) protein as a regulator of Lys63-linked polyubiquitination of HIF1α. Lys63-linked ubiquitination of HIF1α by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys63-linked polyubiquitination promotes HIF1α nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys63-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1α, promoter occupancy, HIF-dependent gene expression and cell viability. Our data reveals an additional and significant level of control of the HIF1 by XIAP, with important implications in understanding the role of HIF1 and XIAP in human disease.
Author(s): Park CV, Ivanova IG, Kenneth NS
Publication type: Article
Publication status: Published
Journal: Nucleic Acids Research
Year: 2017
Volume: 45
Issue: 16
Pages: 9336-9347
Print publication date: 19/09/2017
Online publication date: 28/06/2017
Acceptance date: 26/06/2017
Date deposited: 06/11/2017
ISSN (print): 0305-1048
ISSN (electronic): 1362-4962
Publisher: Oxford University Press
URL: https://doi.org/10.1093/nar/gkx549
DOI: 10.1093/nar/gkx549
PubMed id: 28666324
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