Cezanne regulates E2F1-dependent HIF2? expression.

ABSTRACT: Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIF? subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIF? 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 HIF2? (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2? mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2? gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2? transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2?, demonstrating that the HIF2? promoter is regulated by E2F1 directly and that Cezanne regulates HIF2? expression through control of E2F1 levels. Our results thus suggest that HIF2? is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling.

SUBMITTER: Moniz S 

PROVIDER: S-EPMC4541044 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature