Cezanne regulates E2F1-dependent HIF2 expression

Moniz, S., Bandarra, D., Biddlestone, J., Campbell, K.J., Komander, D., Bremm, A. and Rocha, S. (2015) Cezanne regulates E2F1-dependent HIF2 expression. Journal of Cell Science, 128(16), pp. 3082-3093. (doi: 10.1242/jcs.168864) (PMID:26148512) (PMCID:PMC4541044)

109840.pdf - Published Version
Available under License Creative Commons Attribution.



Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Campbell, Dr Kirsteen
Authors: Moniz, S., Bandarra, D., Biddlestone, J., Campbell, K.J., Komander, D., Bremm, A., and Rocha, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Cell Science
Publisher:The Company of Biologists Ltd.
ISSN (Online):1477-9137
Copyright Holders:Copyright © 2015 The Company of Biologists Ltd.
First Published:First published in Journal of Cell Science 128(16):3082-3093
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record