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KMID : 0620920080400050479
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Experimental & Molecular Medicine
2008 Volume.40 No. 5 p.479 ~ p.485
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STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination
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Jung Joo-Eun
Kang Gyeong-Hoon
Ye Sang-Gyu
Kim Sung-Joon
Chung Myung-Hee
Kim Hong-Sook
Lee Chang-Seok
Shin Yong-Jae
Kim Yong-Nyun
Juhnn Yong-Sung
Park Jong-Wan
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Abstract
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Hypoxia-inducible factor 1a (HIF-1a) is rapidly degraded by the ubiquitin-proteasome pathway under normoxic conditions. Ubiquitination of HIF-1a 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-1a 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-1a stability. We found that STAT3 interacts with C-terminal domain of HIF-1a and stabilizes HIF-1a by inhibition of pVHL binding to HIF-1a. The binding between HIF-1a and pVHL, negative regulator of HIF-1a stability, was interfered dose-dependently by overexpressed constitutive active STAT3. Moreover, we found that the enhanced HIF-1a protein levels by active STAT3 are due to decrease of poly-ubiquitination of HIF-1a protein via inhibition of interaction between pVHL and HIF-1a. Taken together, our results suggest that STAT3 decreases the pVHL-mediated ubiquitination of HIF-1a through competition with pVHL for binding to HIF-1 a, and then stabilizes HIF-1a protein levels.
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KEYWORD
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anoxia, hypoxia-inducible factor1, αsubunit, neoplasms, STAT3 transcription factor, ubiquitination, von Hippel-Lindau tumor suppressor protein
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