Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5
- Lynne Bemis1,
- Denise A. Chan4,5,
- Carla V. Finkielstein2,
- Lin Qi3,
- Patrick D. Sutphin4,5,
- Xiaojiang Chen2,
- Kurt Stenmark1,
- Amato J. Giaccia4,5, and
- Wayne Zundel6,7,8
- Departments of 1Medicine and 2Biochemistry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA; 3Division of Urology, Xiangya Hospital, Changsha, P.R. China; 4Program in Cancer Biology and 5Department of Radiation Oncology, Stanford University, Stanford, California 94303, USA; 6Department of Radiation Oncology and 7Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA
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 suppressor. 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 hypoxia, but is required for optimal hypoxia-mediated HIF-1α stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1α stability by different mechanisms during oncogenesis.
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Footnotes
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1180104.
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Corresponding author.
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↵8 E-MAIL Wayne.Zundel{at}uchsc.edu; FAX (303) 315-8825.
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- Accepted March 1, 2004.
- Received December 18, 2003.
- Cold Spring Harbor Laboratory Press
