Abstract
ABSTRACTMechanisms 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.
Highlights
Adaptation to changes in the microenvironment requires tight regulation of gene expression
Cezanne regulates HIF2α transcript through E2F1 Our results suggest that Cezanne-dependent stabilisation of E2F1 is required for HIF2α expression
We describe the regulation of HIF2α protein levels and activity by a deubiquitylase, Cezanne, and show that Cezanne regulates HIF2α gene expression by modulating the protein levels of E2F1, an important transcription factor associated with cell cycle progression (Stevens and La Thangue, 2003)
Summary
Adaptation to changes in the microenvironment requires tight regulation of gene expression. In response to low O2 levels, gene expression is mainly regulated by the hypoxia inducible factor (HIF) family of transcription factors, which enact a transcriptional programme that allows cell survival as well as the reestablishment of O2 supply. Most studies regarding HIF regulation have been directed towards HIF1α, and little is known. HIF1α and HIF2α share sequence similarity and a number of transcriptional targets, the tissue distribution and functional properties of the two proteins are considerably different (Chiavarina et al, 2012; Gordan et al, 2007a). HIF2α has been associated with tumour-promoting properties in different types of tumours (Bangoura et al, 2007; Chiavarina et al, 2012; Holmquist-Mengelbier et al, 2006; Noguera et al, 2009; Raval et al, 2005; Scrideli et al, 2007)
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