SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1α ubiquitination and degradation

M. Tan, Q. Gu, H. He, D. Pamarthy, G. L. Semenza, Y. Sun

Research output: Contribution to journalArticlepeer-review

Abstract

SAG (sensitive to apoptosis gene) or ROC2/RBX2 is the second family member of ROC1/RBX1, a component of SCF (Skp1, Cullin, F-box protein) and VCB (von Hippel-Lindau (VHL), Cullin and Elongin B/C) E3 ubiquitin ligases. SAG protected cells from hypoxia-induced apoptosis when overexpressed. We report here that SAG was subjected to hypoxia induction at the levels of mRNA and protein. Hypoxia induction of SAG was largely HIF-1α dependent. A consensus HIF-1-binding site, GCGTG was identified in the first intron of the SAG gene. In response to hypoxia, HIF-1 bound to this site and transactivated SAG expression. SAG transactivation required both the intact binding site in cis and HIF-1α in trans. On the other hand, like its family member, ROC1, SAG promoted VHL-mediated HIF-1α ubiquitination and degradation, which was significantly inhibited upon small interfering RNA silencing of SAG or ROC1. Furthermore, the endogenous HIF-1α at both basal and hypoxia-induced levels was significantly increased upon SAG silencing. Finally, SAG forms in vivo complex with Cul-5 and VHL under hypoxia condition. These results suggest an HIF-1-SAG feedback loop in response to hypoxia, as follows: hypoxia induces HIF-1 to transactivate SAG. Induced SAG then promotes HIF-1α ubiquitination and degradation. This feedback loop may serve as a cellular defensive mechanism to reduce potential cytotoxic effects of prolonged HIF-1 activation under hypoxia.

Original languageEnglish (US)
Pages (from-to)1404-1411
Number of pages8
JournalOncogene
Volume27
Issue number10
DOIs
StatePublished - Feb 28 2008

Keywords

  • E3 ligase
  • HIF-1
  • Hypoxia
  • SAG
  • Transcription
  • Ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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