Amato J. Giaccia

Publication Details

• Distinct aerobic and hypoxic mechanisms of HIF-alpha regulation by CSN5.

  Bemis L, Chan DA, Finkielstein CV, Qi L, Sutphin PD, Chen X, Stenmark K, Giaccia AJ, Zundel W. Genes Dev. 2004; 18 (7): 739-44

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

  PubMedID: 15082527