Nature Medicine
- 12, 809 - 816 (2006)
Published online: 2 July 2006; | doi:10.1038/nm1440
E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasisCho-Rok Jung1, Kyung-Sun Hwang1, Jinsang Yoo1, Won-Kyung Cho1, Jin-Man Kim2, Woo Ho Kim3 & Dong-Soo Im11
Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Yusong-gu, Daejeon 305-333, Republic of Korea. 2
Department of Pathology, Chung-Nam National University School of Medicine, Chung-gu, Daejeon 301-721, Republic of Korea. 3
Department of Pathology, Seoul National University College of Medicine, Jongro-gu, Seoul 110-799, Republic of Korea.
Correspondence should be addressed to imdongsu@kribb.re.kr 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-1 (HIF-1), 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-1. UCP is detected coincidently with HIF-1 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-1 and may be a new molecular target for therapeutic intervention in human cancers.
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