Exp Mol Med.
2008 Oct;40(5):479-485. 10.3858/emm.2008.40.5.479.
STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination
- Affiliations
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- 1Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. sangkyu@snu.ac.kr
- 2Pediatric Oncology Branch, Division of Specific Organs Cancer Center, National Cancer Center, Goyang, Korea.
- 3Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
- 4Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
- 5Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
- 6Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
- 7Department of Biochemistry, Seoul National University College of Medicine, Seoul, Korea.
- 8Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
- KMID: 1104801
- DOI: http://doi.org/10.3858/emm.2008.40.5.479
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.
Keyword
MeSH Terms
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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
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