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

• Published in: Genes & development 2004-04, Vol.18 (7), p.739-744
• Main Authors: Bemis, Lynne, Chan, Denise A, Finkielstein, Carla V, Qi, Lin, Sutphin, Patrick D, Chen, Xiaojiang, Stenmark, Kurt, Giaccia, Amato J, Zundel, Wayne
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Cell Cycle Proteins - metabolism; COP9 Signalosome Complex; Cullin Proteins - metabolism; DNA-Binding Proteins - physiology; Electrophoresis, Gel, Two-Dimensional; Homeostasis; Humans; Hydroxylation; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit; Intracellular Signaling Peptides and Proteins; Male; Mass Spectrometry; Molecular Sequence Data; Multiprotein Complexes; Oxygen - metabolism; Peptide Hydrolases; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Conformation; Proteins - physiology; Research Communications; RNA, Small Interfering - pharmacology; Transcription Factors - metabolism; Transcription Factors - physiology; Tumor Cells, Cultured; Tumor Suppressor Proteins - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Von Hippel-Lindau Tumor Suppressor Protein
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.1180104

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.