Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5

Lynne Bemis, Denise A. Chan, Carla V. Finkielstein, Lin Qi, Patrick D. Sutphin, Xiaojiang Chen, Kurt Stenmark, Amato J. Giaccia, Wayne Zundel

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Abstract

Mammalian oxygen homeostasis is dependent on the HIF family of transcription factors. The CSN subunit, CSN5, binds both the CODD of HIF-1α and the pVHL tumor suppressor. High CSN5 expression generates a pVHL-independent form of CSN5 that stabilizes HIF-1α aerobically by inhibiting HIF-1α prolyl-564 hydroxylation. Aerobic CSN5 association with HIF-1α occurs independently of the CSN holocomplex, leading to HIF-1α stabilization independent of Cullin 2 deneddylation. CSN5 weakly associates with HIF-1α under hypoxia, but is required for optimal hypoxia-mediated HIF-1α stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1α stability by different mechanisms during oncogenesis.

Original languageEnglish (US)
Pages (from-to)739-744
Number of pages6
JournalGenes and Development
Volume18
Issue number7
DOIs
StatePublished - Apr 1 2004

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Keywords

  • COP9 signalosome
  • Hypoxia inducible factor-1α
  • Von Hippel-Lindau

Cite this

Bemis, L., Chan, D. A., Finkielstein, C. V., Qi, L., Sutphin, P. D., Chen, X., Stenmark, K., Giaccia, A. J., & Zundel, W. (2004). Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5. Genes and Development, 18(7), 739-744. https://doi.org/10.1101/gad.1180104