1. Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5.
- Author
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Bemis, Lynne, Chan, Denise A., Finkielstein, Carla V., Lin Qi, Sutphin, Patrick D., Xiaojiang Chen, Stenmark, Kurt, Giaccia, Amato J., and Zundel, Wayne
- Subjects
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CHROMOSOMES , *TRANSCRIPTION factors , *HOMEOSTASIS , *GENE expression , *GENETIC regulation - 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 suppresser. 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 hypoxic, but is required for optimal hypoxic-mediated HIF-1α stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1α stability by different mechanisms during oncogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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