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

Lynne Bemis; Denise A. Chan; Carla V. Finkielstein; Lin Qi; Patrick D. Sutphin; Xiaojiang Chen; Kurt Stenmark; Amato J. Giaccia; Wayne Zundel

doi:10.1101/gad.1180104

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

Lynne Bemis, Denise A. Chan, Carla V. Finkielstein, Lin Qi, Patrick D. Sutphin, Xiaojiang Chen, Kurt Stenmark, Amato J. Giaccia, Wayne Zundel

Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	739-744
Number of pages	6
Journal	Genes and Development
Volume	18
Issue number	7
DOIs	https://doi.org/10.1101/gad.1180104
State	Published - Apr 1 2004

Keywords

COP9 signalosome
Hypoxia inducible factor-1α
Von Hippel-Lindau

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5",

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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AU - Chan, Denise A.

AU - Finkielstein, Carla V.

AU - Qi, Lin

AU - Sutphin, Patrick D.

AU - Chen, Xiaojiang

AU - Stenmark, Kurt

AU - Giaccia, Amato J.

AU - Zundel, Wayne

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N2 - 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.

AB - 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.

KW - COP9 signalosome

KW - Hypoxia inducible factor-1α

KW - Von Hippel-Lindau

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

Abstract

Keywords

UN SDGs

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