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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.

Original publication

DOI

10.1101/gad.1180104

Type

Journal article

Journal

Genes Dev

Publication Date

01/04/2004

Volume

18

Pages

739 - 744

Keywords

Amino Acid Sequence, COP9 Signalosome Complex, Cell Cycle Proteins, Cullin Proteins, DNA-Binding Proteins, Electrophoresis, Gel, Two-Dimensional, Homeostasis, Humans, Hydroxylation, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Intracellular Signaling Peptides and Proteins, Male, Mass Spectrometry, Molecular Sequence Data, Multiprotein Complexes, Oxygen, Peptide Hydrolases, Prostatic Neoplasms, Protein Conformation, Proteins, RNA, Small Interfering, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein