title: STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination.
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-1 alpha, and then stabilizes HIF-1alpha protein levels.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Hong Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.forename: Yong Jae
authors.initials: YJ
authors.lastname: Shin
authors.forename: Yong Nyun
authors.initials: YN
authors.lastname: Kim
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.forename: Tae You
authors.initials: TY
authors.lastname: Kim
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Juhnn
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jong Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Sang Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Chung
mesh_terms: 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*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein