J Korean Med Sci.  2015 Oct;30(10):1388-1395. 10.3346/jkms.2015.30.10.1388.

HIF-1alpha Upregulation due to Depletion of the Free Ubiquitin Pool

• Kim J
• So D
• Shin HW
• Chun YS
• Park JW

• KMID: 2344170
• DOI: http://doi.org/10.3346/jkms.2015.30.10.1388

Abstract

Hypoxia-inducible factor 1alpha (HIF-1alpha), which transactivates a variety of hypoxia-induced genes, is rapidly degraded under nomoxia through the hydroxylation-ubiquitination-proteasome pathway. In this study, we addressed how HIF-1alpha is stabilized by proteasome inhibitors. The ubiquitin pool was rapidly reduced after proteasome inhibition, followed by the accumulation of non-ubiquitinated HIF-1alpha. The poly-ubiquitination of HIF-1alpha was resumed by restoration of free ubiquitin, which suggests that the HIF-1alpha stabilization under proteasome inhibition is attributed to depletion of the free ubiquitin pool. Ni2+ and Zn2+ also stabilized HIF-1alpha with depletion of the free ubiquitin pool and these effects of metal ions were attenuated by restoration of free ubiquitin. Ni2+ and Zn2+ may disturb the recycling of free ubiquitin, as MG132 does. Based on these results, the state of the ubiquitin pool seems to be another critical factor determining the cellular level of HIF-1alpha.

Keyword

Hypoxia-inducible Factor 1, Alpha Subunit; Proteasome Inhibitors; Transition Metal Ions; Poly-ubiquitination; Ubiquitin Depletion

MeSH Terms

Cell Hypoxia/physiology
Cell Line, Tumor
HCT116 Cells
HEK293 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*metabolism
Leupeptins/pharmacology
Nickel/chemistry
Proteasome Endopeptidase Complex/*metabolism
Proteasome Inhibitors/*pharmacology
Ubiquitin/*metabolism
Ubiquitination/*physiology
Up-Regulation
Zinc/chemistry
Hypoxia-Inducible Factor 1, alpha Subunit
Leupeptins
Nickel
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Ubiquitin
Zinc