Abstract
The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1α (HIF-1α), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1α. UCP is detected coincidently with HIF-1α in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1α and may be a new molecular target for therapeutic intervention in human cancers.
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Acknowledgements
We are grateful to the members of the Center for Functional Analysis of Human Genome and 21C Frontier Human Gene Bank, Republic of Korea; Y.I. Yeom and N.S. Kim for providing full-length cDNAs; J.H. Lee for providing invasion and metastasis assays and C8161 cell line; D.G. Kim, I.P. Choi, and Y.S. Kim for providing tumor cell lines; C.K. Lee and D.Y. Yu for the use of animal facility. We also thank the reviewers for helpful remarks that improved this manuscript. This work was supported by a grant of 21C Frontier Functional Genome Project from the Ministry of Science and Technology, Republic of Korea.
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Supplementary information
Supplementary Fig. 1
F-UCP expressed in UCP-negative cells co-sediments with pVHL. (PDF 98 kb)
Supplementary Fig. 2
UCP targets pVHL in cells under hypoxic conditions, thereby accumulating active HIF-1α. (PDF 89 kb)
Supplementary Fig. 3
Recombinant GST-UCP, but not GST-UCPm is catalytically active. (PDF 90 kb)
Supplementary Fig. 4
UCP ubiquitinates pVHL in vitro (PDF 119 kb)
Supplementary Fig. 5
UCP specifically targets pVHL for degradation. (PDF 125 kb)
Supplementary Fig. 6
UCP targets pVHL for degradation in Ck-K1 cells, thereby stabilizing HIF-1α. (PDF 85 kb)
Supplementary Fig. 7
The specificity for UCP-siRNA. (PDF 114 kb)
Supplementary Fig. 8
Detection of Ad.F-UCP genome and F-UCP transcript in tumors excised from mice. (PDF 111 kb)
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Jung, CR., Hwang, KS., Yoo, J. et al. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis. Nat Med 12, 809–816 (2006). https://doi.org/10.1038/nm1440
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DOI: https://doi.org/10.1038/nm1440
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