HIF-1alpha Upregulation due to Depletion of the Free Ubiquitin Pool.
10.3346/jkms.2015.30.10.1388
- Author:
Jiyoung KIM
1
;
Daeho SO
;
Hyun Woo SHIN
;
Yang Sook CHUN
;
Jong Wan PARK
Author Information
1. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. parkjw@snu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Hypoxia-inducible Factor 1, Alpha Subunit;
Proteasome Inhibitors;
Transition Metal Ions;
Poly-ubiquitination;
Ubiquitin Depletion
- MeSH:
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
- From:Journal of Korean Medical Science
2015;30(10):1388-1395
- CountryRepublic of Korea
- Language:English
-
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.
