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Cezanne regulates E2F1-dependent HIF2α expression.

Sonia Moniz1, Daniel Bandarra1, John Biddlestone1

  • 1Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Journal of Cell Science
|July 8, 2015
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Summary
This summary is machine-generated.

The deubiquitylase Cezanne regulates hypoxia-inducible factor 2 alpha (HIF2α) expression by controlling the stability of the transcription factor E2F1. This reveals a novel transcriptional regulation mechanism for HIF2α, independent of oxygen levels.

Keywords:
Cell cycleCezanneChIPE2F1HIF2αHypoxia

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Protein degradation mechanisms are crucial for regulating transcription factors like hypoxia-inducible factor (HIF).
  • While HIFα degradation via the proteasome is well-studied, the role of deubiquitylases in this process remains largely unknown.
  • Deubiquitylases reverse ubiquitylation, impacting protein stability and function.

Purpose of the Study:

  • To investigate the role of the deubiquitylase Cezanne (OTUD7B) in regulating HIF2α (EPAS1) expression.
  • To elucidate the mechanism by which Cezanne influences HIF2α levels.
  • To explore the potential link between Cezanne, E2F1, and HIF2α transcriptional control.

Main Methods:

  • Gene knockdown experiments targeting Cezanne.
  • Analysis of HIF2α mRNA, protein, and activity levels.
  • Investigation of the interaction between Cezanne, E2F1, and the HIF2α promoter.
  • Assessment of E2F1 stability and rescue experiments with exogenous E2F1.

Main Results:

  • Cezanne knockdown significantly downregulates HIF2α mRNA, protein, and activity, independent of hypoxia or proteasomal degradation.
  • HIF2α gene expression is directly controlled by the transcription factor E2F1.
  • Cezanne regulates the stability of E2F1, thereby controlling HIF2α expression.
  • Exogenous E2F1 can restore HIF2α expression in Cezanne-depleted cells.

Conclusions:

  • Cezanne acts as a novel regulator of HIF2α expression through its control over E2F1 stability.
  • HIF2α is transcriptionally regulated by E2F1 directly, suggesting a cell-cycle-dependent mechanism.
  • This pathway highlights a new regulatory axis for HIF2α, potentially linked to oncogenic signaling.