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2015 ; 128
(16
): 3082-93
Nephropedia Template TP
Moniz S
; Bandarra D
; Biddlestone J
; Campbell KJ
; Komander D
; Bremm A
; Rocha S
J Cell Sci
2015[Aug]; 128
(16
): 3082-93
PMID26148512
show ga
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.
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