STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination.
10.3858/emm.2008.40.5.479
- Author:
Joo Eun JUNG
1
;
Hong Sook KIM
;
Chang Seok LEE
;
Yong Jae SHIN
;
Yong Nyun KIM
;
Gyeong Hoon KANG
;
Tae You KIM
;
Yong Sung JUHNN
;
Sung Joon KIM
;
Jong Wan PARK
;
Sang Kyu YE
;
Myung Hee CHUNG
Author Information
1. Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. sangkyu@snu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
anoxia;
hypoxia-inducible factor1, alpha subunit;
neoplasms;
STAT3 transcription factor;
ubiquitination;
von Hippel-Lindau tumor suppressor protein
- MeSH:
Animals;
COS Cells;
Cell Line, Tumor;
Cercopithecus aethiops;
Humans;
Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism;
Immunoblotting;
Immunoprecipitation;
Protein Binding;
STAT3 Transcription Factor/genetics/*metabolism;
Signal Transduction/genetics/physiology;
Transfection;
Ubiquitination;
Von Hippel-Lindau Tumor Suppressor Protein/genetics/*metabolism
- From:Experimental & Molecular Medicine
2008;40(5):479-485
- CountryRepublic of Korea
- Language:English
-
Abstract:
Hypoxia-inducible factor 1alpha (HIF-1alpha) is rapidly degraded by the ubiquitin-proteasome pathway under normoxic conditions. Ubiquitination of HIF-1alpha is mediated by interaction with von Hippel-Lindau tumor suppressor protein (pVHL). In our previous report, we found that hypoxia-induced active signal transducer and activator of transcription3 (STAT3) accelerated the accumulation of HIF-1alpha protein and prolonged its half-life in solid tumor cells. However, its specific mechanisms are not fully understood. Thus, we examined the role of STAT3 in the mechanism of pVHL-mediated HIF-1alpha stability. We found that STAT3 interacts with C-terminal domain of HIF-1alpha and stabilizes HIF-1alpha by inhibition of pVHL binding to HIF-1alpha. The binding between HIF-1alpha and pVHL, negative regulator of HIF-1alpha stability, was interfered dose-dependently by overexpressed constitutive active STAT3. Moreover, we found that the enhanced HIF-1alpha protein levels by active STAT3 are due to decrease of poly-ubiquitination of HIF-1alpha protein via inhibition of interaction between pVHL and HIF-1alpha. Taken together, our results suggest that STAT3 decreases the pVHL-mediated ubiquitination of HIF-1alpha through competition with pVHL for binding to HIF-1alpha, and then stabilizes HIF-1alpha protein levels.
