STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination.
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-1 alpha, and then stabilizes HIF-1alpha protein levels.
Jung
Joo Eun
JE
Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Kim
Hong Sook
HS
Lee
Chang Seok
CS
Shin
Yong Jae
YJ
Kim
Yong Nyun
YN
Kang
Gyeong Hoon
GH
Kim
Tae You
TY
Juhnn
Yong Sung
YS
Kim
Sung Joon
SJ
Park
Jong Wan
JW
Ye
Sang Kyu
SK
Chung
Myung Hee
MH
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein