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Genes Dev. 2004 Apr 1;18(7):739-44.

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

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1
Departments of Medicine and Biochemistry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

Abstract

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.

PMID:
15082527
PMCID:
PMC387414
DOI:
10.1101/gad.1180104
[Indexed for MEDLINE]
Free PMC Article

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