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STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination.

Research paper by Joo Eun JE Jung, Hong Sook HS Kim, Chang Seok CS Lee, Yong Jae YJ Shin, Yong Nyun YN Kim, Gyeong Hoon GH Kang, Tae You TY Kim, Yong Sung YS Juhnn, Sung Joon SJ Kim, Jong Wan JW Park, Sang Kyu SK Ye, Myung Hee MH Chung

Indexed on: 06 Nov '08Published on: 06 Nov '08Published in: Experimental & Molecular Medicine



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.