E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis.
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-1alpha (HIF-1alpha), 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-1alpha. UCP is detected coincidently with HIF-1alpha 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-1alpha and may be a new molecular target for therapeutic intervention in human cancers.
Jung
Cho-Rok
CR
Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Yusong-gu, Daejeon 305-333, Republic of Korea.
Hwang
Kyung-Sun
KS
Yoo
Jinsang
J
Cho
Won-Kyung
WK
Kim
Jin-Man
JM
Kim
Woo Ho
WH
Im
Dong-Soo
DS
D001483:Base Sequence; D002455:Cell Division; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008099:Liver / Q000502:physiology; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014475:Uncoupling Agents / Q000633:toxicity*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000473:pathology*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D025801:Ubiquitin; D014475:Uncoupling Agents; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human